Archive for the ‘Bone Marrow Stem Cells’ Category

Grady Smith, 10, and Southfield resident Jessica Carroll were able to meet for the first time via Zoom in September at the DKMS Gala. Carroll was the bone marrow donor that helped save the boys life.

Photo provided by the Smith family

SOUTHFIELD If you were to take one look at 10-year-old Grady Smith, youd see a young boy who enjoys sports and school.

But the young Salem, New Hampshire, boy has been through more in 10 years than some people have in 50.

Grady was diagnosed with adrenoleukodystrophy, or ALD, back in 2018.

According to Boston Childrens Hospital, ALD is a rare genetic condition that causes the buildup of very long chain fatty acids in the brain. When the fatty acids accumulate, they destroy the protective myelin sheath around nerve cells, responsible for brain function. Without the myelin sheath, the nerves can no longer relay information to and from the brain.

Every single thing I read said, terminal, slow deterioration to death, one to five years, horrible, horrible death, Jillian Smith said. We just died. I havent been the same person since that day. It just changes you for the rest of your life.

With a diagnosis, Grady and his parents looked for options on how to help. Grady had a lesion with a Loes score which is a way of rating severity of 10. Scores range from 0-34.

His parents werent sure Grady would qualify for a bone marrow transplant because they usually only perform transplants for boys with scores of 9 and under. Grady was in luck, however, as Boston Childrens Hospital decided to move forward anyway.

The next move was to find a match for the boy, but that process could take weeks, months or even years. In Gradys case, it took just a few weeks.

Southfield resident Jessica Carroll registered as a potential bone marrow/blood stem cell donor with DKMS, a German bone marrow donor file, in 2014, but she didnt think much would come of it.

Four years later she got a call from the nonprofit organization letting her know that she was a match for a young boy. After some research, Carroll was totally on board with donating.

It was great knowing during that donation that this little bit that I went through was potentially saving somebodys life, Carroll said. Thats all I really cared about, was that I was helping somebody.

Grady was able to get his transplant in 2018.

According to his mother, Grady hasnt had any progression and has even made some recovery. Hes back in line with his academics and is playing sports again.

Grady has auditory processing issues, which make it hard for him to comprehend language and sound. His mother said he relies on reading lips to communicate.

Theres still a lot to it. It stopped the monster thats how we look at it but its not just so cut and dry, Jillian said. Hes a very rare outcome with his Loes score and with just how well hes doing. Hes just a really, really good boy. He works really hard to help bring awareness.

Carroll and the Smiths have talked via text, and they were able to meet virtually for the first time in September at the DKMS Gala.

For the Smiths and Carroll, the meeting was emotional. Grady was finally able to put a face to his donor, and vice versa for Carroll.

It was of course emotional, Carroll said. Being able to hear everything they went through, though, definitely made me so happy that I had chosen to register.

The Smiths and Carroll still talk periodically throughout the year, and Sept. 20 was the two-year anniversary of the transplant.

They are hoping to be able to meet in person soon, and the DKMS team wants to bring them to next years gala to help make that happen. However, they hope it will be sooner.

Throughout this journey with Grady, the Smiths have advocated, learned and spoken more about ALD.

Prior to Gradys birth, Massachusetts wasnt testing for ALD in newborns, but it has since started. New Hampshire wasnt either, but the Smiths got the state to add ALD to the newborn screening panel.

The next goal is to get more states to add the ALD screening. The family has also spoken at conferences to share Gradys story and have become big proponents of what DKMS has been able to do for not only their family, but families around the world.

I think a big thing, too, that we really want to get out there is bone marrow transplant or stem cell transplant, how easy it is, Jillian said. All people need to do is go on DKMSs website, and they can get a packet sent out to them. They just swab their cheeks, send it in and they could be saving anyones life, someone just like Grady.

According to the DKMS website, the organization is dedicated to the fight against blood cancer and blood disorders by creating awareness, recruiting bone marrow donors to provide a second chance at life, raising funds to match donor registration costs and supporting the improvement of blood cancer therapies by our own research.

Those looking for more information or wanting to register can visit dkms.org/en or call (212) 209-6700.

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Southfield woman meets boy she saved with bone marrow donation - C&G Newspapers

Boise State engineers have been awarded $315,000 from the National Science Foundation (NSF) to launch stem cell research into space.

Alexander Regner, masters student in materials science engineering, has been working on stem cell research for nearly three years. Through Regners research, he has studied the health and maintenance of bone and bone marrow.

As you exercise and move, your bone marrow stimulates cells, which is a vital part of maintaining health, according to Regner.

Thats why exercise is so good for you. We know all of this contributes to health and maintenance, but we dont actually know what it looks like mechanically to these cells, Regner said.

Regner and his associates Gunes Uzer, assistant professor of mechanical and biomedical engineering, and Aykut Satici, assistant professor of mechanical and biomedical engineering, have created a model to mimic the bone marrow mechanical environment and analyze what kind of mechanical environment is causing the cells to react in certain ways.

Regner uses a computer simulation that matches a 3D printed physical sample. This allows Regner to understand what the mechanical environment looks like so they can correlate the mechanical environment to the cellular response.

Through this research, Regner asks the big question, is there a different mechanical environment generated due to changes in bone architecture?

Gunes and Satici looked at Regners research and wanted to bring it to a bigger audience. Their new goal was to determine how stem cell research can benefit Earth. According to Gunes, space travel tends to produce tissue types and cell behavior that is similar to aging. This aging happens over a matter of weeks in space, as opposed to a matter of years on Earth.

We take one of these bone cells and we age them for a year or two. But obviously, these bones have a shelf life, Gunes said. Maybe we can do that in space in three weeks and do the experiment in space. Maybe we can learn more about how the bone mechanical environment contributes to the aging process. Thats really the project, take Alexs work and send it to space.

Saticis contribution to this research is from a different perspective, robotics. According to Satici, there needs to be mechanical vibrations applied to particular cells. To accomplish this, there needs to be a robotic mechanism to perform that motion in a consistent matter.

Center for the Advancement of Science in Space (CASIS) holds a subcontract with the International Space Station along with the National Science Foundation (NSF). Each year, they ask the question, what type of research can we perform in space that can teach us something about Earth and improve advanced science on Earth?

Regner, Gunes and Satici argued that they cannot properly age experiments on Earth, and proposed that space could be a good platform for their research. They wrote a grant proposal for their research, what they have done in the past, what they plan to do and who is a part of the research team.

Regner, Gunes and Satici also work closely with the University of Texas, Rensselaer Polytechnic Institute and Space Tango to complete this research.

Through this extensive research, Regner, Satici and Gunes emphasize the importance of working hard to accomplish ones goals.

Just because its fun to do, doesnt mean you are going to learn it. You have to persevere and do the dirty work. Try to improve yourself with any resources you can get, Satici said.

Regner advocates for students to continuously work hard to help solve modern problems. There are a lot of job opportunities in the STEM field, and many jobs that may not require a STEM background at all, like politics.

A lot of our modern problems we are dealing with are multidisciplinary things. It requires the involvement of everyone. Space flight, for example, you need people to understand not only the mechanics but make sure were safe while were doing it, Regner said. [There are] a lot of problems we are facing in the middle age. If youre interested in helping solve them, there are so many different opportunities to get involved. If you want to go into politics, we need people to advocate for science in politics to make sure that we have adequate funding and focused goals for where we are going and what we are doing.

Gunes hopes students who want to get involved and achieve their goals will start with volunteer work.

Go to a lab youre interested in and say Hey, I want to do volunteering involving research. Before you know it you start getting your masters, your Ph.D., and then you become a scientist. If youre interested in [science] then stop thinking about it and do it, Gunes said.

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Boise State engineers given the opportunity to send stem cell research into space - Boise State University The Arbiter Online

MINNEAPOLIS, Oct. 6, 2020 /PRNewswire/ --The National Marrow Donor Program (NMDP)/Be The Match today announced a collaboration with the Minnesota health system M Health Fairview and Marcus Center for Cellular Cures (MC3)/Carolinas Cord Blood Bank at Duke University (Duke) to offer cryopreservation services to transplant centers through the Be The Match BioBank. The collaboration brings together industry-leading expertise in cryopreservation and storage of patient-directed donor blood stem cell products to improve donor availability, collection quality, and ultimately, to provide a more reliable path to transplant for patients.

Through the Be The Match BioBank, blood stem cell donors will be able to donate bone marrow or peripheral blood stem cells (PBSC) for an intended patient on a timeline that is convenient for the donor. The cells are then cryopreserved and stored for the transplant center at no cost to them and shipped to coincide with initiation of the patient's conditioning regimen and optimal treatment timeline.

"We're excited to expand our partnership with Duke University by adding the expertise of physicians and researchers at M Health Fairview University of Minnesota Medical Center to continue to overcome logistical barriers to blood and marrow transplantation that might otherwise disrupt optimal patient care. Through the flexibility offered by the Be The Match BioBank, we believe we can provide transplant centers with a well-matched, available donor more often, and allow the transplant to occur at the best time for the patient," explained Steven Devine, MD, Chief Medical Officer, NMDP/Be The Match, and Associate Scientific Director, CIBMTR (Center for International Blood and Marrow Transplant Research). "The team at the Duke University lab was instrumental in the development of the Be The Match BioBank, as well as supporting donor product cryopreservation during the COVID-19 pandemic to ensure patients can continue to receive the transplants they need."

"We are proud to extend our partnership with the NMDP/Be The Match in a new way. Be The Match BioBank is an innovative way to remove barriers that otherwise may stand in the way of a patient's transplant," said Joanne Kurtzberg, MD, who leads the Marcus Center for Cellular Cures (MC3)/Carolinas Cord Blood Bank at Duke University.

"We are thrilled to be working with the NMDP/Be The Match to offer Be The Match BioBank. Through this partnership, transplant physicians can have confidence a high-quality bone marrow or PBSC product will be available from the donor they requested in the timeframe that works best for their patient," said David McKenna, MD, who leads the Molecular and Cellular Therapeutics program at M Health Fairview.

Be The Match BioBank can be used by any transplant center in the NMDP/Be The Match Network of more than 180 transplant centers worldwide. Blood stem cell donors are informed that the transplant center is requesting cryopreservation and provide consent prior to collection. Donors can also consent to having their donated cells made available to other searching patients in the unlikely event the intended patient is unable to proceed to transplant as planned.

To learn more about Be The Match BioBank, visit Network.BeTheMatchClinical.org/BioBank.

About the National Marrow Donor Program/Be The Match The National Marrow Donor Program/Be The Match is the global leader in providing a cure to patients with life-threatening blood and marrow cancers like leukemia and lymphoma, as well as other diseases. The organization manages the world's largest registry of potential blood stem cell donors and cord blood units. The NMDP/Be The Match partners with a global network to connect patients to their donor match for a transplant, and provides education and support for patients. Through Be The Match BioTherapies, the NMDP/Be The Match partners with cell and gene therapy companies to support the development and delivery of new therapies. The organization conducts research through its research program, CIBMTR (Center for International Blood and Marrow Transplant Research), in collaboration with Medical College of Wisconsin.

About M Health Fairview M Health Fairview is the newly expanded collaboration betweenthe University of Minnesota, University of Minnesota Physicians,and Fairview Health Services. The healthcare system combines the best of academic and community medicine expanding access to world-class, breakthrough care through its 10 hospitals and 60 clinics.

SOURCE Be The Match

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NMDP/Be The Match partners with M Health Fairview and Duke University cryopreservation labs to launch Be The Match BioBank - PRNewswire

By Dylan Adams News Editor

Timothy Ray Brown, the first known person to be cured of HIV, died on Sept. 29 at age 54 after battling cancer.

Timothy Ray Brown, a figurehead in the AIDS and HIV community, passed away surrounded by friends after a five-month battle with leukemia, stated Tim Hoeffgen, Browns partner.

Brown received a positive HIV diagnosis in 1995 while studying in Berlin.

In 2006, Brown was diagnosed with acute myeloid leukemia, which is a cancer that builds in the bone marrow and blood interfering with blood cell production. After bouts of infections from several rough rounds of chemotherapy, Browns leukemia came out of remission.

Due to leukemia in his bones, Brown required a stem cell transplant, a process that allows healthy stem cells to be introduced into a host to stimulate the immune system and healthy bone marrow growth. At the time, the survival rates for stem cell transplant were around fifty percent.

Doctors found a match to Browns genetic type, a donor with the CCR5 Delta 32 mutation, a protein that acts as a doorway to stop the HIV from infecting new cells. Three months after Brown stopped taking his HIV medication, doctors found he no longer had HIV in his blood.

After another round of stem cell treatment in February of 2008, Brown went through several near-death complications, almost going blind and becoming paralyzed but slowly recovering. His body was still successfully fighting off HIV.

In July 2012, the Timothy Ray Brown Foundation was created during the World AIDS Conference in Washington, DC. This foundation was built for Brown to show his support and work with medical institutions and scientists to develop a unifying cure and vaccination against HIV.

Brown would often donate large amounts of blood and tissue samples to researchers in the hope of progressing closer towards an HIV cure. According to his partner, Hoeffgen, Tims lifework was to tell his story about his HIV cure and become an ambassador of hope to those in need.

Doctors have since used Brown as a blueprint to work on a potential cure and vaccine for HIV. Most notably for the second person to ever be cured of HIV the London Patient, Adam Castillejo who went through similar stem cell transplants in 2019 before coming forward to the public.

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First Man Cured of AIDS Dies From Cancer - The Keystone Newspaper

When thinking about donating bone marrow, most will break out in a cold sweat.

The thought of needles, prodding and poking is enough to put anyone off from becoming a donor but Ndinae Muligwe, Sustainability and Donor Recruitment Coordinator for the South African Bone Marrow Registry (SABMR) explained that it is a less complicated and relatively painless process.

The SABMR was established in 1991 and is a non-profit organisation that conducts searches to find matching bone marrow donors for critically ill children and adults in South Africa who cannot find a match in their own families.

Bone marrow transplants help to treat and even sometimes cure illnesses like leukaemia, Non-Hodgkin lymphoma, bone marrow failure, and some genetic blood and immune-system disorders.

Ndinae explained that the likelihood of a donor finding a match is about one in 100 000. What is more concerning is that there are currently only around 74 000 local donors on the South African Bone Marrow Registry.

Although they do form part of the World Marrow Donor Association that represents about 38 million donors, there are not enough donors for the South African demographic.

Ethnicity plays a role when it comes to who is able to donate, and at the moment the numbers do not match the ethnic groups represented in South Africa. You are more likely to find a match within your own ethnic group.

But how do you become a donor and what is the process involved?

Ndinae said it is as easy as registering on the website. Of course there are some questionnaires to fill in and you will have to meet the criteria and be healthy.

The donating age has recently been lowered from 18 to 16 years of age, and applicants must be between 16 and 45 to register as a potential donor.

If you are eligible you will then be contacted by the SABMR to do a cheek swab free of charge.

Peripheral blood stem cell (PBSC) collection is the most likely way of collecting stem cells. These cells are found in your bone marrow and also the blood stream. A five-day course of growth factor or Granulocyte-Colony Stimulating Factors is given prior to the donation to encourage the stem cells to move from your marrow to your blood.

At the time of donation a needle is placed in one arm. The blood is then passed through a machine that collects the stem cells, and the remaining blood is returned to your body similar to donating blood platelets.

You do not have to pay for anything to make a tissue or blood donation of your bone marrow stem cells, the SABMR covers the cost of testing and collection.

Visitwww.sabmr.co.zafor more information.

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Becoming a donor easier than you think - Randfontein Herald

NEW YORK, Oct. 08, 2020 (GLOBE NEWSWIRE) -- Bragar Eagel & Squire, P.C., a nationally recognized shareholder rights law firm, announces that a class action lawsuit has been filed in the United States District Court for the Southern District of New York on behalf of investors that purchased Mesoblast Limited (NASDAQ: MESO) securities between April 16, 2019 and October 1, 2020 (the Class Period). Investors have until December 7, 2020 to apply to the Court to be appointed as lead plaintiff in the lawsuit.

Click here to participate in the action.

Mesoblast develops allogeneic cellular medicines using its proprietary mesenchymal lineage cell therapy platform. Its lead product candidate, RYONCIL (remestemcel-L), is an investigational therapy comprising mesenchymal stem cells derived from bone marrow. In February 2018, the Company announced that remestemcel-L met its primary endpoint in a Phase 3 trial to treat children with steroid refractory acute graft versus host disease (aGVHD).

In early 2020, Mesoblast completed its rolling submission of its Biologics License Application (BLA) with the FDA to secure marketing authorization to commercialize remestemcel-L for children with steroid refractory aGVHD.

On August 11, 2020, the FDA released briefing materials for its Oncologic Drugs Advisory Committee (ODAC) meeting to be held on August 13, 2020. Therein, the FDA stated that Mesoblast provided post hoc analyses of other studies to further establish the appropriateness of 45% as the null Day-28 ORR for its primary endpoint. The briefing materials stated that, due to design differences between these historical studies and Mesoblasts submitted study, it is unclear that these study results are relevant to the proposed indication.

On this news, the Companys share price fell $6.09, or approximately 35%, to close at $11.33 per share on August 11, 2020.

On October 1, 2020, Mesoblast disclosed that it had received a Complete Response Letter (CRL) from the FDA regarding its marketing application for remestemcel-L for treatment of SR-aGVHD in pediatric patients. According to the CRL, the FDA recommended that the Company conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGVHD. The CRL also identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the products biologic activity.

On this news, the Companys share price fell $6.56, or 35%, to close at $12.03 per share on October 2, 2020.

The complaint, filed on October 8, 2020, alleges that throughout the Class Period defendants made materially false and/or misleading statements, as well as failed to disclose material adverse facts about the Companys business, operations, and prospects. Specifically, defendants failed to disclose to investors: (1) that comparative analyses between Mesoblasts Phase 3 trial and three historical studies did not support the effectiveness of remestemcel-L for steroid refractory aGVHD due to design differences between the four studies; (2) that, as a result, the FDA was reasonably likely to require further clinical studies; (3) that, as a result, the commercialization of remestemcel-L in the U.S. was likely to be delayed; and (4) that, as a result of the foregoing, defendants positive statements about the Companys business, operations, and prospects were materially misleading and/or lacked a reasonable basis.

If you purchased Mesoblast securities during the Class Period and suffered a loss, have information, would like to learn more about these claims, or have any questions concerning this announcement or your rights or interests with respect to these matters, please contact Brandon Walker, Melissa Fortunato, or Marion Passmore by email at investigations@bespc.com, telephone at (212) 355-4648, or by filling out this contact form. There is no cost or obligation to you.

About Bragar Eagel & Squire, P.C.:Bragar Eagel & Squire, P.C. is a nationally recognized law firm with offices in New York and California. The firm represents individual and institutional investors in commercial, securities, derivative, and other complex litigation in state and federal courts across the country. For more information about the firm, please visit http://www.bespc.com. Attorney advertising. Prior results do not guarantee similar outcomes.

Contact Information:Bragar Eagel & Squire, P.C.Brandon Walker, Esq.Melissa Fortunato, Esq.Marion Passmore, Esq.(212) 355-4648investigations@bespc.comwww.bespc.com

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MESOBLAST ALERT: Bragar Eagel & Squire, PC Announces That a Class Action Lawsuit Has Been Filed Against Mesoblast Limited and Encourages Investors...

DetailsCategory: DNA RNA and CellsPublished on Thursday, 08 October 2020 15:15Hits: 536

NEW YORK, NY, USA and PARIS, France I October 08, 2020 I Cytovia Therapeutics ("Cytovia"), an emerging biopharmaceutical company, announces today that it has entered a research and licensing agreement with Inserm to develop NK engager bi-specific antibodies and iPSC CAR NK cell therapy targeting CD38, a key marker of multiple myeloma. The licensing agreement has been negotiated and signed by Inserm Transfert, the private subsidiary of Inserm, on behalf of Inserm (the French National Institute of Health and Medical Research) and its academic partners. Cytovia is licensing Inserm's CD38 antibody and Chimeric Antigen Receptor (CAR) patent and applying its proprietary NK engager bispecific antibody and iPSC CAR NK technology platforms. The research agreement will include evaluation of the therapeutic candidates at Hpital Saint-Louis Research Institute (Inserm Unit 976) under the leadership of Professors Armand Bensussan and Jean-Christophe Bories.

Dr Daniel Teper, Cytovia's Chairman and CEO commented: "We are delighted to partner with one of the top centers of excellence in the world for research and treatment in hematology. CD38 is a validated target and Natural Killer cells have significant cytotoxicity to Myeloma cells. We are looking forward to bringing promising new options to address the unmet needs of patients with Multiple Myeloma and aim for a cure."

Professor Armand Bensussan, Director of The Immuno-Oncology Research Institute at Hpital Saint-Louis added: "We have demonstrated the selectivity of our novel CD38 antibody in killing myeloma cells but not normal cells such as NK, T, and B cells. The activation of NK cells through NKp46 may enhance the efficacy of the bispecific antibody in patients not responsive to CD38 monoclonal antibody therapy. CD38 CAR NK is a promising approach forrelapsed/refractory patients and an alternative to CAR T therapies."

About Multiple MyelomaMultiple Myeloma is a currently incurable cancer, affecting a type of white blood cell known as plasma cells. It leads to an accumulation of tumor cells in the bone marrow, rapidly outnumbering healthy blood cells. Instead of producing beneficial antibodies, cancerous cells release abnormal proteins causing several complications. While symptoms are not always present, the majority of patients are diagnosed due to symptoms such as bone pain or fracture, low red blood cell counts, fatigue, high calcium levels, kidney problems, and infections. According to the World Cancer Research Fund, Multiple Myeloma is the second most common blood cancer, with nearly 160,000 new annual cases worldwide, including close to 50,000 in Europe. 32,000 in the US, and 30,000 in Eastern Asia. Over 95% of cases are diagnosed late, with a 5-year survival rate of 51%. Initial treatment comprises of a combination of different therapies, including biological and targeted therapies, corticosteroids, and chemotherapy, with the option for bone marrow transplants for eligible patients. Immunotherapy and cell therapy are the most promising new treatment option for Multiple Myeloma, with the potential for long term cancer remission.

About CAR NK cellsChimeric Antigen Receptors (CAR) are fusion proteins that combine an extracellular antigen recognition domain with an intracellular co-stimulatory signaling domain. Natural Killer (NK) cells are modified genetically to allow insertion of a CAR. CAR-NK cell therapy has demonstrated initial clinical relevance without the limitations of CAR-T, such as Cytokine Release Syndrome, neurotoxicity or Graft vs Host Disease (GVHD). Induced Pluripotent Stem Cells (iPSC) - derived CAR-NKs are naturally allogeneic, available off-the-shelf and may be able to be administered on an outpatient basis. Recent innovative developments with the iPSC, an innovative technology, allow large quantities of homogeneous genetically modified CAR NK cells to be produced from a master cell bank, and thus hold promise to expand access to cell therapy for many patients.

About CytoviaCytovia Therapeutics Inc is an emerging biotechnology company that aims to accelerate patient access to transformational immunotherapies, addressing several of the most challenging unmet medical needs in cancer and severe acute infectious diseases. Cytovia focuses on Natural Killer (NK) cell biology and is leveraging multiple advanced patented technologies, including an induced pluripotent stem cell (iPSC) platform for CAR (Chimeric Antigen Receptors) NK cell therapy, next-generation precision gene-editing to enhance targeting of NK cells, and NK engager multi-functional antibodies. Our initial product portfolio focuses on both hematological malignancies such as multiple myeloma and solid tumors including hepatocellular carcinoma and glioblastoma. The company partners with the University of California San Francisco (UCSF), the New York Stem Cell Foundation (NYSCF), the Hebrew University of Jerusalem, and CytoImmune Therapeutics. Learn more at http://www.cytoviatx.com

About InsermFounded in 1964, the French National Institute of Health and Medical Research (Inserm) is a public science and technology institute, jointly supervised by the French Ministry of National Education, Higher Education and Research, and the Ministry of Social Affairs, Health and Womens Rights. Inserm is the only French public research institute to focus entirely on human health and position itself on the pathway from the research laboratory to the patients bedside. The mission of its scientists is to study all diseases, from the most common to the rarest. With an initial 2020 budget of 927.28 million, Inserm supports nearly 350 laboratories throughout France, with a team of nearly 14,000 researchers, engineers, technicians, and post-doctoral students. http://www.inserm.fr

SOURCE: Cytovia Therapeutics

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Cytovia Therapeutics partners with Inserm to develop selective CD38 NK therapeutics and offer new treatment options for Multiple Myeloma patients |...

There are only a few specialised childhood cancer centres in Southern Africa.

Leukaemia and lymphoma are two of the most prevalent cancers in children in South Africa with between 800 and 1000 children diagnosed annually. Tragically, it is estimated that half of the children with cancer in this country are never diagnosed.

Dr Marion Morkel, Chief Medical Officer at Sanlam, believes that we all need to educate ourselves so we can recognise the symptoms of cancer.

Below, Dr Morkel explains what can be done in the fight against leukaemia and lymphoma.

Knowledge is key

You must be aware of the symptoms related to leukaemia and lymphoma so that you can notify your health professional should you see these symptoms in your child.

Leukaemia

Leukaemia is the most common childhood cancer accounting for 25% of all cases in South Africa.

Symptoms include:

Lymphoma

Lymphoma primarily originates from the lymph nodes and can often appear like any other illness that triggers an inflammatory response.

Symptoms to look out for include:

While other childhood illnesses can present in the same manner as leukaemia and lymphoma, health professionals have been trained to look out for symptoms that persist after routine treatment and will conduct tests to rule out the possibility of these childhood blood-related cancers.

Parents are encouraged to consult their doctor if there are any concerns about their childs health.

ALSO READ|Should I be worried if my child has pain in his tummy?

Register to become a blood stem cell (bone marrow) donor

The Sunflower Fund is a non-profit organisation that fights blood diseases through a blood stem cell transplant which replaces a persons defective stem cells with healthy ones and can be a potentially life-saving treatment for more than 70 different diseases.

Kim Webster, Head of Communications at The Sunflower Fund advises that finding a matching donor for a stem cell transplant is not as easy as finding a blood type match.

There is only a 1:100 000 chance of a patient finding their life-saving match with siblings only having a 25% chance of a match.

You can register to become a donor online via http://www.sunflowerfund.org.

Submitted to Parent24 by Atmosphere

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Knowledge is key: What you need to know about the most common childhood cancer in SA - News24

Gosselies, Belgium, 5 October 2020, 7am CEST BONE THERAPEUTICS(Euronext Brussels and Paris: BOTHE), the cell therapy company addressing unmet medical needs in orthopedics and other diseases, Link Health Pharma Co., Ltd (Link Health) and Shenzhen Pregene Biopharma Company, Ltd (Pregene) today announce the signing of an exclusive license agreement for the manufacturing, clinical development and commercialization of Bone Therapeutics allogeneic, off-the-shelf, bone cell therapy platform ALLOB in China (including Hong Kong and Macau), Taiwan, Singapore, South Korea, and Thailand.

Under the agreement, Bone Therapeutics is eligible to receive up to 55 million in development, regulatory and commercial milestone payments including 10 million in upfront and milestone payments anticipated in the next 24 months. Bone Therapeutics is also entitled to receive tiered double-digit royalties on annual net sales of ALLOB. Bone Therapeutics retains development and commercialization rights to ALLOB in all other geographies outside of those covered by this agreement. As a result, Bone Therapeutics will continue to concentrate on its development and commercialization plans for ALLOB in the US and Europe and novel innovative cell-based products globally.

This collaboration between Bone Therapeutics, Link Health and Pregene expands our geographic reach and demonstrates the global commercial potential of ALLOB,said Miguel Forte, MD, PhD, Chief Executive Officer of Bone Therapeutics. We already have operational experience in Asia with the Phase III clinical trial of our lead product JTA-004 in Hong Kong. We selected Link Health and Pregene to partner with us in Asia as a result of their expertise in advanced therapeutics and cell therapies, their proven track record of development and commercial implementation in Chinese and Asian markets, and Pregenes well established cell therapy manufacturing capacity. Bone Therapeutics will continue to develop the ALLOB cell therapy platform for other markets while exploring additional partnership opportunities in the U.S. and Europe.

The agreement grants Link Health and Pregene exclusive rights to clinically develop and commercialize ALLOB for the treatment of human bone disorders in Greater China, Taiwan, Singapore, South Korea, and Thailand. All rights for China will be transferred to Pregene and Link Health will gain rights for the remaining countries Bone Therapeutics will share its patented proprietary manufacturing expertise for the expansion and differentiation of bone-forming cells and has the option to sell clinical supplies to Link Health and Pregene in preparation for their clinical development of ALLOB.

This collaboration and license agreement for Bone Therapeutics ALLOB provides a strong addition to our pipeline. ALLOB has demonstrated the potential to reduce the recovery time and stimulate bone growth for a variety of bone conditions, and to have a considerable impact on patients lives,said Yan Song, PhD, Chief Executive Officer of Link Health. It is important for Link Health to collaborate with companies that have strong therapeutic product portfolios and entrepreneurial management. This partnership with Bone Therapeutics is a direct result of our shared commitment to appreciate the enormous potential of cell therapy and regenerative medicine.

Pregene now has a flourishing portfolio of CAR-T cell therapy-based cancer treatments. Bone Therapeutics ALLOB provides anallogeneic, off-the-shelf cell therapy that expands our portfolio of cell therapies to include the sizable commercial potential of orthopedics,said Hongjian Li, Co-founder and Chief Executive Officer of Pregene. We expect to be able to leverage our extensive international cell and gene therapy experience to develop Bone Therapeutics ALLOB platform and subsequently launch products in China and Southeast Asian markets.

ALLOB, an allogeneic and off-the-shelf cell therapy product manufactured through a proprietary, scalable production process, consists of human bone-forming cells derived from cultured bone marrow mesenchymal stem cells of healthy adult donors. In preclinical studies ALLOB has shown to reduce healing time in a delayed-union fracture model by half, and has demonstrated good tolerability and signs of efficacy in two Phase IIa studies for two separate indications. The Companys randomized, placebo-controlled, double-blind Phase IIb clinical trial in patients with difficult tibial fractures has received approval from regulatory authorities in six of the seven planned European countries to date, and is expected to enroll the first patient later this year.

About Link Health Pharma Co., Ltd

Link Health is a leading Chinese pharmaceutical company based in Guangzhou, Southern China, focusing on the development of innovative drugs for unmet medical needs.

Link Health has created a highly professional team with diverse expertise in drug development, medical affairs and regulatory affairs. Leveraging deep understanding of China market, regulatory environment and strong network with global biopharmaceutical companies, Link Health is well positioned to bring innovative drugs to the market efficiently. The company has a drug development pipeline of 5 clinical stage assets and 1 under NDA reviewing in China.

The company has also established a fully owned subsidiary in Amsterdam, the Netherlands. The Dutch office builds and further strengthen collaborations with global pharma/biotech partners and research institutes.

About Pregene Biopharma Co., Ltd

Shenzhen Pregene Biopharma Co. Ltd is a leading enterprise in the cell and gene therapy field with the core technology for industrialization. The companys core team comes from well-known institutions and companies including the Academy of Military Medical Sciences, the University of Toronto, and the US FDA.

Pregene has established the gene editing platform, viral vector and cell production platform, nanobody selection platform and other small to pilot trial manufacturing system, with total investment over 100 million CNY. It has the laboratories and GMP plants for cell and gene therapy of over 10,000 square meter.

The company focuses on the research and development of cell and gene therapy drugs, and participated in the drafting the national standard Considerations for CAR-T Cell Quality Study and Non-clinical Evaluation issued by the National Institutes for Food and Drug Control in June 2018. The CAR-T cell therapy for the treatment of multiple myeloma have obtained NMPA IND clearance as the Class I new drug, which is the first in China and fastest in the world using the humanized single domain antibody in CAR construct, and phase I clinical trials are now in progress. Other pipelines such as CAR-T, TCR-T and mRNA drugs for tumors, autoimmune diseases and other indications are in the development at different stages. The company has broad development prospects with the abundant backup technologies.

Looking forward to the future, the company will build the core capacity in one-stop solution for cell and gene therapy drugs, and fulfill the Express of innovative medicine development from drug discovery to clinical products.

About Bone Therapeutics

Bone Therapeutics is a leading biotech company focused on the development of innovative products to address high unmet needs in orthopedics and other diseases. The Company has a, diversified portfolio of cell and biologic therapies at different stages ranging from pre-clinical programs in immunomodulation to mid-to-late stage clinical development for orthopedic conditions, targeting markets with large unmet medical needs and limited innovation.

Bone Therapeutics is developing an off-the-shelf next-generation improved viscosupplement, JTA-004, which is currently in phase III development for the treatment of pain in knee osteoarthritis. Consisting of a unique combination of plasma proteins, hyaluronic acid a natural component of knee synovial fluid, and a fast-acting analgesic, JTA-004 intends to provide added lubrication and protection to the cartilage of the arthritic joint and to alleviate osteoarthritic pain and inflammation. Positive phase IIb efficacy results in patients with knee osteoarthritis showed a statistically significant improvement in pain relief compared to a leading viscosupplement.

Bone Therapeutics core technology is based on its cutting-edge allogeneic cell therapy platform with differentiated bone marrow sourced Mesenchymal Stromal Cells (MSCs) which can be stored at the point of use in the hospital. Currently in pre-clinical development, BT-20, the most recent product candidate from this technology, targets inflammatory conditions, while the leading investigational medicinal product, ALLOB, represents a unique, proprietary approach to bone regeneration, which turns undifferentiated stromal cells from healthy donors into bone-forming cells. These cells are produced via the Bone Therapeutics scalable manufacturing process. Following the CTA approval by regulatory authorities in Europe, the Company is ready to start the phase IIb clinical trial with ALLOB in patients with difficult tibial fractures, using its optimized production process. ALLOB continues to be evaluated for other orthopedic indications including spinal fusion, osteotomy, maxillofacial and dental.

Bone Therapeutics cell therapy products are manufactured to the highest GMP standards and are protected by a broad IP (Intellectual Property) portfolio covering ten patent families as well as knowhow. The Company is based in the BioPark in Gosselies, Belgium. Further information is available atwww.bonetherapeutics.com.

For further information, please contact:

Bone Therapeutics SAMiguel Forte, MD, PhD, Chief Executive OfficerJean-Luc Vandebroek, Chief Financial OfficerTel: +32 (0)71 12 10 00investorrelations@bonetherapeutics.com

For Belgian Media and Investor Enquiries:BepublicCatherine HaquenneTel: +32 (0)497 75 63 56catherine@bepublic.be

International Media Enquiries:Image Box CommunicationsNeil Hunter / Michelle BoxallTel: +44 (0)20 8943 4685neil.hunter@ibcomms.agency / michelle@ibcomms.agency

For French Media and Investor Enquiries:NewCap Investor Relations & Financial CommunicationsPierre Laurent, Louis-Victor Delouvrier and Arthur RouillTel: +33 (0)1 44 71 94 94bone@newcap.eu

For US Media and Investor Enquiries:LHA Investor RelationsYvonne BriggsTel: +1 310 691 7100ybriggs@lhai.com

Certain statements, beliefs and opinions in this press release are forward-looking, which reflect the Company or, as appropriate, the Company directors current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this press release regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this press release as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its subsidiary undertakings or any such persons officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this press release or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this press release.

Continued here:
Bone Therapeutics, Link Health and Pregene to develop and commercialize the ALLOB allogeneic bone cell therapy platform in China and Southeast Asia -...

LONDON, UK / ACCESSWIRE / October 6, 2020 / Hemogenyx Pharmaceuticals plc (LSE:HEMO), the biopharmaceutical group developing new therapies and treatments for blood diseases, is pleased to announce the following update on its activities.

As previously announced, Hemogenyx Pharmaceuticals' CDX bi-specific antibody has the potential to treat Acute Myeloid Leukemia ("AML") directly as well as to provide a benign conditioning regimen for blood stem cell replacement therapy. The Company has now carried out extensive work developing treatments for AML and has to date obtained encouraging results.

As announced on 20 February 2020, the Company has constructed and successfully tested in vivo Chimeric Antigen Receptor ("CAR") programmed T cells ("HEMO-CAR-T") for the potential treatment of AML. HEMO-CAR was constructed using the Company's proprietary humanized monoclonal antibody against a target on the surface of AML cells.

It was also announced that the Company was engaging in additional engineering of HEMO-CAR-T cells to increase their safety and versatility. The Company has now introduced and successfully in vitro tested a safety switch within the HEMO-CAR. The aim of this safety switch is to modulate the activity of HEMO-CAR-T cells and to turn them into a "controllable drug" - SAFE-HEMO-CAR-T. The purpose of these efforts is to dramatically improve the safety and potential versatility of HEMO-CAR-T cells for the treatment of AML and/or conditioning of bone marrow transplants, as well as a number of additional potential indications.

Following the successful completion of these in vitro tests, in vivo tests of the efficacy of SAFE-HEMO-CAR-T against AML are being conducted using a model of AML established on the background of Advanced peripheral blood Hematopoietic Chimera (ApbHC) - humanized mice developed by Immugenyx, LLC, a subsidiary of Hemogenyx Pharmaceuticals. If these in vivo tests are successful, the Company will discuss its findings with its partners under the Sponsored Research Agreement with the University of Pennsylvania, announced on 11 August 2020, with a view to considering the inclusion of SAFE-HEMO-CAR-T in the program of pre-clinical trials currently underway there.

Dr Vladislav Sandler, Chief Executive Officer, commented, "We are encouraged by this new data which demonstrates our continuing progress in the development of novel treatments for blood cancers such as AML. The development of SAFE-HEMO-CAR-T further expands the Company's pipeline and advances it into a cutting-edge area of cell-based immune therapy. We are excited to have developed another unique product candidate that should, if successful, provide a new and potentially effective treatment for blood cancers for which survival rates are currently very poor."

About AML and CAR-T

AML, the most common type of acute leukemia in adults, has poor survival rates (a five-year survival rate of less than 25% in adults) and is currently treated using chemotherapy, rather than the potentially more benign and effective form of therapy being developed by Hemogenyx Pharmaceuticals. The successful development of the new therapy for AML would have a major impact on treatment and survival rates for the disease.

CAR-T therapy is a treatment in which a patient's own T cells, a type of immune cell, are modified to recognize and kill the patient's cancer cells. The procedure involves: isolating T cells from the patient, modifying the isolated T cells in a laboratory using a CAR gene construct (which allows the cells to recognize the patient's cancer); amplifying (growing to large numbers) the newly modified cells; and re-introducing the cells back into the patient.

Market Abuse Regulation (MAR) Disclosure

Certain information contained in this announcement would have been deemed inside information for the purposes of Article 7 of Regulation (EU) No 596/2014 until the release of this announcement.

Enquiries:

Hemogenyx Pharmaceuticals plc

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Dr Vladislav Sandler, Chief Executive Officer & Co-Founder

headquarters@hemogenyx.com

Peter Redmond, Director

peter.redmond@hemogenyx.com

SP Angel Corporate Finance LLP

Tel: +44 (0)20 3470 0470

Matthew Johnson, Vadim Alexandre, Soltan Tagiev

Peterhouse Capital Limited

Tel: +44 (0)20 7469 0930

Lucy Williams, Duncan Vasey, Charles Goodfellow

About Hemogenyx Pharmaceuticals plc

Hemogenyx Pharmaceuticals is a publicly traded company (LSE: HEMO) headquartered in London, with its US operating subsidiaries, Hemogenyx LLC and Immugenyx LLC, located in New York City at its state-of-the-art research facility.

The Company is a pre-clinical stage biopharmaceutical group developing new medicines and treatments to treat blood and autoimmune disease and to bring the curative power of bone marrow transplantation to a greater number of patients suffering from otherwise incurable life-threatening diseases. Hemogenyx Pharmaceuticals is developing several distinct and complementary product candidates, as well as a platform technology that it uses as an engine for novel product development.

For more than 50 years, bone marrow transplantation has been used to save the lives of patients suffering from blood diseases. The risks of toxicity and death that are associated with bone marrow transplantation, however, have meant that the procedure is restricted to use only as a last resort. The Company's technology has the potential to enable many more patients suffering from devastating blood diseases such as leukemia and lymphoma, as well as severe autoimmune diseases such as multiple sclerosis, aplastic anemia and systemic lupus erythematosus (Lupus), to benefit from bone marrow transplantation.

This information is provided by RNS, the news service of the London Stock Exchange. RNS is approved by the Financial Conduct Authority to act as a Primary Information Provider in the United Kingdom. Terms and conditions relating to the use and distribution of this information may apply. For further information, please contact rns@lseg.com or visit http://www.rns.com.

SOURCE: Hemogenyx Pharmaceuticals PLC

View source version on accesswire.com:https://www.accesswire.com/609275/Hemogenyx-Pharmaceuticals-PLC-Announces-SAFE-HEMO-CAR-T-Effective-against-AML-in-vitro

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Hemogenyx Pharmaceuticals PLC Announces SAFE-HEMO-CAR-T Effective against AML in vitro - BioSpace

Hematopoietic Stem Cell Transplantation (HSCT) Market Scenario 2020-2026:

The Global Hematopoietic Stem Cell Transplantation (HSCT) market exhibits comprehensive information that is a valuable source of insightful data for business strategists during the decade 2014-2026. On the basis of historical data, Hematopoietic Stem Cell Transplantation (HSCT) market report provides key segments and their sub-segments, revenue and demand & supply data. Considering technological breakthroughs of the market Hematopoietic Stem Cell Transplantation (HSCT) industry is likely to appear as a commendable platform for emerging Hematopoietic Stem Cell Transplantation (HSCT) market investors.

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Topmost Leading Manufacturer Covered in this report:Escape Therapeutics Inc., Cryo-Save AG, Regen Biopharma Inc., CBR Systems Inc., ViaCord Inc., Lonza Group Ltd., Pluristem Therapeutics Inc., China Cord Blood Corp.

Product Segment Analysis: Allogeneic, Autologous

Application Segment Analysis:Peripheral Blood Stem Cells Transplant (PBSCT), Bone Marrow Transplant (BMT), Cord Blood Transplant (CBT)

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Regional Analysis For Hematopoietic Stem Cell Transplantation (HSCT)Market

North America(the United States, Canada, and Mexico)Europe(Germany, France, UK, Russia, and Italy)Asia-Pacific(China, Japan, Korea, India, and Southeast Asia)South America(Brazil, Argentina, Colombia, etc.)The Middle East and Africa(Saudi Arabia, UAE, Egypt, Nigeria, and South Africa)

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Hematopoietic Stem Cell Transplantation (HSCT) Market to eyewitness massive growth by 2026 | Escape Therapeutics Inc., Cryo-Save AG, Regen Biopharma...

The market research report on the Stem Cell Therapy Market provides a comprehensive analysis of the market dynamics, including development trends, application, types, competitive environment, value chain optimization, and region. Besides this, the report also provides key statistics on the Stem Cell Therapy Market status of the leading market players, key trends, and potential growth opportunities in the market.

The Stem Cell Therapy Market was valued at USD 117.66 Million in 2019 and is projected to reach USD 255.37 Million by 2027, growing at aCAGR of 10.97% from 2020 to 2027.

These study reports are designed with the goal to help the reader in favorable retrieve information and make decisions that are helpful to grow their business. Further, it also provides an examination of the economic synopsis, along with the benefits, drivers, restraints, production, supply, demand, and the level of market growth.

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The varying landscape for the overall Stem Cell Therapy industry is offered in the report providing a comprehensive pattern of the Stem Cell Therapy industry and its rapidly changing market landscape. The details mentioned in the report can assist the players in formulating strategies and approaches to gain a robust footing in the industry. Profitable insights and analytical data have been covered in the report to offer insight into global expansion strategies. Each key manufacturer and producer have been thoroughly assessed in the report.

The report covers extensive analysis of the key market players in the market, along with their business overview, expansion plans, and strategies. The key players studied in the report include:

The market report sheds light on the latest strategic developments and growth patterns of the market players to provide a clear view. The report is an investigative study that provides insights for the players to formulate their business expansion strategies and expand their footing in the market.

1.Stem Cell Therapy Market, By Cell Source:

Adipose Tissue-Derived Mesenchymal Stem Cells Bone Marrow-Derived Mesenchymal Stem Cells Cord Blood/Embryonic Stem Cells Other Cell Sources

2.Stem Cell Therapy Market, By Therapeutic Application:

Musculoskeletal Disorders Wounds and Injuries Cardiovascular Diseases Surgeries Gastrointestinal Diseases Other Applications

3.Stem Cell Therapy Market, By Type:

Allogeneic Stem Cell Therapy Market, By Application Musculoskeletal Disorders Wounds and Injuries Surgeries Acute Graft-Versus-Host Disease (AGVHD) Other Applications Autologous Stem Cell Therapy Market, By Application Cardiovascular Diseases Wounds and Injuries Gastrointestinal Diseases Other Applications

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Table of Content:

Market Overview: This is the first section of the report that includes an overview of the scope of products offered in the Stem Cell Therapy market, segments by product and application, and market size.

Market Competition by Player: Here, the report shows how the competition in the Stem Cell Therapy market is growing or decreasing based on deep analysis of market concentrate rate, competitive situations and trends, expansions, merger and acquisition deals, and other subjects. It also shows how different companies are progressing in the Stem Cell Therapy market in terms of revenue, production, sales, and market share.

Company Profiles and Sales Data: This part of the report is very important as it gives statistical as well as other types of analysis of leading manufacturers in the Stem Cell Therapy market. It assesses each and every player studied in the report on the basis of main business, gross margin, revenue, sales, price, competitors, manufacturing base, product specification, product application, and product category.

Market Status and Outlook by Region: The report studies the status and outlook of different regional markets such as Europe, North America, the MEA, Asia Pacific, and South America. All of the regional markets researched about in the report are examined based on price, gross margin, revenue, production, and sales. Here, the size and CAGR of the regional markets are also provided.

Market by Product: This section carefully analyzes all product segments of the Stem Cell Therapy market.

Market by Application: Here, various application segments of the Stem Cell Therapy market are taken into account for research study.

Market Forecast: It starts with revenue forecast and then continues with sales, sales growth rate, and revenue growth rate forecasts of the Stem Cell Therapy market. The forecasts are also provided taking into consideration product, application, and regional segments of the Stem Cell Therapy market.

Upstream Raw Materials: This section includes industrial chain analysis, manufacturing cost structure analysis, and key raw materials analysis of the Stem Cell Therapy market.

Marketing Strategy Analysis, Distributors: Here, the research study digs deep into behavior and other factors of downstream customers, distributors, development trends of marketing channels, and marketing channels such as indirect marketing and direct marketing.

Research Findings and Conclusion: This section is solely dedicated to the conclusion and findings of the research study on the Stem Cell Therapy market.

Appendix: This is the last section of the report that focuses on data sources, viz. primary and secondary sources, market breakdown and data triangulation, market size estimation, research programs and design, research approach and methodology, and the publishers disclaimer.

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Stem Cell Therapy Market Growth Factors, Rising Trends and Outlook 2020 to 2027 - X Herald

Massachusetts-based AVROBIO announced today that it has entered an exclusive global license agreement, as well as a collaborative research funding agreement, with The University of Manchester. Together, the university and AVROBIO will look into an investigational lentiviral gene therapy for mucopolysaccharidosis type II (MPS II), or Hunter syndrome.

The condition, which impacts an estimated one in 100,000 males worldwide, causes complications throughout the body and brain. Children with severe cases typically show symptoms beginning in their toddler years. At the moment, the standard of care is weekly enzyme replacement therapy, but it does not halt progression of the disease or address cognitive issues that may arise.

We believe a lentiviral gene therapy approach is well suited to treat a progressive and pervasive disease such as Hunter syndrome, which affects organs throughout the body and severely impairs cognitive function. If we treat children early, before their symptoms arise, we hope to prevent the tragic complications that rob these young children of their futures, said Geoff MacKay, AVROBIOs president and CEO. We believe our deep experience with investigational gene therapies for lysosomal disorders will enable us to efficiently move the program through clinical development in collaboration with Prof. Brian Bigger, who has done tremendous work to develop and optimize this investigational gene therapy. Were proud to add this program to our leading lysosomal disorder pipeline and excited about its potential to change the lives of patients and families living with Hunter syndrome.

The investigational gene therapy, titled AVR-RD-05, includes ex vivo transduction of the patients own hematopoietic stem cells with a therapeutic transgene. The transgene is meant to express functional enzymes that the patient needs to maintain cellular health. When reinfused back into the patient, the modified stem cells are designed to engraft in the bone marrow and produce generations of daughter cells, each carrying the transgene.

This is just one company looking toward making an impact in the MPS II realm as of late. REGENXBIO announced at the end of September that it was expanding its RGX-121 program, looking into the treatment of MPS II. RGX-121 is an investigational one-time gene therapy that uses the AAV9 vector to deliver the gene that encodes the iduronate-2-sulfatase (I2S) enzyme directly to the central nervous system.

An ongoing Phase I/II study is evaluating a single intracisternal administration of RGX-121 in severe instances of MPS II in patients under the age of five. As of Sept. 16, RGX-121 was reported to be well-tolerated in patients and there were no drug-related serious adverse events.

"MPS II is a serious and debilitating lysosomal disease that affects 1 in 100,000 children, and available treatments are inadequate to treat the neurodegenerative manifestations of the disease, said Terri Klein, President and Chief Executive Officer of the National MPS Society. Initiating a natural history study will increase the understanding of neurocognitive effects and key biomarkers of severe MPS II, and is critical to advancing the development of new treatment options. We are grateful for REGENXBIO's dedication to MPS and commitment to share the learnings from this observational study with the community.

REGENXBIO has also announced that the U.S. Food and Drug Administration cleared an Investigational New Drug application. The company plans on initiating a second Phase I/II multicenter, open-label trial of RGX-121 for the treatment of pediatric patients with severe MPS II between the ages of five and 18.

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AVROBIO and University of Manchester Enter Agreement for MPS II Research - BioSpace

A diagnosis of acute myeloid leukemia (AML) is particularly challenging in older adults, whose age makes them highly susceptible to the disease and treatment-related toxicity. To help patients and practitioners navigate the clinical decision-making process, the American Society of Hematology (ASH) convened an panel of experts who conducted a thorough review of the literature. The result of their work can be found in a new set of guidelines for the treatment of newly diagnosed AML in older adults.

Dr Mikkael Sekeres

Medscape spoke with Mikkael Sekeres, MD, chair of the ASH AML guideline panel and director of the Leukemia Program at Cleveland Clinic Taussig Cancer Institute. Sekeres shared the rationale behind the panel's key recommendations and the importance of keeping the patient's goals in mind.

Medscape: What is the average life expectancy of a 75-year-old developing AML compared with someone of the same age without AML?

Dr Sekeres: A 75-year-old developing AML has an average life expectancy measured in fewer than 6 months. Somebody who is 75 without leukemia in the United States has a life expectancy that can be measured in a decade or more. AML is a really serious diagnosis when someone is older and significantly truncates expected survival.

What is the median age at AML diagnosis in the United States?

About 67 years.

What are the biological underpinnings for poor outcomes in older AML patients?

There are a few of them. Older adults with AML tend to have a leukemia that has evolved from a known or unknown previous bone marrow condition such as myelodysplastic syndrome. Older adults also have worse genetics driving their leukemia, which makes the leukemia cells more resistant to chemotherapy. And the leukemia cells may even have drug efflux pumps that extrude chemotherapy that tries to enter the cell. Finally, older adults are more likely to have comorbidities that make their ability to tolerate chemotherapy much lower than for younger adults.

In someone who is newly diagnosed with AML, what initial options are they routinely given?

For someone who is older, we divide those options into three main categories.

The first is to take intensive chemotherapy, which requires a 4-6 week hospitalization and has a chance of getting somebody who is older into a remission of approximately 50% to 60%. But this also carries with it significant treatment-related mortality that may be as high as 10% to 20%. So, I have to look my older patients in the eyes when I talk about intensive chemotherapy and say, "There is a 1 in 10 or 1 in 5 chance that you might not make it out of the hospital alive."

The second prong is lower-dose therapy. While the more-intensive therapy requiring hospitalization does have a low, but real, chance of curing that person, less-intensive therapy is not curative. Our best hope with less-intensive therapy is that our patients enter a remission and live longer. With less-intensive therapy, the chance that someone will go into remission is probably around 20%, but again it is not curative. The flip side to that is that it improves a person's immediate quality of life, because they're not in the hospital for 4 to 6 weeks.

The final prong is to discuss palliative care or hospice upfront. We designed these guidelines to be focused on a patient's goals of therapy and to constantly revisit those goals to make sure that the treatment options we are offering are aligning with them.

The panel's first recommendation is to offer antileukemic therapy over best supportive care in patients who are appropriate candidates. Can you provide some context for this recommendation?

Doesn't that strike you as funny that we even have to make a recommendation about getting chemotherapy? Some database studies conducted over the past two decades show that, as recently as 15 years ago, only one third of patients who were over the age of 65 received any type of chemotherapy for AML. More recently, as we have had a few more drugs available that allow us to use lower-dose approaches, that number has crept up to probably about 50%. We still have half the patients offered no therapy at all. So, we felt that we had to deliberately make a recommendation saying that, if it aligns with a patient's goals, he or she should be offered chemotherapy.

The second recommendation is that patients considered candidates for intensive antileukemic therapy should receive it over less-intensive antileukemic therapy. How did you get to that recommendation?

There is a debate in our field about whether older adults should be offered intensive inpatient chemotherapy at all or whether we should be treating all of them with less-intensive therapy. There are not a huge amount of high-quality studies out there to answer some of these questions, in particular whether intensive chemotherapy should be recommended over less-intensive therapy. But with the available evidence, what we believe is that patients live longer if they are offered intensive antileukemic chemotherapy. So, again, if it aligns with a patient's goals, we support that patient receiving more-intensive therapy in the hospital.

What does the panel recommend for patients who achieve remission after at least a single cycle of intensive antileukemic therapy and who are not candidates for allogeneic hematopoietic stem cell transplantation?

Once again, this may seem at first blush to be an obvious recommendation. The standard treatment of someone who is younger with AML is to offer intensive inpatient chemotherapy to induce remission. This is followed by a few cycles of chemotherapy, mostly in an outpatient setting, to consolidate that remission.

What is the underlying philosophy for this approach?

Every time we give chemotherapy, we probably get about a 3 to 4 log kill of leukemia cells. Imagine when a person first presents with AML, they may have 10 billion leukemia cells in his or her body. We are reducing that 3 to 4 log with the first course of chemotherapy.

When we then look at a bone marrow biopsy, it may appear to be normal. When leukemia is at a lower level in the body, we simply can't see it using standard techniques. But that doesn't mean the leukemia is gone. For younger patients, we give another cycle of chemotherapy, then another, then another, and then even another to reduce the number of leukemia cells left over in the body until that person has a durable remission and hopefully cure.

For someone who is older, the data are less clear. While some studies have shown that if you give too much chemotherapy after the initial course, it doesn't help that much, there is a paucity of studies that show that any chemotherapy at all after the first induction course is helpful. Consequently, we have to use indirect data. Older people who are long-term survivors from their acute leukemia always seem to have gotten more than one course of chemotherapy. In other words, the initial course of chemotherapy that a patient receives in the hospital isn't enough. They should receive more than that.

What about older adults with AML considered appropriate for antileukemic therapy but not for intensive antileukemic therapy?

This again gets to the question of what are a patient's goals. It takes a very involved conversation with a person at the time of their AML diagnosis to determine whether he or she would want to pursue an aggressive approach or a less-aggressive approach. If a person wants a less-aggressive approach, and wants nothing to do with a hospital stay, then he or she is also prioritizing initial quality of life. In this recommendation, based on existing studies, we didn't have a preference for which of the available less-aggressive chemotherapies a person selects.

There's also debate about what to do in those considered appropriate for antileukemic therapy, such as hypomethylating agents (azacitidine and decitabine) or low-dose cytarabine, but not for intensive antileukemic therapy. What did the available evidence seem to indicate about this issue?

There have been a lot of studies trying to add two drugs together to see if those do better than one drug alone in patients who are older and who choose less-intensive therapy. The majority of those studies have shown no advantage to getting two drugs over one drug.

Our recommendation is that in these situations a patient gets one drug, not two, but there are a couple of caveats. One caveat is that there has been a small study showing the effectiveness of one of those low-dose chemotherapies combined with the drug glasdegib. The second caveat is that there have been results presented combining one of these low-dose chemotherapies with the drug venetoclax. One of those was a negative study, and another was a positive study showing a survival advantage to the combination vs the low-dose therapy alone. We had to couch our recommendation a little bit because we knew this other study had been presented at a conference, but it hadn't come out in final form yet. It did recently, however, and we will now revisit this recommendation.

The other complicated aspect to this is that we weren't 100% convinced that the combination of venetoclax with one of these lower-dose therapies is truly less-intensive therapy. We think it is starting to creep up toward more-intensive chemotherapy, even though it is commonly given to patients in the outpatient setting. It gets into the very complicated area of what are we defining as more-intensive therapy and less-intensive therapy.

Is there a recommended strategy for older adults with AML who achieve a response after receiving less-intensive therapy?

This is also challenging because there are no randomized studies in which patients received less-intensive therapy for a finite period of time vs receiving those therapies ad infinitum. Given the lack of data and also given a lot of anecdotal data out there about patients who stopped a certain therapy and relapsed thereafter, we recommended that patients continue the less-intensive therapy ad infinitum. So as long as they are receiving a response to that therapy, they continue on the drug.

Of course, there are also unique considerations faced by older patients who are no longer receiving antileukemic therapy, and have moved on to receiving end-of-life care or hospice care. What advice do the guidelines offer in this situation?

There are a lot of aspects of these recommendations that I think are special. The first is the focus on patient goals of care at every point in these guidelines. The second is that the guidelines follow the real disease course and a real conversation that doctors and patients have at every step of the way to help guide the decisions that have to be made in real time.

A problem we have in the United States is that once patients enter a hospice, most will not allow blood transfusions. One reason is that some say it is antithetical to their philosophy and consider it aggressive care. The second reason is that, to be completely blunt, economically it doesn't make sense for hospices to allow blood transfusions. The amount that they are reimbursed by Medicare is much lower than the cost of receiving blood in an infusion center.

We wanted to make a clear recommendation that we consider transfusions in a patient who is in a palliative care or hospice mode to be supportive and necessary, and that these should be provided to patients even if they are in hospice, and as always if consistent with a patient's goals of care.

How does a patient's age inform the discussion surrounding what intensity treatment to offer?

With younger adults, this is not as complicated a conversation. A younger person has a better chance of being cured with intensive chemotherapy and is much more likely to tolerate that intensive chemotherapy. For someone who is younger, we offer intensive chemotherapy and the chance of going into remission is higher, at 70% to 80%. The chance of dying is lower, usually less than 5%. It is an easy decision to make.

For an older adult, the riskbenefit ratio shifts and it becomes a more complicated option. Less-intensive therapy or best supportive care or hospice become viable.

Are there other factors confounding the treatment decision-making process in older adults with AML that practitioners should consider?

Someone who is older is making a different decision than I would. I have school-aged children and believe that my job as a parent is to successfully get them to adulthood, so I would take any treatment under the sun to make sure that happens. People who have lived a longer life than I have may have children and even grandchildren who are adults, and they might have different goals of care. My goals are not going to be the same as my patient's goals.

It is also harder because someone who is older may feel that he or she has lived a good life and doesn't need to go through heroic measures to try to be around as long as possible, and those goals may not align with the goals of that person's children who want their parent to be around as long as possible. One of the confounding factors in this is navigating the different goals of the different family members.

Dr Sekeres has disclosed no relevant financial relationships.

Kate O'Rourke is a freelance writer in Portland, Maine. She has covered the field of oncology for over 10 years.

For more news, follow Medscape on Facebook, Twitter, Instagram, andYouTube.

Continued here:
A Uniquely Patient-Focused Take on Treating AML in Older Adults - Medscape

WASHINGTON Heres a look at how Georgias members of Congress voted over the previous week.

Along with its roll call votes this week, the House also passed the Cyber Sense Act (H.R. 360) to require the Secretary of Energy to establish a voluntary Cyber Sense program to test the cybersecurity of products and technologies intended for use in the bulk-power system; the Consumer Product Safety Inspection Enhancement Act (H.R. 8134) to support the Consumer Product Safety Commissions capability to protect consumers from unsafe consumer products; the School-Based Allergies and Asthma Management Program Act (H.R. 2468) to increase the preference given in awarding certain allergies and asthma-related grants to states that require certain public schools to have allergies and asthma management programs; and the Effective Suicide Screening and Assessment in the Emergency Department Act (H.R. 4861) to establish a program to improve the identification, assessment and treatment of patients in the emergency department who are at risk of suicide.

DISCLOSING TIES TO UYGHUR LABOR: The House has passed the Uyghur Forced Labor Disclosure Act (H.R. 6270) sponsored by Rep. Jennifer Wexton, D-Va., to require publicly traded companies to disclose whether they have business ties to Chinas Uyghur Autonomous Region in Xinjiang province. Wexton said the requirement would let investors know of a given companys passive complicity or active exploitation of one of the most pressing and ongoing human rights violations of our lifetime. A bill opponent, Rep. Anthony Gonzalez, R-Ohio, said it wrongly tried to have the Securities and Exchange Commission police human rights violations, a role that would be better handled by the Treasury Department. The vote, on Sept. 30, was 253 yeas to 163 nays.

NAYS: Loudermilk R-GA (11th), Allen R-GA (12th), Scott, Austin R-GA (8th), Collins R-GA (9th), Carter R-GA (1st), Woodall R-GA (7th), Ferguson R-GA (3rd), Hice R-GA (10th)

YEAS: Bishop D-GA (2nd), Scott, David D-GA (13th), McBath D-GA (6th), Johnson D-GA (4th)

NOT VOTING: Graves R-GA (14th)

PRESIDENTIAL ELECTION: The House has passed a resolution (H. Res. 1155) sponsored by Rep. Eric Swalwell, D-Calif., reaffirming the Houses commitment to an orderly and peaceful transfer of presidential power after the November election. Swalwell said: The peaceful transition of power is not only a bedrock principle of Americas founding, it is a living ideal that we must exercise and pass down to our children. An opponent, Rep. Matt Gaetz, R-Fla., called the resolution a way for Democrats to attack the president and disguise the fact that they will refuse to accept the election results unless they win. The vote, on Sept. 29, was 397 yeas to 5 nays.

YEAS: Entire delegation, except Collins R-GA (9th), Graves R-GA (14th), who did not vote

DISEASE THERAPIES: The House has passed the Timely ReAuthorization of Necessary Stem-cell Programs Lends Access to Needed Therapies Act (H.R. 4764) sponsored by Rep. Doris O. Matsui, D-Calif. The bill would reauthorize a program for transplanting umbilical cord blood, stem cells, and bone marrow to adults and children suffering from various diseases. The vote, on Sept. 30, was unanimous with 414 yeas.

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YEAS: Entire delegation, except Graves R-GA (14th), who did not vote

FURTHER COVID-19 SPENDING: The House has approved an amendment to the Americas Conservation Enhancement Act (H.R. 925). The amendment would spend $2.2 trillion on new COVID-19 measures, including testing and treatment efforts and unemployment benefits. A supporter, Rep. James P. McGovern, D-Mass., said the spending was needed for families to pay for necessities like food, utilities, and rent during this pandemic. An opponent, Rep. Tom Cole, R-Okla., said the amendment had been hurriedly brought to the floor without minority input or adequate time for review, and that it would not pass the Senate. The vote, on Oct. 1, was 214 yeas to 207 nays.

NOT VOTING: Loudermilk R-GA (11th), Graves R-GA (14th)

YEAS: Bishop D-GA (2nd), Scott, David D-GA (13th), McBath D-GA (6th), Johnson D-GA (4th)

NAYS: Allen R-GA (12th), Scott, Austin R-GA (8th), Collins R-GA (9th), Carter R-GA (1st), Woodall R-GA (7th), Ferguson R-GA (3rd), Hice R-GA (10th)

CONTINUING APPROPRIATIONS: The Senate has passed the Continuing Appropriations Act and Other Extensions Act (H.R. 8337) sponsored by Rep. Nita M. Lowey, D-N.Y., to extend through Dec. 11 funding for health programs, including Medicare, surface transportation, and many other government programs. The vote, on Sept. 30, was 84 yeas to 10 nays.

AFFORDABLE CARE ACT LITIGATION: The Senate has rejected a cloture motion to end debate on a motion to consider a bill (S. 4653) sponsored by Senate Minority Leader Chuck Schumer, D-N.Y., that would block the Justice Department from making arguments in court for cancelling any provision of the 2010 health care reform law (ACA). The vote to end debate on Oct. 1, was 51 yeas to 43 nays, with a three-fifths majority needed for approval.

See the rest here:
Congress Votes | News | albanyherald.com - The Albany Herald

Next, to accommodate the donors immune cells, they had to wipe out Mr. Browns own immune system by bombarding him with chemotherapy and radiation. Next came the transplant procedure itself. On that same February day, Mr. Brown stopped taking his antiretroviral medication. Three months later, after a grueling recovery in which he almost died, he was H.I.V.-free.

For Mr. Brown, the epiphany came one day in the gym, when he found that he was developing muscles again after years of wasting away. That was kind of my proof that it was gone, he said.

Many hurdles remained. A recurrence of leukemia required a second transplant a year later. A brain biopsy left Mr. Brown temporarily paralyzed and nearly blind. He had to be taught how to walk and talk again. His recovery, complicated by injuries from a 2009 mugging in Berlin, left him with a stiff shoulder, limited vision and neurological damage, which prevented him from resuming his work as a translator.

My life is far from perfect, he said in 2015, but it is still my life.

He was living in Nevada in 2013 when he met Mr. Hoeffgen on the Scruff dating app. They moved to Southern California in 2015. In April, Mr. Brown was admitted to a cancer hospital; his leukemia, unrelated to H.I.V., had returned. Covid-19 restrictions kept the couple together on the medical campus for weeks.

This month, Mr. Hoeffgen told Mark S. King, a blogger and AIDS activist, that Mr. Brown had terminal cancer and had been receiving home hospice care. Mr. Brown was aware that he was dying.

I have asked him what he wants me to tell people when we make his situation public, Mr. Hoeffgen said. He said: Tell people to keep fighting. Fight for a cure for H.I.V. that works for everyone. I never wanted to be the only one.

In addition to Mr. Hoeffgen, Mr. Brown is survived by his mother.

One researcher asked whether the couple would consider donating Mr. Browns body to science.

I said, Thank you, but no, Mr. Hoeffgen said. I think hes done enough.

See the original post here:
Timothy Ray Brown, First Patient Cured of H.I.V., Dies at 54 - The New York Times

Smiths 2005 stem cell law to be reauthorized by House

Rep. Chris Smith (R-NJ)statement submitted during debate in the House of Representatives

on the Stem Cell Therapeutic and Research ActSeptember 29, 2020

Margaret Hahnmy mother-in-lawpassed away on Friday and a Mass of Christian burial will be held today at St. Mary Church in South Amboy, New Jersey. She was 96 and was deeply loved and will be deeply missed.

MargaretPegwas a great womanwife, mother, grandmother, and great-grandmother. She selflessly devoted her life to public service including her amazing work as Sayreville Borough Clerk for twenty years. She had an incredible reputation for getting things done for the people. No matter who served as mayor or on Council, everyone knew she was the power.

My wife Marie and I will join family and friends today at her funeral and internment making it impossible for me to speak today during the debate on the reauthorization of a law I originally authored fifteen years agothe Stem Cell Therapeutic and Research Act of 2005and the Stem Cell Therapeutic and Research Act of 2015.

So, I submit these comments for the Congressional Record.

Madam Speaker, today the House of Representatives will vote to reauthorize the Stem Cell Therapeutic and Research Act.

This was an original idea of mine 20 years ago. Joined by 70 cosponsors, I introduced it in 2001 and again in 2003.

After five long years of hard work and numerous setbacks, my bill was finally enacted into law in 2005.

Beginning in 2001, Dr. Joanne Kurtzberg, who is President of the Cord Blood Association, helped draft my original law.Dr. Kurtzberg has said, Cord blood transplantation is now an established field with enormous potential. In the future, it may emerge as a source of cells for cellular therapies focused on tissue repair and regeneration.

The new law created a nationwide umbilical cord blood stem cell program, designed to collect, derive, type, and freeze cord blood units for transplantation into patients to mitigate and to even cure serious disease. Pursuant to the law, it also provided stem cells for research. The new cord blood program was combined in our 2005 law with an expanded bone marrow initiative, which was crafted over several years by our distinguished colleague, CongressmanBill Young.

I was the prime sponsor again when it was reauthorized in 2015.

Umbilical cord blood stem cells, obtained after the birth of a child, have proved highly efficacious in treating 70 diseases, including sickle-cell disease, lymphoma, and leukemia. And scientists are continuing to study and better understand the regenerative effects of cord blood cell therapies for other diseases and conditions. Bone marrow donations provide lifesaving transplants to treat diseases like blood cancer, sickle cell anemia, or inherited metabolic or immune system disorders.

The National Cord Blood Inventory (NCBI) provides funding to public cord blood banks participating in the program to allow them to expand the national inventory of cord blood units available for transplant. These units are then listed on the registry by the Be the Match Program. The funds appropriated thus far have led to an important increase in the overall number of high-quality cord blood units available through the national registry, including 150,000 NCBI units. Within the Be the Match registry, there are more than 783,000 NCBI units worldwide.

The Program registry allows patients and physicians to locate matching cord blood units, as well as adult donors for marrow and peripheral blood stem cells, when a family donor is not available. The Program is the worlds largest, most diverse donor registry, with more than 22 million volunteers and more than 300,000 public cord blood units. To date, the National Marrow Donor Program/Be The Match (NMDP), through its operation of the Program, has facilitated more than 100,000 transplants. More than 45,000 patients have receivedcord bloodtransplants, according Dr. Joanne Kurtzberg.

The reauthorization before us authorizes $23 million to be appropriated for fiscal year 2021 through fiscal year 2025. It also authorizes $30 million to be appropriated for fiscal years 2021 through 2025 for the bone marrow transplant program. This continues funding at the same levels authorized in the 2015 authorization bill.

Madam Speaker, each year nearly 4 million babies are born in America. In the past, virtually every placenta and umbilical cord was tossed as medical waste. Today, doctors have turned this medical waste into medical miracles.

Not only has God in His wisdom and goodness created a placenta and umbilical cord to nurture and protect the precious life of an unborn child, but now we know that another gift awaits us immediately after birth. Something very special is left behindcord blood that is teeming with lifesaving stem cells. Indeed, it remains one of the best kept secrets in America that umbilical cord blood stem cells and adult stem cells in general are curing people of a myriad of terrible conditions and diseasesover 70 diseases in adults as well as in children.

The legislation that is before us will enable even more patients to receive the treatments that they so desperately need.

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Smith's 2005 stem cell law to be reauthorized by House - InsiderNJ

When 5-year-old Sawyer was diagnosed with sickle cell at a young age, his fraternal twin, Saxton, turned out to be a perfect match.

ATLANTA This is not just a birthday party, its a celebration of second chances.

We are so blessed, said OShea Guillory. We want to share this.

It is also a commitment to help others, too.

Mikari Tarpley is 16. She is at the small birthday celebration and sang her heart out for 5-year-old Sawyer and his brother Saxton. She sings from a place of understanding.

She and Sawyer, her neighbor, have both been through a lot this year.

We found out about Sawyers sickle cell disease at a very early age, Guillory said. He was about three weeks old.

Sawyers mom said she was absolutely devastated. She refused to accept there was nothing she could do to help her son.

I did a ton of research," she said. I found an organization called Be The Match.

She discovered information about transplants that could be a potential cure. Doctors take stem cells from the bone marrow of a donor and transplant it into the recipient.

They just needed a donor.

It turns out Sawyer was born with his cure, Guillory said. His twin, Saxton, was a perfect sibling match.

Across the cul-de-sac, Mikari Tarpley, an actress, was fighting Hodgkins Lymphoma and finishing chemotherapy.

She knew Sawyer has been battling sickle cell. Theyd both lost their hair from treatment. She decided she wanted to use her Sweet 16th birthday to raise money for children like Sawyer.

We couldnt do much for my sixteenth because of COVID, so we thought it would be a great idea to do a fundraiser to help others, Mikari said.

She reached her goal of $16,000 to help children being treated for sickle cell disease at the Aflac Cancer and Blood Disorders Center.

Five-year-old Sawyer received a bone marrow transplant from his fraternal twin, Saxton. It was a success. Before long, Sawyer was riding a tricycle around Childrens Healthcare of Atlanta, racing his nurses and giggling along the way.

I truly have little warriors, Guillory said. My son, who helped save his brothers life - and my son - who was able to go through all of that and come out even stronger.

Now Sawyer, Saxton and their parents are spending their 5th birthday following Mikaris lead by paying it forward.

Sawyers mom OShea is starting a nonprofit, Sawyers Sickle Circle, to spread awareness and knowledge about sickle cell, Beads of Courage and Be the Match program. They launched a fundraiser on Sawyer and Saxtons birthday.

The Guillory family said the best present they could wish for is for other kids to have the chance to celebrate many more birthdays to come.

Link:
A perfect match: Bone marrow transplant saves twin brother's life. Now their family pays it forward - 11Alive.com WXIA

In 2004, after President George W. Bush cut off all federal funding for embryonic stem-cell research on religious grounds, Californians strongly backed Proposition 71, a $3-billion bond measure to fund this kind of research, even though such funding is usually not the purview of states.

Supporters of the proposition including this editorial board believed it would allow California to stand out as a leader in this field, advance a budding avenue of research that might save lives and alleviate suffering, bolster its biotech sector and fund possible blockbuster treatments that might earn the state royalties as well. Embryonic stem cells are particularly valuable to research because they are undifferentiated, meaning they do not have a particular function, and researchers could conceivably turn them into specialized cells in order to regenerate human cells and tissue.

In the years since, Proposition 71 gave rise to a burst of scientific discovery. Two cancer treatments it helped fund, for blood and bone-marrow cancers, have been approved by the FDA, though neither of those employed embryonic stem cells and could have been funded even under Bush administration rules. It has also supported promising advances in the treatment of diabetes, bubble boy immune deficiency and vision-robbing retinitis pigmentosa, but other efforts have fallen short in clinical trials.

Moreover, the money helped build laboratories and other infrastructure that give California a head start on research and development, making the state the it place for stem-cell research. Researchers in the state moved to the head of the pack for private grants, because projects are less likely to need the time and money to create facilities before work can begin.

Now that Proposition 71 funding has practically run out, the issue is back on the November ballot with Proposition 14, which seeks nearly double the amount worth of bonds $5.5 billion to continue the juggernaut.

This time, voters should reject the measure, with the caveat that the issue could be reconsidered in a couple of years, if its proponents bring it back in better-designed and more modest form and if there are more successes in human trials and financial payback.

We have long had reservations about how the California Institute for Regenerative Medicine, established as a result of Proposition 71, was set up. Though funded publicly, it is not overseen by the governor and Legislature like other state agencies, and its governing board is too large, at 29 members. Those members generally have ties to the advocacy organizations and research institutions that have received most of the money.

The driving force behind the initiative has been Robert N. Klein II, a Bay Area lawyer and real estate investor. There is no doubting Kleins sincerity in his cause. He knows too well the suffering inflicted by intractable diseases; his son Jordan died of complications of Type I diabetes in 2016. His accomplishment in persuading the state to invest billions in a specific avenue of biomedical research has been exceptional.

However, Klein developed these initiatives largely behind closed doors with little to no public input; he has strong ideas about how things should be run on the stem-cell front and has steadfastly resisted more government oversight. Thats fine when hes investing his own money; its a fatal flaw when he is asking voters for nearly $8 billion, the estimated cost of paying off the bonds over time, according to the Legislative Analysts Office.

Kleins role and the bloated structure of CIRMs super-sized governing board have given rise to some serious ethical mishaps, including a board member who improperly intervened to try to get funding for his organization. (He is no longer on the board.) After this and several other examples of impropriety, rules were tightened. Board members must recuse themselves from votes when there is a conflict of interest, but with 29 members who all want certain projects to receive funding, there is too much potential for mutual back-scratching. Instead of repairing this problem, the new proposition would expand CIRMs board to 35 members and retain its troubling independence from oversight by the governor and Legislature, leaving it open to further conflicts of interest.

Proposition 71 hasnt yet yielded a significant financial return on investment for the state or the cures that were ballyhooed at the time. Though no one ever promised quick medical miracles, campaign ads strongly implied they were around the corner if only the funding came through. Proponents oversold the initiatives and voters cant be blamed if they view this new proposal with skepticism.

In the years since Proposition 71 passed, more resources have become available. President Obama reversed Bushs order and restored federal funding, which meant that between CIRM and the National Institutes of Health, along with private grant and investment funding, stem-cell research has been healthy, if not downright flush. That funding has stayed and even grown under President Trump, to more than $2 billion a year, with about $321 million of that in human embryonic stem-cell research. (There have, though, been recent threats to embryonic research from a group of conservative senators.)

The idea was never for California to become the long-term replacement for federal funding. It was to kick-start an industry that would then operate on its own. If that has failed to happen under Proposition 71 as promised, it shouldnt be the responsibility of California taxpayers to fix it. Thats especially true right now, at a time of yawning needs to address the cost of twin health and economic crises and the worsening effects of climate change. Private money for stem cell-work will continue to be available; its not as though research will collapse.

No doubt, the pace of responsible science is incremental and the outcomes uncertain even with the best research efforts. Yet the backers still couch the possibilities in grandiose terms. In a recent interview with the Times editorial board, Klein talked about the money that would be saved by wiping out Alzheimers disease which has so far has frustrated attempts to treat it effectively, despite many billions of dollars in research.

Embryonic stem cell research remains important, and there might be ways in which the state can contribute less grandiose funding while maximizing its investment. For example, scientific research has a well-known valley of death, where many projects cant get funding to make the transition from laboratory to human clinical trials.

Offering some matching help to get projects through that phase might attract businesses and scientists to California, while spending far less than the billions proposed in Proposition 14. Its worth noting that stem-cell work isnt the only kind of research that faces the valley of death problem; its an issue for most basic research that seeks to make the leap to human trials and that might be equally in need of state help.

Now is not the time for a huge new investment in specialized medical research. First, it makes sense to wait until after the election; if Democrats do well, there should be growing support for embryonic stem-cell research at the federal level, which is where such funding should take place. The future of Californias pandemic-battered economy and budget remains to be seen. Waiting also would give voters a chance to find out how well the states stem-cell research projects continue without state dollars, and whether some of the promising advances lead to breakthrough therapies and a return on Californias investment.

There would be an opportunity to rethink and rewrite any future proposals, which should include a far more modest ask of taxpayers as well as fixes to the structure and inflated size of the CIRM board. The institute should also be placed under the same state oversight as other agencies reporting to the governor.

If CIRM needs money for a basic operating budget over the next couple of years, that could be covered by the states general fund. The agency still needs to administer already-funded projects and could use that time to discuss a more affordable path forward. Right now, the state has other, more urgent spending priorities.

Editors note: This newspapers owner, the physician and scientist Dr. Patrick Soon-Shiong, played no role in the editorial boards deliberations on this measure.

Continue reading here:
No on Prop 14: Not the best way to support stem-cell research - Los Angeles Times

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Regen Biopharma IncChina Cord Blood CorpCBR Systems IncEscape Therapeutics IncCryo-Save AGLonza Group LtdPluristem Therapeutics IncViaCord I

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Global Hematopoietic Stem Cell Transplantation (HSCT) Market How the Market has witnessed Substantial Growth in recent years? - The Daily Chronicle

Asymmetrex discusses new advances for supply of traditional drug development and advanced therapy medicinal product (ATMP) clinical trials

BOSTON (PRWEB) October 01, 2020

Adapting to the present COVID crisis, this year the 2020 Outsourcing in Clinical Trials USA Conference, one of several international clinical trials supply trade conferences organized by Arena International Events Group each year, adopted a virtual meeting format. The conference, scheduled for September 30-October 1, continued its tradition of bringing together contract research organization suppliers and company sponsors in the clinical trials supply industry to discuss new developments and best practices.

Among the many industry members invited to speak in the event, James L. Sherley, M.D., Ph.D., founder and director of Massachusetts stem cell biotechnology company Asymmetrex, presented on September 30. Dr. Sherleys presentation highlighted a growing new area of the clinical trials supply industry. More and more, the clinical trials supply industry is considering better technology and practices to support stem cell clinical trials and gene therapy clinical trials that utilize advanced therapy medicinal products. In particular, Dr. Sherley discussed the value of implementing new quantification technologies for ATMPs developed with tissue stem cells. He answered the rhetorical question that was the title of his talk How can we outsource stem cell clinical trials without counting tissue stem cells? by detailing places in ATMP supply chains where instituting counting technologies would provide significant benefits to the stem-gene clinical trials supply industry and the patients it serves.

Sherley also presented innovation proposals for traditional pharmaceutical and biopharmaceutical clinical trials supply. He described how tissue stem cell counting technologies represented advantages both for discovery of novel drugs and for toxicology evaluations of new drug candidates. A major value presented was the opportunity for drug companies to realize hundreds of millions of dollars in reduced costs each year by using tissue stem cell counting tests for earlier identification of drugs that would fail late in clinical trials because of inducing chronic failure of organs and tissues like the liver and bone marrow. Currently applied animal toxicology studies miss many drugs with this disastrous character. Sherley described how such drugs could be detected in inexpensive cell culture tests by counting how stem cell-specific number and viability changed in their presence.

Though not a main focus of the presentation, Sherley ended his presentation with acknowledgement of Asymmetrexs recent introduction of the first-in-kind technology for counting therapeutic tissue stem cells and determining their dosage. The company holds issued patents for the technology and its use for drug evaluations in both the U.S. and U.K. In August of this year, it published a peer-reviewed report, co-authored with its partner AlphaSTAR Corporation, that describes the new method and its applications for stem cell therapy and drug evaluations. In September, the company was awarded a research and development grant from the National Institutes of Health-National Heart, Lung, and Blood Institute for continued development of the technology and its commercialization. These plans for the companys AlphaSTEM Test tissue stem cell counting technology were recently reported.

About Asymmetrex

Asymmetrex, LLC is a Massachusetts life sciences company with a focus on developing technologies to advance stem cell medicine. The companys U.S. and U.K. patent portfolio contains biotechnologies that solve the two main technical problems production and quantification that have stood in the way of effective use of human adult tissue stem cells for regenerative medicine and drug development. Asymmetrex markets the first technology for determination of the dose and quality of tissue stem cell preparations (the AlphaSTEM Test) for use in stem cell transplantation therapies and pre-clinical drug evaluations. Asymmetrex is a member company of the Advanced Regenerative Manufacturing Institute BioFabUSA and the Massachusetts Biotechnology Council.

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Asymmetrex Presents the Value of Tissue Stem Cell Counting For Supplying Stem Cell Clinical Trials and Drug Development Clinical Trials - PR Web

The global stem cell banking market was valued at $1,986 million in 2016, and is estimated to reach $6,956 million by 2023, registering a CAGR of 19.5% from 2017 to 2023. Stem cell banking is a process where the stem cell care isolated from different sources such as umbilical cord and bone marrow that is stored and preserved for future use. These cells can be cryo-frozen and stored for decades. Private and public banks are different types of banks available to store stem cells.

Top Companies Covered in this Report: Cord Blood Registry,ViaCord,Cryo-Cell, China Cord Blood Corporation, Cryo-Save, New York Cord Blood Program, CordVida, Americord, CryoHoldco, Vita34

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Increase in R&D activities in regards with applications of stem cells and increase in prevalence of fatal chronic diseases majorly drive the growth of the global stem cell banking market. Moreover, the large number of births occurring globally and growth in GDP & disposable income help increase the number of stem cell units stored, which would help fuel the market growth. However, legal and ethical issues related to stem cell collections and high processing & storage cost are projected to hamper the market growth. The initiative taken by organizations and companies to spread awareness in regards with the benefits of stem cells and untapped market in the developing regions help to open new avenues for the growth of stem cell banking market in the near future.

The global stem cell banking market is segmented based on cell type, bank type, service type, utilization, and region. Based on cell type, the market is classified into umbilical cord stem cells, adult stem cells, and embryonic stem cells. Depending on bank type, it is bifurcated into public and private. By service type, it is categorized into collection & transportation, processing, analysis, and storage. By utilization, it is classified into used and unused. Based on region, it is analyzed across North America, Europe, Asia-Pacific, and LAMEA.

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Table Of Content

CHAPTER 1: INTRODUCTION

CHAPTER 2: EXECUTIVE SUMMARY

CHAPTER 3: MARKET OVERVIEW

CHAPTER 4: STEM CELL BANKING MARKET, BY CELL TYPE

CHAPTER 5: STEM CELL BANKING MARKET, BY BANK TYPE

CHAPTER 6: STEM CELL BANKING MARKET, BY SERVICE TYPE

CHAPTER 7: STEM CELL BANKING MARKET, BY UTILIZATION

CHAPTER 8: STEM CELL BANKING MARKET, BY REGION

CHAPTER 9: COMPANY PROFILES

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Stem Cell Banking Market is forecast to reach $6,956 million by 2023 | ViaCord,Cryo-Cell, China Cord Blood Corporation, Cryo-Save - The Daily...

Bluebird bio could be just a few months away from approval of its gene therapy for rare disease cerebral adrenoleukodystrophy (CALD) in the EU, after the EMA started an accelerated review.

If approved, Lenti-D (elivaldogene autotemcel or eli-cel) could transform the prospects of people with CALD, the most severe form of the neurodegenerative disease ALD that usually emerges in boys during early childhood and causes physical and mental disabilities as well as behavioural problems.

Around 40% of patients develop the cerebral form of ALD, which in turn affects around one in 17,000 live births.

A few weeks ago, Bluebird reported new data from the phase 2/3 STARBEAM trial of Lenti-D which showed that 87% of CALD patients were still alive and free of major functional disabilities after at least two years follow-up.

The EU filing comes ahead of a filing for eli-cel in the US, which Bluebird says should take place sometime towards the middle of next year, having been delayed by the coronavirus pandemic.

If approved, eli-cel would provide a one-shot treatment for CALD, holding back the progressive breakdown in the protective myelin that sheathes neurons.

It would be the first alternative to a stem cell transplant to treat the disease, a therapy that can provide significant improvements and even halt progression in some patients if given early enough.

However it requires high-dose chemotherapy to destroy the bone marrow, and that poses significant risks to patients in its own right, and can also lead to graft-versus-host disease, a potentially life-threatening complication in which the bone marrow donors immune cells attack the recipients cells and tissues.

CALD is caused by mutations in the ABCD1 gene located on the X chromosome, which provides instructions for the production of the ALD protein.

ALD protein is needed to clear toxic molecules called very long-chain fatty acids (VLCFAs) in the brain, and if mutated causes the VLCFAs to accumulate and damage the myelin sheath.

Using eli-cel, the patients own stem cells are modified in the lab to produce a working version of the ABCD1 gene, producing functional ALD protein that can help to flush VLCFAs from the body.

CALD is a devastating disease, often marked by rapid neurodegeneration, the development of major functional disabilities, and eventual death, said Gary Fortin, head of severe genetic disease programmes at Bluebird.

If approved, eli-cel would represent the first therapy for CALD that uses a patients own haematopoietic stem cells, potentially mitigating the risk of life-threatening immune complications associated with transplant using cells from a donor, he added.

Aside from STARBEAM, which will follow treated patients for up to 15 years, Bluebird is also conducting the phase 3 ALD-104 trial of eli-cel in CALD, which is due to generate results in 2024.

The EU filing for eli-cel comes shortly after Bluebirds development partner received a 27 March 2021 FDA review date for anti-BCMA CAR-T cell therapy ide-cel, a potential therapy for multiple myeloma.

The biotech already has approval in Europe for Zynteglo, a gene therapy for haematological disease beta thalassaemia, and is due to file its related therapy LentiGlobin for sickle cell disease next year. The two therapies have been tipped to generate $1.5 billion-plus in peak sales by some analysts.

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EMA starts rapid review of Bluebird's gene therapy for rare disease CALD - - pharmaphorum

Heres a look at how Maines members of Congress voted over the previous week.

Along with its roll call votes this week, the House also passed these measures: the Cyber Sense Act (H.R. 360), to require the Secretary of Energy to establish a voluntary Cyber Sense program to test the cybersecurity of products and technologies intended for use in the bulk-power system; the Consumer Product Safety Inspection Enhancement Act (H.R. 8134), to support the Consumer Product Safety Commissions capability to protect consumers from unsafe consumer products; the School-Based Allergies and Asthma Management Program Act (H.R. 2468), to increase the preference given, in awarding certain allergies and asthma-related grants, to states that require certain public schools to have allergies and asthma management programs; and the Effective Suicide Screening and Assessment in the Emergency Department Act (H.R. 4861), to establish a program to improve the identification, assessment, and treatment of patients in the emergency department who are at risk of suicide.

House Vote 1:

PRESIDENTIAL ELECTION: The House has passed a resolution (H. Res. 1155), sponsored by Rep. Eric Swalwell, D-Calif., reaffirming the Houses commitment to an orderly and peaceful transfer of presidential power after the November election. Swalwell said: The peaceful transition of power is not only a bedrock principle of Americas founding; it is a living ideal that we must exercise and pass down to our children. An opponent, Rep. Matt Gaetz, R-Fla., called the resolution a way for Democrats to attack the president and disguise the fact that they will refuse to accept the election results unless they win. The vote, on Sept. 29, was 397 yeas to 5 nays.

YEAS: Pingree D-ME (1st), Golden D-ME (2nd)

House Vote 2:

DISCLOSING TIES TO UYGHUR LABOR: The House has passed the Uyghur Forced Labor Disclosure Act (H.R. 6270), sponsored by Rep. Jennifer Wexton, D-Va., to require publicly traded companies to disclose whether they have business ties to Chinas Uyghur Autonomous Region in Xinjiang province. Wexton said the requirement would let investors know of a given companys passive complicity or active exploitation of one of the most pressing and ongoing human rights violations of our lifetime. A bill opponent, Rep. Anthony Gonzalez, R-Ohio, said it wrongly tried to have the Securities and Exchange Commission police human rights violations, a role that would be better handled by the Treasury Department. The vote, on Sept. 30, was 253 yeas to 163 nays.

YEAS: Pingree D-ME (1st), Golden D-ME (2nd)

House Vote 3:

DISEASE THERAPIES: The House has passed the Timely ReAuthorization of Necessary Stem-cell Programs Lends Access to Needed Therapies Act (H.R. 4764), sponsored by Rep. Doris O. Matsui, D-Calif. The bill would reauthorize a program for transplanting umbilical cord blood, stem cells and bone marrow to adults and children suffering from various diseases. The vote, on Sept. 30, was unanimous with 414 yeas.

YEAS: Pingree D-ME (1st), Golden D-ME (2nd)

House Vote 4:

FURTHER COVID-19 SPENDING: The House has approved an amendment to the Americas Conservation Enhancement Act (H.R. 925). The amendment would spend $2.2 trillion on new COVID-19 measures, including testing and treatment efforts and unemployment benefits. A supporter, Rep. James P. McGovern, D-Mass., said the spending was needed for families to pay for necessities like food, utilities, and rent during this pandemic. An opponent, Rep. Tom Cole, R-Okla., said the amendment had been hurriedly brought to the floor without minority input or adequate time for review, and that it would not pass the Senate. The vote, on Oct. 1, was 214 yeas to 207 nays.

YEAS: Pingree D-ME (1st)

NAYS: Golden D-ME (2nd)

Senate Vote 1:

CONTINUING APPROPRIATIONS: The Senate has passed the Continuing Appropriations Act and Other Extensions Act (H.R. 8337), sponsored by Rep. Nita M. Lowey, D-N.Y., to extend through December 11 funding for health programs, including Medicare, surface transportation, and many other government programs. The vote, on Sept. 30, was 84 yeas to 10 nays.

YEAS: Collins R-ME, King I-ME

Senate Vote 2:

OBAMACARE LITIGATION: The Senate has rejected a cloture motion to end debate on a motion to consider a bill (S. 4653), sponsored by Senate Minority Leader Chuck Schumer, D-N.Y., that would block the Justice Department from making arguments in court for cancelling any provision of the 2010 health care reform law (Obamacare). The vote to end debate, on Oct. 1, was 51 yeas to 43 nays, with a three-fifths majority needed for approval.

YEAS: Collins R-ME, King I-ME

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How Maine's members of Congress voted this week - Bangor Daily News

INTRODUCTION

Rotavirus (RV) remains a scourge to humanity, causing severe distress (morbidity) to many children and contributes to thousands of childhood deaths annually, particularly in developing countries wherein RV vaccines have only moderate efficacy (1). RV is a double-stranded RNA virus that primarily infects intestinal epithelial cells (IEC) that line the villus tips of the ileum, resulting in severe life-threatening diarrhea in young children and moderate gastrointestinal distress in adults (24). Such tropism and pathogenesis is faithfully recapitulated in RV-infected mice, making the mouse model of RV useful for studying basic aspects of RV immunity and disease pathophysiology. Furthermore, the RV mouse model may prove a useful platform for discovery of novel means to treat and prevent RV infection, especially in scenarios when adaptive immunity, which normally plays an essential role in clearing RV, is not functioning adequately. Toward this end, we previously reported that administration of bacterial flagellin rapidly cured, and/or protected against, RV infection. Such protection was independent of interferon and adaptive immunity and dependent on the generation of both Toll-like receptor 5 (TLR5)mediated interleukin-22 (IL-22) and nucleotide-binding oligomerization domainlike receptor C4 (NLRC4)mediated IL-18, which together resulted in prevention and/or cure of RV infection, and its associated diarrhea (5). However, the mechanisms by which these cytokines impede RV infection remained unknown. Herein, we report that IL-22 acts upon IEC to drive proliferation, migration, and ultimately extrusion of infected IEC into the intestinal lumen, whereas IL-18 drives rapid death of RV-infected IEC. The combined actions of IL-22 and IL-18 eliminate RV from the intestine independent of adaptive immunity.

We previously reported that systemic administration of bacterial flagellin elicits TLR5-mediated production of IL-22 and NLRC4-mediated generation of IL-18 that can act in concert to prevent or treat RV and some other enteric viral infections (5). Specifically, as shown in fig. S1 and our previous work, chronic RV infections that developed in RV-inoculated immune-deficient C57BL/6 Rag-1/ mice were cured by combined systemic treatment with IL-18 and IL-22, whereas injection of either cytokine alone reduced RV loads but did not clear the virus, regardless of cytokine dose and duration of administration. In these particular experiments, RV infection was assayed by measuring fecal RV antigens by enzyme-linked immunosorbent assay (ELISA), but measurement of RV genomes in the intestine yields similar results (5). In wild-type (WT) mice, a sufficiently high doses of recombinant IL-22 can, by itself, fully prevent RV infection, whereas lower doses of exogenously administered IL-22 and IL-18 markedly reduced the extent of RV infection, while the combination of these cytokines eliminated evidence of infection (Fig. 1A). The central goal of this study was to elucidate mechanisms by which these cytokines act in concert to control and prevent RV infection.

Mice were administered PBS, IL-22 (2 g), and/or IL-18 (1 g) via intraperitoneal injection, 2 hours before, or 2, 4, 6, or 8 days after (indicated by arrows) oral inoculation with mRV. Fecal RV levels were measured over time by ELISA. (A) C57BL/6 mice n = 4. (B) IL-22/ mice, n = 5 and 7 for PBS and IL-18, respectively. (C) IL-18/ mice, n = 5. * indicates significantly different from PBS by two-way analysis of variance (ANOVA), P < 0.0001. dpi, days post-inoculation.

In the context of parasitic infection, both IL-18 and IL-22 promote expression of each other, and loss of either impairs immunity to Toxoplasma gondii (6). We thus hypothesized that administration of IL-18 might impede RV as a result of its ability to induce IL-22 expression. This hypothesis predicted that the ability of IL-18 to protect against RV infection would be largely absent in IL-22/ mice. However, administration of IL-18 upon RV inoculation clearly reduced the extent of RV infection in IL-22/ mice, which argued strongly against this hypothesis (Fig. 1B). We considered the converse hypothesis, namely, that IL-22 might impede RV infection by elicitation of IL-18, but we observed that recombinant IL-22 markedly prevented RV infection in IL-18/ mice (Fig. 1C). Although IL-18 and IL-22 may play important roles in inducing each others expression, our results indicate that they each activate distinct signaling pathways that cooperate to impede RV infection.

Next, we examined the extent by which IL-18 and IL-22 acted upon the hematopoietic or nonhematopoietic compartment to impede RV infection. We used WT, IL-18-R/, and IL-22-R/ mice to generate irradiated bone marrow chimeric mice that expressed the receptors for IL-22 or IL-18 in only bone marrowderived or radioresistant cells. Such mice were inoculated with RV, treated with recombinant IL-22 or IL-18, and RV infection was monitored via measuring fecal RV antigens by ELISA. Figure 1 used a relatively low dose of cytokine that highlighted the cooperativity of IL-18 and IL-22, but successive experiments used fivefold higher doses to enable a robust effect that could be dissected via bone marrow chimeric mice. Mice that expressed the IL-22 receptor only in bone marrowderived cells were not protected from RV infection by treatment with IL-22 (Fig. 2A), whereas mice with IL-22 receptor only in radioresistant cells were almost completely protected by this cytokine (Fig. 2B). These results suggest that IL-22 protects mice from RV infection by acting on IEC, which are known to be populated from radioresistant stem cells and responsive to IL-22 (7). In accord with this notion, we observed that multiple IEC cell lines are responsive to IL-22 in vitro via STAT3 phosphorylation, although IL-22, like flagellin and IL-18, did not affect RV infection in vitro (fig. S2). Studies with IL-18-R chimeric mice similarly revealed that expression of this receptor in only bone marrowderived cells conferred only a modest nonsignificant reduction (12 3.8%) in the extent of RV infection upon IL-18 administration (Fig. 2C). In contrast, in mice that expressed IL-18-R in only radioresistant cells, IL-18 reduced extent of RV infection by 76 8.7% (Fig. 2D). Together, these results suggest that agonizing IL-18 and IL-22 receptors on IEC result in generation of signals that impede RV in vivo but not in vitro.

Indicated bone marrowirradiated chimeric mice were administered PBS (control), IL-22 (10 g), or IL-18 (2 g) via intraperitoneal injection, 2 hours before or 2, 4, 6, or 8 days after oral inoculation with mRV. Fecal RV levels were measured over time by ELISA. Differences between control and cytokine groups for each chimera/panel were analyzed by two-way ANOVA. (A) n = 7, P = 0.7715. (B) n = 4 and 7 for PBS and IL-22, respectively. (C) n = 7 and 6 for PBS and IL-18, respectively. (D) n = 4 and 6 for PBS and IL-18, respectively. * indicates significantly different from PBS by two-way ANOVA, P < 0.0001.

In cell culture and organoid models, IL-22 promotes IEC proliferation, migration, and stem cell regeneration (810), which together are thought to contribute to ability of IL-22 to promote healing in response to an array of insults, including exposure to radiation and dextran sodium sulfate in vivo (1114). In contrast to such severe injuries, RV infection is generally characterized by a lack of overt intestinal inflammation (15, 16). We hypothesized that IL-22 may promote IEC proliferation and/or migration that might reduce the extent of RV infection by increasing the rate of IEC turnover, especially near villus tips, which is the predominant site of RV infection (24). We further reasoned that IL-18 might trigger the same kind of response and further increase IEC proliferation and turnover. Mice were administered 5-bromo-2-deoxyuridine (BrdU) and treated with IL-22 and/or IL-18. Sixteen hours later, mice were euthanized, and intestines were subjected to fluorescence microscopy to measure rates at which IEC migrated toward villus tips (17). In accord with our hypothesis, administration of IL-22 approximately doubled the rate at which IEC migrated toward villus tips (Fig. 3, A and B). IL-18 administration also increased the rate of IEC migration to a lesser extent. The combination of these cytokines did not result in a faster rate of IEC migration relative to IL-22 alone. Epidermal growth factor (EGF) is known to promote IEC proliferation and migration (18, 19), so we tested whether this cytokine might protect against RV infection. In accord with EGF promoting proliferation in a variety of tissues, EGF treatment induced IEC migration up the crypt villus axis (Fig. 3, C and D), albeit not quite as robustly as IL-22 (1.43- versus 1.95-fold increase respectively). Moreover, EGF had the ability to reduce the extent of RV infection (Fig. 3E), but not as completely as IL-22. Together, these results support the hypothesis that IL-22 and IL-18 promote IEC replication and migration, which contributes to protection against RV infection.

Mice were intraperitoneally injected with PBS, IL-22, (10 g) IL-18 (2 g), both cytokines, or mEGF. One hour later, mice were administered BrdU. Mice were euthanized 16 hours after BrdU administration, and BrDU was visualized (A and C) and migration was measured (B and D) by microscopy and image analysis, respectively. Images shown in (A) and (C) are representative. Scale bar equals 50 m. For (B) and (D), sections were scored at least from 50 villus per group of mice (n = 5). Distance of the foremost migrating cells along the crypt-villus axis was measured with ImageJ software. Results are presented as means SEM. Statistical significance was evaluated by Students t test (****P < 0.0001). (E) Mice were intraperitoneally injected with PBS or EGF (10 g) mEGF 2 hours before or 2, 4, 6, or 8 days after oral inoculation with mRV. Fecal RV levels were measured over time by ELISA. Data are means SEM, n = 5 * indicates significantly different from PBS by two-way ANOVA, P < 0.0001.

We next considered how promoting IEC proliferation might impede RV infection. Increased extrusion of IEC into the lumen is a likely consequence of increased IEC proliferation/migration, which is thought to occur such that cells remain alive until extrusion is completed to preserve the gut barrier (20). We hypothesized that increased proliferation/migration induced by IL-22 and/or IL-18 treatments might result in increased extrusion of villus tip cells, which are the site of RV infection. We investigated this hypothesis using a previously described method (21) in which cross sections of hematoxylin and eosinstained pieces of ileum are examined for visual evidence of cell shedding. We were unable to consistently distinguish IEC from other luminal contents, so we visualized cells using the DNA stain. This approach suggested a greater presence of IEC in the lumen of mice treated with cytokines, particularly IL-22 (Fig. 4A), but it was difficult to quantitate such a difference via cell counting, so we sought to evaluate levels of host cells via quantitative polymerase chain reaction (qPCR) of 18S DNA in the ileum. The highly degradative environment of the intestine would likely degrade IEC shed into the lumen, but because such cells are extruded in a relatively intact state, their DNA might survive long enough to enable quantitation by qPCR. Small intestinal contents were extracted, and 18S DNA quantitated and expressed as number of cells per 100 mg of luminal content using known numbers of mouse epithelial cells to generate a standard curve. This approach indicated that IL-22 treatment markedly increased the level of IEC present in the lumen (Fig. 4B), suggesting increased IEC shedding. IL-18 induced only a modest level of IEC shedding that appeared to be additive to the shedding induced by IL-22. A generally similar pattern was observed in the cecum (Fig. 4C). In contrast, these cytokines did not affect levels of 18S DNA present in the lumen of the colon (Fig. 4D), perhaps reflecting that the impact of these cytokines on IEC shedding is specific to the ileum/cecum and/or that the DNA of shed IEC is quickly degraded in the bacterial-dense colon. An even greater amount of shedding of IEC into the ileum was induced by treating mice with flagellin, although two treatments of IL-18/22 could match this level, which suggested that production of these cytokines might be sufficient to recapitulate the IEC shedding induced by flagellin (Fig. 4E). The greater potency of flagellin may reflect ability of IL-18 and IL-22 to promote each others expression. Use of IL-22/ and IL-18/ mice revealed that these cytokines, both of which are necessary for flagellins anti-RV action (5), were both necessary for flagellin-induced cell shedding (Fig. 4F). Collectively, these results support the notion that increased extrusion of IEC, particularly in response to IL-22, might be central to this cytokines ability to impede RV infection, but these data did not offer insight into how IL-22 and IL-18 cooperate to offer stronger protection against this virus.

Mice [WT or indicated knockout (KO) strain] received a single (except where indicated otherwise) intraperitoneal injection of PBS, IL-22, (10 g), IL-18 (2 g), both cytokines or bacterial flagellin, FliC (15 g). Eight hours later, mice were euthanized, intestine was isolated, and luminal content was collected. (A) Microscopic appearance of DAPI-stained section to visualize shed cells in lumen. Scale bar equals 50 m. (B to F) Measurements of shed cells in different regions of the gastrointestinal tract via 18s by q-PCR (B, E, and F) small intestine, (C) cecum, (D) colon [double doses of IL-22 and IL-18 in (E) were 12 hours apart]. Data in (B) to (F) are means SEM (B), with significance assessed by Students t test, n = 5 to 15 mice as indicated by number of data points. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. n.s., not significant; SI, small intestine.

Next, we examined how IL-22 and IL-18 might affect IEC in the presence of an active RV infection. We used WT mice 3 days after inoculation with RV, a time approaching peak levels of RV shedding (Fig. 1A). RV-infected and uninfected mice were administered IL-22 and/or IL-18 and euthanized 6 hours later, and small intestinal content was isolated. Like IL-18/22 administration, RV infection up-regulated IEC extrusion, with a marked further increase in IEC extrusion being observed by administration of IL-18/22 to RV-infected mice (Fig. 5A). This suggests that increased IEC extrusion may normally contribute to innate defense against RV (2) and that exogenously administered IL-18/22 (or flagellin) may enhance this protective mechanism. Yet, like the case in uninfected mice, the promotion of IEC extrusion appeared to be driven by IL-22 and not IL-18 (Fig. 5B).

Mice were orally inoculated with mRV, or not(sham?) and were intraperitoneally injected at 3 dpi with PBS, IL-22, (10 g) IL-18 (2 g), or both cytokines. Mice were euthanized 6 hours later and following assays were carried out. (A and B) Assay of cell extrusion (i.e., measure of cells in lumen) as performed in response to cytokines in Fig. 4. (C and D) Assay cleaved caspase-3 in IEC was assayed by SDS-PAGE immunoblotting. (E and F) Visualization of cell death by TUNEL staining, counterstained with DAPI. (G) Quantitation of TUNEL-positive cells at villus tip region based on visual counts. Data in (A), (B), and (G) are means SEM. Panels (A) and (B) used five mice per condition to generate one value per mouse. Panel (G) used five mice per condition and assayed 6 to 10 villi per mouse, which are indicated by data points. Significance was determined by Students t test. *P < 0.05 and ****P < 0.0001.

Next, we sought to investigate events in IEC that remained part of the small intestine at the time of increased IEC extrusion. Specifically, we examined whether IL-18 and/or IL-22 might affect cell death. We observed that IL-18/22 or RV induced modest and variable induction of cleaved caspase-3. In contrast, administration of these cytokines to RV-infected mice induced marked elevations in cleaved caspase-3 (Fig. 5C). Caspase-3 cleavage was also observed in response to IL-18 but not IL-22 (Fig. 5D). Quantitation of cell death by terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick end labeling (TUNEL) yielded a similar pattern of results. Specifically, both IL-18/22 and RV by themselves resulted in a modest increase in TUNEL-positive cells, which appeared sporadically throughout the villi (Fig. 5E and fig. S3, A and B). In contrast, treating RV-infected mice with IL-18 or the combination of IL-18 and IL-22, but not IL-22 itself, resulted in notable TUNEL positivity at the villus tips (Fig. 5, E to G), known sites of RV infection. Cytokine-induced TUNEL positivity, which did not occur in the absence of RV, appeared to localize in the villus tip, where RV was localized before cytokine treatment, thus suggesting that IL-18 was promoting cell death in RV-infected cells (fig. S3C).

Cell death can occur via numerous pathways, so we hypothesized that IL-18induced cell death might occur via pyroptosis, which appears to be a frequent form of cell death for infected cells (22). In accord with this possibility, IL-18 administration to RV-infected mice results in cleaved gasdermin D (Fig. 6A), whose activity is essential for pyroptosis. To test the role of gasdermin D activation in IL-18induced cell death, we performed experiments in mice lacking gasdermin D and gasdermin E, the latter of which is thought to compensate for lack of gasdermin D in some scenarios. Our initial experiments found that gasdermin-deficient mice were highly resistant to RV infection (fig. S4). However, such resistance was associated with high levels of segmented filamentous bacteria (SFB), which we have recently shown drives spontaneous resistance to RV in Rag1/ mice (23). Cross-fostering on gasdermin-deficient mice removed SFB and restored susceptibility to RV infection, thus extending our recent findings to mice with functional adaptive immunity. This model could also address if the IL-18induced cell death that associates with clearance of RV is mediated by pyroptosis. IL-18 administration did not induce cleaved gasdermin D in mice lacking this gene (Fig. 6A), thus verifying the specificity of the antibody we used. IL-18induced cell death of RV-infected mice proceeded at least as robustly as had been observed in WT mice (Fig. 6B). Specifically, although gasdermin-deficient mice had mild elevations in basal caspase-3, they still up-regulated this caspase in response to IL-18, albeit at markedly lower levels compared with WT mice. IL-18 induced marked TUNEL positivity in these mice (Fig. 6, C and D) and fully protected gasdermin-deficient mice against RV infection (Fig. 6E). These results argue that IL-18induced cell death and associated clearance of RV are not mediated by pyroptosis.

(A to D) Gasdermin-deficient, or WT, mice were administered PBS or IL-18 (2 g) 3 days after mRV inoculation. Mice were euthanized 6 hours later and jejunums were analyzed. (A and B) IEC were analyzed by SDS-PAGE immunoblotting for detection of gasdermin D, cleaved gasdermin D, and cleaved caspase-3, respectively. (C) Cell death by TUNEL, counterstained with DAPI. (D) Quantitation of TUNEL-positive cells at villus tip region based on visual counts. Experiments included five mice per condition. Data in (D) was based on assay 6 to 8 villi per mouse, which are indicated by data points ****P < 0.0001 by Students t test. (E) Gasdermin-deficient mice were administered PBS or IL-18 (2 g) via intraperitoneal injection, 2 hours before, or 2, 4, 6 or 8 days after (indicated by arrows), oral inoculation with mRV. Fecal RV levels were measured over time by ELISA. Data are means SEM. n = 5. * indicates significantly different from control by two-way ANOVA, P < 0.0001.

We examined the extent by which IL-22induced IEC extrusion and IL-18induced IEC death were associated with RV reduction in the ileum at 6 and 24 hours after administration of these cytokines. We measured the levels of RV genomes and the ratio of positive to negative (+/) RV strands in both the lumen and IEC, which reflects levels of active replication because most positive strands encode RV proteins and do not get incorporated into virions (24). In accord with our previous work, we observed that, in the epithelium, both IL-22 and IL-18 led to a clear reduction in both the level of RV genomes and RV replication by 6 hours (Fig. 7, A and B). In contrast, the small intestinal lumen had a marked but variable increase in the level of RV genomes and a stark increase in RV +/ strand ratios 6 hours after administration of IL-18 with the combination of IL-18 and IL-22 but not IL-22 alone (Fig. 7, C and D). By 24 hours, levels of RV in the lumen had dropped markedly, whereas the miniscule levels of remaining virus appeared to not be actively replicating (Fig. 7, E and F). Collectively, these results support a model wherein IL-18induced cell death interrupts active RV replication, spewing incompletely replicated virus into the lumen while IL-22 induces IEC migration and subsequent extrusion of the mature IEC that RV targets, thus together working in concert to resolve RV infection.

mRV-infected mice were intraperitoneally injected with PBS, IL-22 (10 g), IL-18 (2 g), or both cytokines on day 3 post-mRV inoculation. Six or 24 hours later, mice were euthanized, and contents of jejunums were isolated. RNA was extracted and used to measure of mRV genomes and replication status as reflected by NSP3 RNA levels and the ratio of NSP3 (+) RNA strand to complimentary NSP3 () RNA strand. (A and B) The overall mRV genome and efficacy of virus replication in small intestinal epithelial cells. (C to F) The overall mRV genome and efficacy of virus replication in luminal content from small intestine (one-way ANOVA, n = 5 to 10, *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001).

The central focus of this study was to determine the mechanisms by which IL-18 and IL-22, which are elicited by bacterial flagellin, contribute to preventing or curing RV infection. We initially considered that the ability of IL-18 and IL-22 to promote each others expression allowed them to use a shared mechanism to promote RV clearance. We found that irrespective of such mutual promotion, IL-18 and IL-22 both impeded RV independent of each other and did so by distinct mechanisms, which is illustrated in Fig. 8. Specifically, IL-22 drove IEC proliferation and migration toward villus tips, thus accelerating the ongoing process of extrusion of highly differentiated IEC at the major site of RV replication. In contrast, administration of IL-18 to RV-infected mice induced rapid cell death, as defined by TUNEL, at villus tips where RV is localized. Such induction of TUNEL positivity, which is not typically seen at significant levels in the intestine, was associated with rapid abortion of the RV replication cycle followed by a marked reduction of RV antigens in the intestinal tract. These actions of IL-22 and IL-18 together resulted in rapid and complete expulsion of RV, thus providing a mechanism that explains how this combination of cytokines prevents and cures RV infection.

IL-22 increases epithelial proliferation thus increasing extrusion of epithelial cells, including RV-infected cells. Into lumen the intestinal lumen, i.e., anoikis. IL-18 induces rapid cell death, associated with loss of cell rupturing of RV-infected cells.

RV does not induce detectable increases in IL-22 expression nor does genetic deletion of IL-22 appear to markedly augment RV infection (5), thus arguing that IL-22 does not normally play a major role in clearance of this pathogen. The known cooperation of IL-22 and interferon- in activating antiviral gene expression (3) suggests the possibility that RV may have evolved strategies to deliberately avoid or block IL-22 induction. Nonetheless, the downstream action of IL-22, particularly its promotion of IEC turnover, may be shared by endogenous anti-RV host defense mechanisms. The role of adaptive immune-independent host defense against RV is most easily appreciated in immune compromised mice wherein RV loads decline markedly from their peak levels, but it may also play a role in protecting against RV even in immune competent mice. Innate host defense against RV is likely multifactorial and may involve type III interferon (3), particularly in neonate mice. Our observations in adult mice indicate that RV infection increases IEC extrusion, and this mechanism combined with previous observations that RV infection activates intestinal stem cell proliferation suggests that increased IEC turnover may limit RV infection (2). We do not think that such a mechanism is necessarily unique to IL-22 as EGF has ability to drive similar events. Moreover, we recently showed that SFB also drives enterocyte proliferation independent of IL-22 and is not required for adaptive immunity (23). Hence, we presume that IL-22 can activate a primitive mechanism of host defense against a variety of challenges, especially those affecting IEC.

IEC are rapidly proliferating cells with average lifetimes of about 3 days (24), which means that the intestine must eliminate vast numbers of cells continuously. The overwhelming majority of IEC are eliminated via cell extrusion at villus tips through a process termed anoikis. A central tenet of anoikis is that cells remain alive at the time of extrusion followed by the lack of attachment to other cells resulting in induction of a programmed death process (25). A key aspect of this process is that cells can be eliminated without comprising gut barrier function, thus avoiding infection and inflammation that might otherwise occur. Accordingly, administration of IL-22 is associated with few adverse effects and has been shown to resolve inflammation in several different scenarios. (26). Moreover, IL-22 plays a broad role of maintaining gut health in the intestinal tract, including mediating microbiota-dependent impacts of dietary fiber (27). It is possible that increasing anoikis via IL-22 results in extrusion of RV-containing cells in a manner that prevents viral escape and, consequent infection of other IEC. However, inability of IL-22 to induce detectable increases in luminal RV argues against this possibility. Rather, we envisage that the cell death process after IEC extrusion might result in destruction of RV in these cells. We also hypothesize that the accelerated IEC turnover induced by IL-22 may result in villus IEC being less differentiated and less susceptible to RV infection. In accord with this possibility, we observed that that flagellin administration resulted in an IL-22dependent increase in CD44+26 IEC (fig. S5), which are known to be RV resistant (28). It is difficult to discern the relative importance of IL-22 in the induction of IEC extrusion versus its impact on differentiation state of villus IEC. IL-22induced reduction in RV levels in chronically infected Rag-1/ mice occurs over a course of several days that supports a role for the latter mechanism. Use of IL-22 receptor bone marrow chimera mice demonstrated that IL-22 acts directly on IEC to affect RV infection. (7). IL-22induced signaling is generally thought to be mediated by STAT3 (5, 10), and IL-22 induced phosphorylation of STAT3 in IEC in vivo. However, we observed that IEC-specific STAT3-knockout mice could still be protected against RV by IL-22, suggesting that this mechanism of action may not proceed by a characterized signaling mechanism (fig. S6). Thus, how the IL-22 receptor signals to affect IEC phenotype remains incompletely understood.

In contrast to IL-22, recent work indicates that induction of IL-18 plays a role in endogenous immunity against RV, wherein caspase-1mediated IL-18 production results from activation of the NLR9pb inflammasome. Such IL-18 induction paralleled gasdermin-dependent cell death, the absence of which resulted in delayed clearance of RV (29, 30). On the basis of this work, we hypothesized that exogenously administered IL-18 might enhance RV-induced death of RV-infected cells and/or increase IEC turnover analogous to IL-22. Administration of IL-18 in the absence of RV elicited a modest increase in the number of TUNEL-positive cells as well as a modest increase in IEC proliferation/migration that was not accompanied by increased IEC extrusion, suggesting the increased proliferation compensated for cell death. However, TUNEL-positive cells were scattered along the villus. In RV-infected mice, IL-18 led to TUNEL-positive cells at the villus tips, which is also the primary site of RV infection. It is tempting to envisage localized impacts of IL-18 reflect the pattern of expression of the IL-18 receptor, including localization to villus tips and/or induced by RV, but limited knowledge of the determinants of its expression and lack of available reagents to study it render these ideas as speculative.

The manner of IL-18induced cell death, namely, its notable TUNEL induction, which was associated with spewing of RV replication intermediates, suggested pyroptotic cell death. However, we found that lack of gasdermin D and E, which are thought to be essential for pyroptosis, did not impede IL-18induced cell death in RV-infected cells thus arguing such cell death does not fit perfectly into any known cell death pathways. Induction of IL-18 receptor-mediated signaling by itself is not sufficient to induce cell death in villus tip epithelial cells but triggers death in cells primed as a result of RV infection. The nature of such priming is not understood but may involve IEC signaling pathways, including NLR9pb, TLR3, and RNA-activated protein kinase, which are capable of recognizing RV components and/or responding to intracellular stress in general (3032). In this context, the ability of IL-22 to enhance IL-18induced TUNEL positivity in RV-infected cells may reflect an intersection of IL-22-R and IL-18-R signaling or be a manifestation of these cytokines to promote each others expression.

The central limitation in our study was that our approaches were largely correlative. Specifically, we lacked modalities to specifically block IEC migration or cell death in response to IL-22 and IL-18, respectively. Another limitation is that we were not able to demonstrate that the TUNEL-positive cells actually contained RV. Our attempts to do so via double-staining were not successful, possibly reflecting that the disappearance of RV after cytokine treatment likely occurs early in the cell death process while the DNA fragmentation that underlies TUNEL positivity is considered a late event in the cell death process. Thus, more specific identification of processes that mediate cell death of RV-infected IEC in response to IL-18 is an important target of future studies.

The improved understanding of the mechanism by which IL-18/22 controls RV infection reported herein should inform use of these cytokines to treat viral infection in humans. Chronic RV infections can occur in immune compromised humans, suggesting that IL-18/22 may be explored as a possible treatment for this and other chronic viral infections. Our results suggest that this cytokine treatment may be effective for viruses that preferentially infect villus epithelial cells and possibly other epithelia that have high cell turnover rates. In contrast, this combination of cytokines seems unlikely to affect viruses that inhabit more long-lived cells, including hematopoietic cells that are generally not responsive to IL-22. We observed that flagellin and IL-18/22 has some efficacy against reovirus, particularly early in infection when it infects gut epithelial cells, as well as some efficacy against influenza, which initially infects lung epithelial cells, but did not show any impact on hepatitis C virus as assayed in mice engrafted with human hepatocytes, which are thought to be long-lived cells. IL-18/22 can protect mice against norovirus infection, which infects B cells and tuft cells (33, 34), but human norovirus is thought to primarily infect epithelial cells, particularly in immunocompromised persons who develop chronic norovirus infections (35). SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19) has also been observed to replicate in IEC (36), and like RV, appears to replicate in mature IEC, which express the SARS-CoV-2 receptor angiotensin-converting enzyme 2. Intestinal replication of SARS-CoV-2 is thought to contribute to extrarespiratory pathologies associated with COVID-19 (37). As such, the use of IL-18/22based therapy may be a potential strategy to treat chronic RV and/or norovirus infections in person with immune dysfunction and, moreover, might serve to mitigate severe cases of COVID-19.

This study sought to ascertain the mechanism by which IL-22 and IL-18 prevent and cure RV infection. Mice were orally administered RV. Extent of infection was assayed my measuring viral genomes and proteins in the intestine. IL-18 and or IL-22 were administered to mice with various genetic deficiencies. Cell extrusion and cell death were measured. All procedures involving mice were approved by GSUs animal care and use committee (Institutional Animal Care and Use Committee no.17047).

All mice used herein were adults (i.e., 4 to 8 weeks old) on a C57BL/6 background bred at Georgia State University (GSU) (Atlanta, GA). RV-infected mice were housed in an animal biosafety level 2 facility. WT, Rag-1/, IL-18/, IL-18-R/, Stat3flox, and Villin-cre were purchased from the Jackson laboratory (Bar Harbor, ME, USA). NLRC4/, IL-22/, and IL-22-R/ mice were provided by Genentech (South San Francisco, CA, USA). TLR5/ and TLR5//NLRC4/ and WT littermates were maintained as previously described (5). Gasdermin D/E/ mice, whose generation and initial characterization were previously described (22), were shipped to GSU and studied in original and cross-fostered state as indicated in results.

Murine Fc-IL-22 was provided by Genentech Inc. Murine IL-18 was purchased from Sino Biological Inc. (Beijing, China). Procedures for isolation of flagellin and verification of purity were described previously (5). Recombinant murine EGF (mEGF) was purchased from PeproTech.

Age- and sex-matched adult mice (8 to 12 weeks of age) were orally administered 100 l of 1.33% sodium bicarbonate (Sigma-Aldrich) and then inoculated with 105 SD50 of murine RV EC strain. Approach used to determine SD50 has been described previously (5).

Five-week-old Rag-1/ mice were infected with murineRV (same infection procedure as described in the Acute models section). Feces were collected 3 weeks after RV inoculation to confirm the establishment of chronic infection.

Cell culture-adapted rhesus RV (RRV) was trypsin-activated [trypsin (10 g/ml)] in serum-free RPMI-1640 (cellgro) at 37C for 30 min. The basolateral side of the polarized Caco-2 cells was stimulated with cytokines, 1.5 hours before expose to RRV infection as previously described (5). The upper chamber of transwells was infected with trypsin-pretreated RRV and allowed to adsorb at 37C for 40 min before being washed with serum-free medium. The presence of cytokines was maintained at a constant level throughout the experiment.

Fecal pellets were collected daily from individual mouse on days 0 to 10 after RV inoculation. Samples were suspended in phosphate-buffered saline (PBS) [10% (w/v)], after centrifugation, supernatants of fecal homogenates were analyzed by ELISA, and after multiple serial dilutions, more detailed descriptions of experimental procedures are previously described (5).

Mice were subjected to x-ray irradiation using an 8.5 gray (Gy) equivalent followed by injection of 2 107 bone marrow cells administered intravenously as previously described (5). All mice were afforded an 8-week recovery period before experimental use. For the first 2 weeks after transfer, mice were maintained in sterile cages and supplied with drinking water containing neomycin (2 mg/ml) (Mediatech/Corning).

Intestinal sections were fixed in methanol-Carnoys fixative solution (60% methanol, 30% chloroform, and 10% glacial acetic acid) for 48 hours at 4C. Fixed tissues were washed two times in dry methanol for 30 min each, followed by two times in absolute ethanol for 20 min each, and then incubated in two baths of xylene before proceeding to paraffin embedding. Thin sections (4 m) were sliced from paraffin-embedded tissues and placed on glass slides after floating on a water bath. The sections were dewaxed by initial incubation at 60C for 20 min, followed by two baths in prewarmed xylene substitute solution for 10 min each. Deparaffinized sections were then hydrated in solutions with decreasing concentration of ethanol (100, 95, 70, 50, and 30%) every 5 min in each bath. Last, slides allowed to dry almost completely and were then mounted with ProLong antifade mounting media containing 4,6-diamidino-2-phenylindole (DAPI) before analysis by fluorescence microscopy.

Intestinal sections were fixed in 10% buffered formalin at room temperature for 48 hours and then embedded in paraffin. Tissues were sectioned at 4 m thickness, and IEC death was detected by TUNEL assay using the In Situ Cell Death Detection Kit, Fluorescein (Roche) according to the manufacturers instructions.

IECs lysate (20 g per lane) was separated by SDSpolyacrylamide gel electrophoresis through 4 to 20% Mini-PROTEAN TGX gel (Bio-Rad, USA), transferred to nitrocellulose membranes, and analyzed by immunoblot, as previously described (5). Briefly, isolated IEC was incubated with radioimmunoprecipitation assay lysis buffer (Santa Cruz Biotechnology, USA) for 30 min at room temperature. Subsequently, cell lysates were homogenized by pipette and subjected to full-speed centrifugation. Protein bands were detected for cleaved caspase-3, phosphor-STAT3, and anti-actin (Cell Signaling Technology) and incubated with horseradish peroxidaseconjugated anti-rabbit secondary antibody. Immunoblotted proteins were visualized with Western blotting detection reagents (GE Healthcare) and then imaged using the ChemiDoc XRS+ system (Bio-Rad).

The entire small intestine was harvested from mice according to indicated experimental design and sliced longitudinally before being washed gently in PBS to remove the luminal content. Tissues were processed and maintained at 4C throughout. Cleaned tissue samples were further minced into 1- to 2-mm3 pieces and shaken in 20 ml of Hanks balanced salt solution (HBSS) containing 2 mM EDTA and 10 mM Hepes for 30 min. An additional step of vigorous vortexing in fresh HBSS (10 mM Hepes) after EDTA incubation facilitated cell disaggregation. IECs were then filtered through 70-m nylon mesh strainer (BD Biosciences), centrifuged, and resuspended in PBS.

Bulk leukocytes and IECs isolated above were incubated with succinimidyl esters (NHS ester)Alexa Fluor 430, which permitted determination of cell viability. Cells were then blocked by incubation with anti-CD16/anti-CD-32 (10 g/ml) (clone 2.4G2, American Type Culture Collection). Twenty minutes later, cells were stained with fluorescently conjugated antibodies: CD26-PE (clone H194-112, eBioscience), CD44-PECy7 (clone IM7, eBioscience), CD45fluorescein isothiocyanate (clone, 30-F11, eBioscience), and CD326-allophycocyanin (clone G8.8, eBioscience). Last, stained cells were fixed with 4% formaldehyde for 10 min before whole-cell population was analyzed on a BD LSR II flow cytometer. Collected data were analyzed using FlowJo.

Host DNA was quantitated from 100 mg of luminal content (100 mg) from small intestine by using the QIAamp DNA Stool Mini kit (Qiagen) and subjected to qPCR using QuantiFast SYBR Green PCR kit (Bio-Rad) in a CDX96 apparatus (Bio-Rad) with specific mouse 18S oligonucleotides primers. The sense and antisense oligonucleotides primers used were: 18s-1F: 5-GTAACCCGTTGAACCCCATT-3 and 18s-1R: 5-CCATCCAATCGGTAGTAGCG-3. PCR results were expressed as actual numbers of IEC shedding per 100 mg of luminal content, calculated using a standard curve, which was generated using twofold serial dilutions of mouse colon carcinoma cell line MC26. DNA was extracted from each vial with known number of MC26 cells after serial dilutions, and then real-time qPCR was performed. The cycle quantification (Cq) values (x axis) are inversely proportional to the amount of target genes (18S) (y axis), and a standard curve is applied to estimate the numbers of cell shedding from luminal content based on the quantity of target copies (18S) from each sample.

To extract RNA, cell pellets were homogenized with TRIzol (Invitrogen), and chloroform was added to the homogenate to separate RNA (an upper aqueous layer) from DNA and proteins (a red lower organic layer). Isopropanol facilitated the precipitation of RNA out of solution, and after centrifugation, the impurities were removed by washing with 75% ethanol. RNA pellets were resuspended in ribonuclease-free water and underwent quantitative reverse transcription PCR. Total RNA from luminal content was purified from the RNeasy PowerMicrobiome Kit according to the manufacturers instructions. Primers that target non-structural protein 3 region: EC.C (+) (5-GTTCGTTGTGCCTCATTCG-3 and EC.C () (5-TCGGAACGTACTTCTGGAC-3) were applied to quantify viral genomes from IEC and luminal content. RV replication was quantitated as previously described (38).

A pulse-chase experimental strategy was used to label intestinal enterocytes with BrdU to estimate the IEC migration rate along the crypt-villus axis over a defined period of time. Briefly, 8-week-old mice were intraperitoneally injected with either PBS or cytokine(s) (IL-22 and/or IL-18) 1 hour before BrdU treatment (50 g/mg of mice body weight, ip). After 16 hours, mice were euthanized, and a segment of the jejunum were resected, immediately embedded in optimal cutting temperature compound (OCT) (Sigma-Adrich) and then underwent tissue sectioning. Tissue sections (4 m) were firstly fixed in 4% formaldehyde for 30 min at room temperature and then washed three times in PBS. DNA denaturation was performed by incubating the sections in prewarmed 1.5 N HCl for 30 min at 37C, and then acid was neutralized by rinsing sections three times in PBS. Before BrdU immunostaining, sections were blocked with rabbit serum (BioGenex, Fremont, CA) for 1 hour at room temperature, then incubated with anti-BrdU (Abcam) 2 hours at 37C, and counterstained with DAPI. The BrdU-labeled cells were visualized by fluorescence microscopy.

The proximal jejunum was imbedded into OCT compound, and then sliced into 6-m-thin sections. Tissue slides were incubated in 4% paraformaldehyde for 15 min, followed by 5 min washing of PBS twice. Autofluorescence caused by free aldehydes was quenched by incubating slides in 50 mM NH4Cl in PBS or 0.1 M glycine in PBS for 14 min at room temperature, followed by 5 min PBS washing three times. Bovine serum albuminPBS (3%) was used to block the tissue samples for 1 hour at room temperature. The slides were then washed with PBS for 5 min, followed by incubation with primary antibody (1:100; hyperimmune guinea pig anti-RRV serum) in blocking buffer overnight at 4C. After slides were washed three times with PBS, secondary antibody (donkey antiguinea pig immunoglobulin G, Jackson ImmunoResearch, 706-586-148) was applied to the sample slides for 1 to 2 hours at room temperature. The fluorescence emission of mRV antigen was detected by fluorescence microscopy.

Significance was determined using the one-way analysis of variance (ANOVA) or students t test (GraphPad Prism software, version 6.04). Differences were noted as significant *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

Funding: This work was supported by NIH grants DK083890 and DK099071 (to A.T.G.). J.Z. is supported by career development award from American Diabetes Association. B.C. is supported by a Starting Grant from the European Research Council, an Innovator Award from the Kenneth Rainin Foundation, and a Chaire dExcellence from Paris University. Author contributions: Z.Z. led performance of all experiments. J.Z. and Z.S. helped with specimen analysis. B.Z., L.E.-M., Y.W., and B.C. advised in experimental design and data interpretation. X.S. and F.S. provided advice and key reagents. A.G. helped design study and drafted manuscript. Competing interests: A.T.G. and B.Z. are inventors on patent application (WO2015054386A1 WIPO) held by GSU that covers Prevention and treatment of rotavirus infection using IL-18 and IL-22. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. All mice are either commercially available or available under a material transfer agreement.

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