Archive for September, 2017

PUBLISHED: 18:08 31 August 2017 | UPDATED: 18:08 31 August 2017

Mia Jankowicz

The Gene and Cell Therapy Catapult is due to open in Autumn 2017. Picture: Daniel Buman

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The Cell and Gene Therapy Catapult is making its home at the Stevenage Bioscience Catalyst campus in Gunnels Wood Road, and is due to open in autumn 2017.

Now an extra 12 million in government funds will go towards fitting out the buildings second floor.

The centre had already attracted 55 million of funding in 2014 from the Department for Business, Innovation and Skills (now the Department for Business, Energy & Industrial Strategy).

The extra funds will double the centres capacity and at full capacity it is predicted to bring 1.2 billion in revenue by 2020.

Chief executive officer Keith Thompson explained to the Comet that Stevenage was a good fit for the site, with the towns closeness to airports as well as the presence of other scientific expertise all big positives.

We went through a very rigorous search across the UK for our site, said Mr Thompson.

Theres a strong pedigree of pharmaceuticals around the area.

Stevenages workforce also stands to benefit, with the potential creation of around 180 support jobs.

The Cell & Gene Therapy Catapult has a mission to accelerate the UKs cell therapy industry and to make Stevenage an industry world leader.

Currently, one problem holding up cell research globally is the low availability of the large numbers of cells needed to perform large-scale clinical trials.

The 7,200-square-metre facility will allow UK businesses that are developing new cell therapy treatments to use its labs to manufacture cells for clinical trials at a large scale.

Cell and gene therapies are showing potential worldwide to combat numerous illnesses.

At the frontier of medical science, cell therapy is a technique which involves the injection of living cells into the human body in order to repair the direct causes of genetic diseases.

For example, the Cell & Gene Therapy Catapult played a large role in the creation of modified cells that are trained to recognise a certain protein in leukaemia cells, and then attack and destroy the cancerous cells.

To find out more visit http://www.ct.catapult.org.uk.

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Stevenage-based Cell and Gene Therapy Catapult gets 12 million ... - Comet 24

Could junk DNA protect our hearts?

Scientists at the University of California at Los Angeles and the Howard Hughes Medical Institute reported that they successfully used gene therapy to lower cholesterol in mouse models of familial hypercholesterolemia. The gene they used, called LeXis, was once considered junk DNA because it seemed to serve no purpose. But when the researchers gave the mice LeXis and then fed them a high-cholesterol diet for 15 weeks (think cheeseburgers and fries), their cholesterol went down, artery blockages opened up andless fat appeared to build upin their livers. The research was published in the journal Circulation. Release

Researchers at the Francis Crick Institute have discovered that acute myeloid leukemia (AML) causes bone marrow to leak blood, which in turn impedes the proper delivery of chemotherapy. So they tried mixing chemo with experimental drugs designed to treat heart and blood vessel disorders, and the results were promising. In mouse models of AML and in human tissue samples, the heart drugs stopped the leaks and the chemo became more effective, the researchers reported in the journal Cancer Cell. They believe the findings may point to a potential new combination of treatments for AML. Release

Researchers at Columbia University have completed mouse studies suggesting that a hormone produced by bone cells, osteocalcin, may be useful in reversing memory loss that occurs as part of aging. They gave aged mice continuous infusions of the hormone for two months and observed improvements on two different memory tests. Similar results were seen when the mice were given plasma from young mice, which have naturally high levels of osteocalcin. They plan to do more research to determine whether their findings, published in the Journal of Experimental Medicine, can be translated to drug therapies for people. Release

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News of NoteGene therapy to protect the heart; boosting chemo with cardio drugs; reversing memory loss - FierceBiotech

Personalized cancer treatments known as CAR-T cells (chimeric antigen receptor T cells) have dominated the headlines lately, thanks to Novartis tisagenlecleucel, which won an early approval from the FDA for the treatment of leukemia on Aug. 30. But CAR-T treatments are labor-intensive and expensive to make, and they can attack healthy tissues in the body, leading to dangerous side effects.

Scientists at the Fred Hutchinson Cancer Research Center have developed a tool that they believe could address both those shortcomings of CAR-T and other forms of cell engineering. They have invented nanoparticles that deliver proteins to cells, which in turn edit those cells genes temporarily. Lead author and bioengineer Matthias Stephan describes it as hit-and-run gene therapy, and he believes the technique will streamline the manufacturing of cell-based therapies.

Heres how it works: The nanoparticles home in on specific cells, such as the T cells in the immune system. They then deposit messenger RNA (mRNA) to those cells, which triggers short-term changes in the proteins the genes produce. The technology does not permanently change the DNA, but it makes enough of an impact on it to produce a therapeutic outcome.

RELATED: Can CAR-T cancer treatments be fine-tuned to avoid toxic side effects?

Whats more, the nanoparticles can be freeze-dried and then activated with a small amount of water. They really let you fulfill all your wishes as a genetic engineer because you can pack in all your different [gene-therapy] components and further improve the therapeutic potential of your cell product without additional manufacturing steps, Stephan said in an article posted on Fred Hutchs website.

Stephans team proved out their concept by testing the nanoparticles in three different cell-engineering applications, one of which was CAR-T. Currently, CAR-T treatments are made by giving T cellsgenes that teach them to destroy cancer cells. The Fred Hutch scientists used their nanoparticles to remove a different gene from T cellsone that normally prompts them to attack healthy tissue.

Then they tried enhancing the CAR-T cells in a different manner. They temporarily gave them genes that have the potential to make central memory T cells, which are able to survive over the long term, remembering their cancerous targets and attacking them should they ever resurface.

The scientists tested their engineered CAR-T cells in mouse models of leukemia and found that the animals that received them lived twice as long as mice that got conventional CAR-T cells. They also tested the nanoparticles in two other cancer-related applications of gene therapy.

Despite all the excitement over CAR-T, concerns about side effects continue to dog the field. A dangerous immune reaction known as a cytokine storm has been seen in trials of both Novartis treatment and Axi-Cel, a CAR-T from Kite Pharma, which is being acquired by Gilead. The third player in the CAR-T field, Juno Therapeutics, saw its late-stage trials delayed when some patients died of neurological side effects.

Fred Hutch scientists have been working on other techniques for improving CAR-T. In December, a set of researchers there who receive funding from Juno announced positive results from a trial of a fine-tuned CAR-T treatment in patients with chronic lymphocytic leukemia (CLL). Instead of using just one type of CAR-T, the team combined two specially selected cell subtypes into one treatment. They also announced they had identified biomarkers that they believe can be used to predict which patients are likely to have severe reactions to the treatment.

Stephans team is now collaborating with several companies to fine-tune CAR-T treatments for cancer, according to Fred Hutch. And they believe their freeze-dried nanoparticles may prove useful in developing treatments for a range of other diseases, too, including HIV and blood disorders caused by defective hemoglobin.

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'Hit-and-run' gene therapy nanoparticles could enhance CAR-T ... - FierceBiotech

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Penn Medicine researchers made huge strides in the medical world Wednesday when the Food and Drug Administration approved a gene-altering cancer treatment that they designed. It's the first of its kind to be approved.

The therapy is marketed as Kymriah and made by Novartis, but was originally developed at Penn by Carl June, a Penn Medicine professor in immunotherapy, and his team, The New York Times reported. The treatment, which is the first-of-its-kind in the United States, uses the patient's genetically altered immune cells to fight the disease.

The FDA called the gene therapy a "historic" act.

Timothy Cripe, an oncologist with Nationwide Children's Hospitalin Columbus, Ohio, referred to the research as the "most exciting thing I've seen in my lifetime," The Washington Post reported.

The treatment is meant for children and young adults with B-cell acute lymphoblastic leukemia, especially those who don't respond well to traditional treatment methods.

According to the New York Times, the first child to receive the therapy was Emily Whitehead in 2012. Whitehead was severely ill from leukemia in 2012, but after treatment, has been free from cancer for more than five years.

Penn researchers have been working on approving this treatment method for years. In 2011, the results of the CAR-T cell therapy, as the treatment was initially called, were published in the New England Journal of Medicine and Science Translational Medicine by June and his team. It was the first demonstration of the use of gene transfer therapy to create serial killer T cells targeting cancerous tumors, according to a press release by the Penn medical school.

A year later, the University partnered with Swiss pharmaceutical company Novartis to continue research on immunotherapy research. At the time, the collaboration was the largest academic-industry agreement in Penns history.

In 2016, Penn Medicine, along with five other peer institutions, partnered with The Parker Institute for Cancer Immunotherapy after receiving a $250 million grant to develop new techniques for cancer treatment.

Novartis said the gene-therapy would cost $475,000 and would be available at an initial network of 20 approved medical centers, as the treatment is hard to administer.

I have to keep pinching myself to see that this happened, June said to The New York Times. It was so improbable that this would ever be a commercially approved therapy, and now its the first gene therapy approved in the United States. Its so different from all the pharmaceutical models. I think the cancer world is forever changed.

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A 'historic' cancer treatment designed by Penn researchers just got approved by the FDA - The Daily Pennsylvanian

FINDINGS

Scientists from UCLA and the Howard Hughes Medical Institute successfully used a gene that suppresses cholesterol levels as part of a treatment to reduce plaque in mice with a disorder called familial hypercholesterolemia. In a preclinical study, researchers found that the gene, LeXis, lowered cholesterol and blockages in the arteries, and the treatment appeared to reduce the build-up of fat in liver cells.

Familial hypercholesterolemia is an inherited condition characterized by extremely high levels of low-density lipoprotein cholesterol (commonly referred to as bad cholesterol) and an increased risk of early heart disease.

The LeXis gene belongs to a unique group of genes that until recently were considered junk DNA because scientists believed they served little purpose. However, evidence from the human genome project led to the discovery that genes like LeXis are actually active. The study of these genes,now referred to as long noncoding ribonucleic acids, or lncRNAs, is a rapidly evolving area in biology.

Researchers wanted to test whether a single injection of LeXis could slow the development of heart disease. To do so, they gave the mice either LeXis or a control gene, and fed them a 15-week diet consisting of food high in sodium and cholesterol the mouse equivalent of fast-food hamburgers and french fries. Researchers then measured the progression of heart disease.

In the next phase of the study, researchers intend to confirm the findings in larger animals and test the therapy in combination with currently available treatments.

Although previous research has shown that lncRNAs can be important, this is the first study to show that they could potentially be used to treat a human disease using gene therapy. Junk genes could one day offer a framework for treating people with familial hypercholesterolemia and other conditions that are otherwise very difficult to treat.

The papers authors are Xiaohui Wu, Zhengyi Zhang and Dr. Tamer Sallam of UCLA; and Dr. Peter Tontonoz, Marius Jones and David Salisbury of the Howard Hughes Medical Institute.

The study waspublished onlinein the journal Circulation.

The research was supported by grants from the National Heart, Lung, and Blood Institute; the American College of Cardiology; and the Lauren B. Leichtman and Arthur E. Levine UCLA Cardiovascular Discovery Fund.

Learn more about the cardiovascular research theme at UCLA.

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Gene therapy using 'junk DNA' could lower risk for heart disease - UCLA Newsroom

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Dr. Gregory Yanik, clinical director of the Pediatric Blood and Marrow Transplantation Program at C.S. Mott Children's Hospital in Ann Arbor, works with Maryam Rasheed of Macomb Township. Maryam was part of a clinical trial using gene therapy to successfully treat her leukemia.(Photo: Sophie Masson/Michigan Medicine)

The U.S. Food and Drug Administrationapproved on Wednesdaythe first-ever gene therapytotreat children and young adults withleukemia.

Called Kymriah, but better known as CAR T-cell treatment, the therapy is being hailed by doctors as revolutionary. Itinvolves genetically modifyinga patient's own T-cells, which thencantarget and kill a form of acute lymphoblastic leukemiacells.

This new treatment has the potential to change the face of cancer therapy for years to come, not just in childhood acute lymphoblastic leukemia but in other cancers in which a patients own T-cells can be collected, genetically modified and redirected to kill a patients tumor," said Dr.Gregory Yanik, clinical director of the Pediatric Blood and Marrow Transplantation Program at the University of Michigan's C.S. Mott Children's Hospital. Mottwas one of a few hospitals nationally to take part inclinical trials of the treatment.

"This allows us to turn patients own cells into a powerful weapon to fight the disease a weapon that does not rely on chemotherapy but takes a whole new approach to attacking childhood leukemia, Yanik said.

The CAR T-cell treatmentoffers new hope for children like Maryam Rasheed, 10, of Macomb Township.

Maryam was diagnosed with B-cell acute lymphoblastic leukemia at age 4, when her family was seeking refuge from religious persecution in Turkey, said Maryam's mother, Asmaa Rasheed.

Maryam Rasheed (right) with her brother, Rashid, and sister Samantha. Maryam, 10 of Macomb Township, survived acute lymphoblastic leukemia.(Photo: Rasheed family photo)

"My country is Iraq," Asmaa Rasheedsaid. "It wasnt safe. We are Christian. It was so hard over there in Baghdad. We run away to Turkey.

"We take her to hospital the first timebecause ... she stopped eating, stopped walking, stopped talking. We bring her to emergency. The doctor decided to take her bone marrow to do tests. Then the results came back, and she have leukemia."

Maryam underwent her firstchemotherapy treatment in Turkey.

"Over there, it was so hard," Rasheed said. "The doctors dont speak English over there. We know English a little bit. We speak Arabic."

Maryam Rasheed of Macomb Township undergoes treatment for acute lymphoblastic leukemia. She is now in remission.(Photo: Rasheed family photo)

Rasheed stayed with her daughter for two months in the Turkish hospital. A few months later,the Rasheed family was able to immigrate to the U.S. and settled in Michigan.

But Maryam's cancer returned. She was treated at Children's Hospital of Michigan with more chemotherapy and radiation. In 2013,her younger brother, Rashid, proved to be a match for a bone marrow transplant.

Still, the cancer wouldn't relent.

The Rasheed family learned of a clinical trial for CAR T-cell therapy under way atMott. It was the family's last chance,Rasheed said.

Maryam Rasheed, 10, of Macomb Township holds up her arms joyfully. She's surrounded by her sister Samantha (left), brother, Rashid, and baby sister Annabell.(Photo: Rasheed family photo)

"There was nothing to do," her mother said."In Detroit, there was chemo, radiation, bone marrow transplant. It returned back three times. She lose her hair three times. It was so hard for her and my family."

She remembers the date Maryam started the clinical trial at Mott: Dec. 17, 2014. Maryam spent Christmas and her seventh birthday in the hospital.

"I think we waited like 100 days,I dont remember exactly, and they did a bone marrow test, and the medicine, it work!" Rasheed said.

"It was like a dream, you know, like light coming from far away when youre in the dark. Theres nothing else we could do. But the CART-cell was like a shining light from far away."

Maryam has been in remission two years, andis starting fourth grade next week at Shawnee Elementary School in Macomb Township.

"Now, shes start her life, and doing everything a little kid is doing," said Rasheed, who says she hopes the treatment helps other children, too.

So does Yanik.

"Acute lymphoblastic leukemia is the most common form of cancer in children, accounting for approximately25% of all childhood cancers," Yanik said. "This particular therapy utilizes a childs own immune system to target their leukemia."

Theclinical trials focused on the 15% to 20% ofchildren whoseB-cell acute lymphoblastic leukemia had either relapsed or who had residual leukemia cells in their bone marrow after treatment.

"Historically, such patients would have an estimated cure rate of approximately 10%," Yanik said. "The two trials were groundbreaking. In the most recent trial, 52 of 63 patients with childhood leukemia successfully entered complete remission with this therapy."

Novartis Pharmaceuticals Corp. got the FDA approval for the gene cell therapy, whichinvolves drawing blood from childrenwith B-cell acute lymphoblastic leukemia. The T-cellsin the child's blood are thenshipped to a lab where they are genetically engineered so theywillseek outa particular protein in the leukemia cells and attack. Patients are then infused with the modified blood, and the T-cells go to work to find and kill the leukemia.

The New York Times reported Wednesday that the therapy will cost $475,000 for the initial treatment, with additional treatments administered at no cost.

Although 83% of the children in the clinical trials for CAR T-cell therapy went into remission, Yaniksaid it's too early to tell howcurative treatmentswill prove in the long run. And, its use will be limited to only a few medical centers in the U.S.

"The University of Michigan is the only site in the state and within this region that is licensed to administer these cells for childhood leukemia," he said.

Offering the treatment at a large medical center like U-Mis essential, said Dr. Rajen Mody,a pediatric oncologist at Mott, because of the severity ofpotential side effects.

"It can cause serious side effects, especially within the first 21 days," said Mody, who is Mott's director of pediatric oncology. "Patients can have high fevers, bleeding complications, trouble breathing, infections. ... Thats why a hospital like the University of Michigan is the ideal place. ... Patients who undergo this treatment are usually so sick after an infusion of the CAR-T cells, that they can't be safely treated at smaller hospitals."

Dr. Rajen Mody, a pediatric oncologist at the University of Michigan's C.S. Mott Children's Hospital.(Photo: University of Michigan)

Yanik is hopeful that successful treatment with CAR T-cell therapy in children with leukemia will open the door for similar therapies targeting other cancers.

"Aseparate CAR T-cell trial targeting diffuse large-cell lymphoma was recently completed with the results in that clinical trial now under review at the FDA," he said. That trial alsoincluded adult patientsat the University of Michigan.

Mody called the gene therapy revolutionary.

"This is clearly a life-saving and potentially curative therapy," he said."Its being tested in other types of leukemia and solid tumors. Its too early to say whether its going to work as well for other cancers.... We are not there yet."

Still, he said, it's made all the difference for Maryam and her family.

"She was one of the lucky ones coming from Iraq, and with all the things she has survived. And then coming here and surviving this,... she clearly has some goodluck.

"I think she should do very well. Patients who actually survive the first six months and still have CAR T-cells detected in their systems tend todo very, very well."

Contact Kristen Jordan Shamus: 313-222-5997 or kshamus@freepress.com. Follow her on Twitter @kristenshamus.

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First gene therapy to treat cancer gets FDA approval; UM only Michigan hospital to use it - Detroit Free Press

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KANSAS CITY, Mo. -- Lucas Novick, 27, has been in a battle with leukemia since his freshman year of college.

"I was having headaches that were so bad that they were causing vomiting pretty regularly and I couldn`t see straight well enough that I felt safe driving myself to school," Novick said.

Since 2009, Novick has endured a number of treatments including chemotherapy and a bone marrow transplant. The treatments have taken a physical and mental toll on Novick's body.

"The transplant that was supposed to save my life also nearly took it from me," Novick said. "The damage chemotherapy did to my body when I was first treated in 2009 and 2010 was such that I was walking with a cane after my 21st birthday. It did so much damage to my hip joints that they were replaced in 2011."

But after Novick's leukemia returned for a second time, he went to Children's Mercy Hospital where doctors were performing an experimental treatment.

"The approval of the CTL019 product for pediatric patients with relapsed refractory acute lymphoblastic leukemia is really exciting for us," Doctor Doug Myers, of Children's Mercy Hospital, said. "We`ve spent a lot of time working on ways to get the immune system into the fight against cancer because we think it can decrease toxicity, decrease the amount of chemotherapy and radiation that we use for these cancers."

Dr. Myers said the treatment helped Novick, a musician, back onto the stage and has held his leukemia awayfor two years.

"Those are really special rewards for us in this field that have seen so many failures of this type of therapy in the past. To see this go forward, move forward, do well enough for a pharmaceutical company will pick this up and take it the rest of the way, that`s a really special time for us," Dr. Myers said.

While doctors believe it's too early to call the new treatment a cure, many agree this is the first step to a new generation of cancer treatment.

"I know at the end of the day that this is the future of medicine," Novick said.

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Man describes new FDA-approved gene therapy for leukemia that changed his life - fox4kc.com

Category: Cardiology | Internal Medicine | Pathology | Pulmonology | Journal

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High levels of SCF linked to lower cardiovascular and all-cause mortality, heart failure, stroke

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THURSDAY, Aug. 31, 2017 (HealthDay News) -- High levels of stem cell factor (SCF) are associated with reduced risk of mortality and cardiovascular events, according to a study published online Aug. 26 in the Journal of Internal Medicine.

Harry Bjrkbacka, Ph.D., from Lund University in Sweden, and colleagues examined the correlation between circulating levels of SCF and risk for development of cardiovascular events and death. SCF was analyzed from plasma from 4,742 participants in the Malm Diet and Cancer Study; participants were followed for a mean of 19.2 years.

The researchers found that participants with high baseline levels of SCF had lower cardiovascular and all-cause mortality and reduced risk of heart failure, stroke, and myocardial infarction. There was a correlation for smoking, diabetes, and high alcohol consumption with lower levels of SCF. After adjustment for traditional cardiovascular risk factors, the highest versus the lowest SCF quartile remained independently associated with lower risk of cardiovascular (hazard ratio, 0.59; 95 percent confidence interval, 0.43 to 0.81) and all-cause mortality (hazard ratio, 0.68; 95 percent confidence interval, 0.57 to 0.81) and with lower risk of heart failure (hazard ratio, 0.5; 95 percent confidence interval, 0.31 to 0.8) and stroke (hazard ratio, 0.66; 95 percent confidence interval, 0.47 to 0.92) but not myocardial infarction (hazard ratio, 0.96; 95 percent confidence interval, 0.72 to 1.27).

"The findings provide clinical support for a protective role of SCF in maintaining cardiovascular integrity," the authors write.

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Stem Cell Factor Tied to Reduced Risk of Cardiac Events, Death - Doctors Lounge

High technology approaches to fertility, including ICSI, are really a two edged sword: they allow us to treat severe male infertility, but they may alter natural selection in that decisions regarding sperm and eggs are made in the laboratory and not by nature.

Dr. Paul Turek

Among the 15% of couples who experience infertility, about 40% of the time the infertility is due to male factors. About half of male infertility cases are due to defined reasons, including varicocele, infection, hormone imbalances, exposures such as drugs or medications, x-rays, tobacco use and hot tubs, blockage of the reproductive tract ducts, and previous surgery that has left scarring. Another cause of male infertility that has been underestimated in the past, but is now gaining in importance is genetic infertility. The reason for its increased importance is that our knowledge about genetics is growing so quickly. Men who may have had unexplained infertility in the past may now be diagnosed with genetic causes of infertility through recently available testing. In fact, this field is progressing so quickly that genetic infertility has already become one of the most commonly diagnosed reasons for male infertility.

Developed in the early 1990s, assisted reproduction in the form of IVF and ICSI (intracytoplasmic sperm injection) is a revolutionary laboratory technique in which a single sperm is placed directly inside an egg for fertilization. This technique has opened the door to fertility for men who formerly had few available treatment options, as it allows men who were previously considered severely infertile or sterile the possibility of fatherhood. However, with ICSI sperm are chosen by laboratory technicians and not by nature and because of this, it is not clear what barriers to natural selection are altered. Thus, along with this technology comes the possibility of passing on to a child certain genetic issues that may have caused the fathers infertility, or even more severe conditions. Another reason to know whether male

Infertility is genetic or not is because classic treatments such as varicocele repair or medications given to improve male infertility. In fact, Dr Turek was one of the first to publish on this issue, showing that varicocele repair was not effective in improving fertility in men with genetic infertility. Because he recognized these issues early on, Dr. Turek, while at UCSF in 1997, founded the first formal genetic counseling and testing program for infertility in the U.S. Called the Program in the Genetics of Infertility (PROGENI), Dr. Tureks program has helped over 2000 patients at risk for genetic infertility to navigate the decision-making waters that surround this condition.

Men with infertility should be seen by a urologist for a thorough medical history, physical examination, and appropriate medical testing. If genetic infertility is a possibility, then a genetic counselor can help couples understand the possible reasons, offer appropriate genetic testing, and discuss the complex emotional and medical implications of the test results. The approach taken early on by Dr. Turek is outlined in Figure 1. Just like the medical diagnosis from a urologist or fertility specialist, information about family history plays a critical role in genetic risk assessment. This approach to genetic evaluation, termed non-prescriptive, has been the corner- stone of Dr. Tureks critically acclaimed clinical program that now has over a dozen publications contributing to our current knowledge in the field. It is important to note that a lack of family history of infertility or other medical problems does not eliminate or reduce the risk of genetic infertility. In fact, a family history review will often be unremarkable. However, family history can provide crucial supporting in- formation toward making a genetic diagnosis (such as a family history of recurrent miscarriages or babies born with problems). Dr. Turek has published that having a genetic counselor obtain family history information is much more accurate than simply giving patients a written questionnaire to fill out and bring to their visit. A genetic counselor can also discuss appropriate genetic testing options and review the test results in patients in a meaningful way.

When speaking to Dr. Tureks genetic counselor about genetic testing, keep in mind that he or she will not tell you what to do. Genetic counselors are trained to provide information, address questions and concerns, and support you in the decision making process. A genetic counselor does not assume which decisions are most appropriate for you.

Among the various infertility diagnoses that men have, some are more commonly associated with genetic causes. Diagnoses that can have genetic causes include men nonobstructive azoospermia (no sperm count), oligospermia (low sperm count), and congenital absence of the vas deferens. A list of some of the best- described causes of genetic male infertility and their frequencies and associated conditions are listed in Table 1.

Nonobstructive azoospermia is defined as zero sperm count in the ejaculate due to an underlying sperm production problem within the testicles. This is quite dif- ferent from obstructive azoospermia in which sperm production within the testes is normal, but there is a blockage in the reproductive tract ducts that prevents thesperm from leavingthe body. There can be changes in the levels of reproductive hormones, such as follicle stimulating hormone (FSH), observed withnonobstructiveazoospermia. Most commonly, the FSH is elevated in this condition, which is an appropriate and safe hormone responseofthe pituitary gland to states of low or no sperm production. This diagnosis is associated with a 15%chance forhaving chromosome abnormalities(Figure 2) and a 13% chance for having gene regions missing on the Y chromosome (termed Y chromosome microdeletions, Figure3). To detect these changes, blood tests are typically offered to men with nonobstructive azoospermia.

Oligospermia that places men at risk for genetic infertility occurs when the ejaculate contains a sperm concentration of <5 million sperm/mL semen. Similar to nonobstructive azoospermia, this is most commonly due to an underlying sperm production problem. With this diagnosis, there is a 2% risk for chromosome abnormalities and 6-8% risk of Y chromosome microdeletions. In general, the lower the sperm count, the higher the chance that a genetic cause is present. Again the appropriate testing includes akaryotype and Y chromosome microdeletion analysis. Thus far, there are no established guidelines for applying these genetic tests in cases of low sperm motility (movement) or poor sperm morphology (shape).

Congenital absence of the vas deferens is characterized by the malformation or absence of the ducts that allow sperm to pass from the testicles into the ejaculate and out of the body during ejaculation. The duct that is affected in this condition is the vas deferens. This is the same duct that is treated during a vasectomy, a procedure for men who want birth control. Men with this condi tion are essentially born with a natural vasectomy. This congenital condition is associated with mutations and/or variations in the genes for cystic fibrosis (the CFTR gene) in 70-80% men if the vas deferens is absent on both sides, but less than this if the duct is missing on only one side. For most men with this condition with a mutation in the cystic fibrosis gene, the missing vas deferens is the only problem that results from this genetic change and they do not have the full spectrum of symptoms associated with cystic fibrosis, the most common genetic disease in the U.S. and generally lethal in early adulthood.

A less common reason for men to have a zero sperm count (azoospermia) than nonobstructive azoospermia is obstructive azoospermia. In essence, this is an unexplained zero sperm count due to a blockage of the reproductive tract ducts leading from the testicle to the ejaculate. Blockages are most commonly found in the epididymis but can also be located in the vas deferens or ejaculatory ducts. Most cases of obstructive azoospermia are amendable to surgical repair and naturally fertility is common. However, a high proportion of these men (47%) have mutations in the cystic fibrosis gene (CFTR) or harbor variations in the CFTR gene, termed 5T alleles. As such, genetic counseling and testing is also important in these patients.

These conditions represent only the most common genetic conditions encountered when evaluating men for genetic infertility. For this reason, consider reading Dr. Turekspublished paper that discusses most of the currently understood syndromes and conditions that are associated with infertility. It is also important to remember that if all genetic test results are normal, there is still a possibility that the infertility has a genetic cause. However, in many cases, medical science is currently unable to offer testing to detect it.

If a man has a chromosome abnormality identified as the cause of infertility, then depending on the chromosome abnormality detected, there may be a higher risk for children to be born with birth defects or mental impairment. This occurs as a result of a child inheriting from the father an imbalance in chromosome material. A genetic counselor can provide more detailed information about such potential risks, and offer other resources for individuals who have been diagnosed with a chromosome abnormality. There may be support organizations available to help men with genetic diagnoses and their partners cope with the impact of this information. Some couples find it helpful to talk to others in similar circumstances.

If a man is diagnosed with a Y chromosome deletion, then he will pass on that Y chromosome deletion to any son he conceives. To his daughters, he will pass on his X chromosome, instead of the Y chromosome. It is assumed that any son inheriting a Y chromosome deletion from his father will also have infertility. It is unclear whether the type and severity of the infertility will be different from the fathers. So far, there have only been a few reports of sons born to fathers with Y chromosome deletions after conception by assisted reproduction. As expected, there has not been an increase in the rate of birth defects or other problems for these boys, although this group is still small in number, and too young to have fertility evalua- tions.

Transmission of CFTR mutations in cases of infertility due to congenital absence of the vas deferens is somewhat more complex than either Y microdeletions or a chromosome abnormality. This is because there are over 1400 described muta- tions in the CFTR gene and the impact of mutations differs depending on which one is present. In general, the partner of an affected man should be tested as well, so that the residual risk of a child having either congenital absence of the vas deferens or full-blown cystic fibrosis can be estimated.

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The Genetics of Male Infertility | The Turek Clinics

August 30, 2017 | Case Western Reserve School of Medicine

[Ahmad Khalil, Assistant Professor of Genetics and Genome Sciences at Case Western Reserve University School of Medicine] and colleagues have been working to understand genetic mechanisms behind male infertility.

His work focuses on long strands of genetic material with elusive functions. The strands, called long non-coding RNAs or lncRNAs dont seem to encode proteins, but have been implicated in everything from cancer to brain function. Many are located in the testes, suggesting they could also play a role in fertility.

A team of seven researchers, led by Khalil, collected and measured lncRNA levels during the process of cellular differentiation that leads to sperm production [in mice]. They found that specific lncRNAs are associated with each stage of sperm development.

We have demonstrated for the first time that new types of genes, lncRNAs, are important for male fertility, Khalil said. This is a step closer to uncovering new genetic causes of infertility.

Our hope is that lncRNAs can be used in future RNA-based therapeutic approaches, Khalil said.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post: Long, mysterious strip of RNA contribute to low sperm count

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New ways to target low sperm count? - Genetic Literacy Project