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Gene therapy research is booming. Since the U.S. Food and Drug Administration (FDA) issued its first approval for a gene therapyin 2017, oncology researchers have been breaking barriers in gene therapy trials, followed by an explosion in mRNA research during the COVID pandemic. Today, this trailblazing science is providing new ways to approach rare diseases and new hope when other investigational interventions have failed. In fact, themajorityof approved gene therapies are for rare diseases 14 are currently in Phase III trials for 10 rare diseases and 45 gene therapies are in early stages of development to treat 30 rare diseases. We see great potential for gene therapies, said Leslie Johnston, senior vice president of biotech delivery for Parexel. As more products are approved, it will gain traction and more companies will look to expand their therapies into other therapeutic indications. This progress presents tremendous potential to change more patients lives across many different diseases. This could be gene therapys moment. But to fully seize it, the industry must clear some complex hurdles. Gene therapies pose several unique challenges for clinical research, including ethical and safety considerations, regulatory hurdles, precarious logistics, and potentially staggering costs. These challenges may already be having ramifications: New U.S. patients treated with gene therapies approved or in development areexpected to fallby one-third from 2025 to 2034. The key to clearing these hurdles? Cooperation between sponsors, sites, regulators, patients, and other stakeholders is essential to expediting the advancement of life-saving gene therapies. Regulators should address risks without limiting innovation Gene therapy trials are strictly regulated and rightly so, due to the novel nature of the intervention and the potential long-term consequences. Gene therapy interventions also carry inherent safety risks, including the potential for unintended genetic changes or adverse immune reactions. Ensuring patient safety requires rigorous monitoring and adherence to strict protocols. However, obtaining regulatory approval under these conditions is time consuming and resource intensive. To avoid hampering scientific progress, regulators should aim to ensure that requirements are appropriately rigorous without being unmanageably onerous. Thankfully, the FDA is paying close attention to gene therapy and has demonstrated a desire to work with drug developers toward the success and approval of these treatments. Dr. Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, has expressed his hope for an exponential, if not logarithmic, increase in gene therapy approvals. There is a lot of excitement that this could potentially make a big difference for the treatment of human disease, said Dr. Marks in hisremarksto the National Press Forum last November. The FDA is going beyond mere rhapsodizing and taking action to accelerate gene therapy. Last year, the agencylaunched a pilot programcalled Support for Clinical Trials Advancing Rare Disease Therapeutics, or START. This program is designed to accelerate the development and approval process for treatments targeting rare diseases by providing regulatory guidance, assistance, and incentives to sponsors conducting clinical trials in this field. The program represents an important step forward in fostering innovation and collaboration between regulatory bodies and sponsors. In addition, the FDA is working toharmonize global requirementsfor the review of gene therapies. Encouraging and facilitating international cooperation and harmonization of regulatory standards including mutual recognition agreements and shared regulatory pathways for multinational clinical trials can help streamline gene therapy development globally and help bring innovations to patients faster. Even with this progress, regulators should continue to help accelerate gene therapy research by streamlining regulatory pathways specifically tailored to gene therapies. This means providing clear guidance on requirements for preclinical and clinical development, fostering collaboration between stakeholders to share knowledge and best practices, and offering expedited review processes for gene therapy products aimed at treating serious or life-threatening diseases. With a staggering2,500 cell and gene therapyinvestigational new drug applications (INDs) on file, the FDA approved justfivecell and gene therapies in 2023. Dr. Marks hassuggestedthat accelerated approval, which has successfully advanced cancer and HIV/AIDS treatments, may be the most appropriate path for this new category of treatments. But, regulators also need to commit to proactively partner with developers to understand the patient population and the risks and benefits of each new therapy. Likewise, researchers, industry stakeholders, and patient advocacy groups should engage with regulators to help them understand the unique challenges and opportunities in the field of gene therapy. This can help regulators adapt regulatory frameworks to ensure patient safety while expediting the development and approval of promising treatments. Sites and sponsors must be prepared Of course, sites and sponsors also have a crucial part to play in advancing this promising field of medicine. Clinical trial sites should enhance their capacity to conduct gene therapy trials safely and effectively and sponsors should do their part to assist sites in these efforts. By working closely with clinicians and regulators, sponsors can ensure that the trial development process aligns with clinical needs and regulatory standards. Sponsors should have a thorough understanding of FDA requirements pertaining to design, preclinical testing, and long-term follow-up. Better alignment from the outset will lead to more efficient trial designs, faster regulatory approvals, and ultimately quicker patient access to therapies. For example, sponsors working with mRNA and other genetically engineered therapies in North America not only have to go through institutional review board (IRB) review, they also have to navigate additional requirements from the U.S. National Institutes of Health (NIH) Office of Science PolicyGuidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules(NIH Guidelines). These requirements usually involve an additional biosafety risk assessment review from an institutional biosafety committee (IBC) in addition to IRB review. NIH Guidelines apply for any research involving recombinant or synthetic nucleic acids (e.g. genetically engineered materials) that receives NIH support or takes place at sites that have received NIH support for such research. Even when there is zero NIH support, IBC review is considered a best practice. IBC review and inspection helps sites ensure they are fully prepared by identifying areas for improved biosafety protections and calling out gaps in current standard operating procedures (SOPs). Proactive coordination and integration of these separate review processes can speed trial timelines and help sponsors consistently address any potential concerns or issues. Sites can also be better prepared by pre-registering an IBC. The NIH takes six to eight weeks or more to approve a new registration, in addition to IBC review time so by registering an IBC before they even have a trial, sites can save a month or more in startup time over a site that waited to register. Clinical trial sites looking to host gene therapy studies must be prepared in other ways, as well, both in terms of knowledge and infrastructure. Gene therapy studies require specialized infrastructure for manufacturing, storing, and administering genetic material to adhere to strict biosafety guidelines. Something as simple as having an upholstered chair in the infusion room which would pose an unacceptable contamination risk if genetic materials were to spill would require the site to rethink their current processes. Rigorous training is also key due to the added risk of spreading genetic material to caregivers and others in close contact with patients. Research staff must be specially trained to handle, deliver, and dispose of this material safely. Of course, these measures can seem intimidating for sites that are already cost-constrained. Large academic medical centers with more resources and experience are more likely to be well-positioned for these studies. For instance, they may already have conducted bench, animal, and/or agricultural research with genetic engineering or have the funding to make any needed adjustments such as purchasing special equipment. But to maximize the potential number of sites where this research can be conducted and therefore reach more potential participants sponsors might consider providing help in the form of financial assistance, training curricula, SOP guidance, and more to smaller sites seeking to conduct gene therapy research. Logistical complexities depending on the investigational medicine and therapeutic area are among the most complicated challenges in gene therapy trials, added Johnston. From collecting the specimen from the patient, modifying it, storing it, transporting it, and then returning it back to the patient all comes with tremendously unique logistical challenges and requires equally unique equipment, technology, and expertise. And it can be cost-prohibitive. Patients must be fully on board Of course, the most essential stakeholder in any clinical trial is the patient. In gene therapy research, which can be particularly demanding, patients must have a complete understanding of and commitment to their involvement. Understanding the potential risks and benefits can help patients make informed decisions and navigate the study process. First, it's crucial for patients to adhere strictly to the protocol provided by the clinical trial team, including following medication schedules, maintaining specific hygiene practices, and attending all study visits. They should strive to maintain optimal health to enhance the body's response to gene therapy. And to avoid delays, patients should maintain open and honest communication with the clinical trial team, reporting any changes in symptoms, side effects, or general health as soon as they occur. Trial participants also need to be in it for the long haul. Because gene therapy interventions aim to produce lasting effects, even cures, they typically require long-term patient follow-up to assess efficacy and safety. But they may also need to have incredible patience. Johnston explained, There are many complexities that can impact study progress. For example, unpredictable logistical challenges like a weather event or vehicle accident could delay a temperature-sensitive delivery to a site, or data review outcomes could require an indeterminate pause period. Patience and agility are must-haves, but it is difficult for patients potentially depending on this new therapy to save or change their lives. Lastly, the industry cannot forget the patient. Involving patients and patient advocacy groups in the regulatory process can help ensure that the development of gene therapies is aligned with patient needs and priorities, as well as shed light on risk-benefit perspectives from a patients viewpoint. The more these perspectives are considered from the beginning, the greater the chance of a trials success. Rita Naman, co-founder of the Mighty Milo Foundation, emphasizes the need for a more collaborative and patient-centered approach to gene therapy development. "For ultra-rare diseases likeSPAX5, gene therapy offers a glimmer of hope where traditional treatments do not. But logistical hurdles make these therapies expensive and inaccessible, explained Naman. Closer collaboration with patients, industry, and regulators could streamline these processes, drive costs down, and speed trials. Patients like my son, and their caregivers, plus advocacy groups should be invited into the earliest discussions to prevent false starts or missed milestones in gene therapy development especially as the patients priorities dont always line up with the sponsors. In the fight for gene therapy breakthroughs, cooperation is key. The road to operationalizing gene therapy clinical trials is laced with land mines and potholes. To capture the full potential of novel gene therapy research, a new level of collaboration between sponsors, CROs, sites, oversight committees, regulatory bodies, and patients is paramount. Patients want access to novel gene treatments, and they want it fast. Sponsors want to deliver but fight logistical and financial obstacles. Regulators want to ensure safety first, especially considering such new, promising science, concluded Johnston. These three goals may seem conflicting at times, so we need to strike a balance of safety and speed, so patients dont miss their only potential treatment opportunity. A seasoned industry veteran with more than 25 years of experience, James Riddle is senior vice president of global review operations at Advarra. Riddles expertise includes large program management and growth, operational processes, development and implementation of technology solutions, and management of large Human Research Protection Programs (HRPP), Biosafety programs (IBC) and Institutional Animal Care and Use programs (IACUC). Riddle has directed numerous clients in achieving Part 11 compliance and meeting computer system validation requirements.

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Gene Therapy is Having its Moment: Can the Clinical Research Ecosystem Seize It? - Contract Pharma

Researchers have engineered a Cas enzyme to enhance activity against RNA viruses, resulting in a system that completely blocked the replication of various SARS-CoV-2 strains.

The research, details of which were published in Cell Discovery, was prompted by the need to overcome a barrier to the use of the Cas13d enzyme as an antiviral against human RNA viruses. Studies have shown that CRISPR/Cas13 systems are programmable tools for manipulating RNAs and Cas13d is the most active subtype of the enzyme in mammalian cells, making it the most promising antiviral candidate.

However, the activity of Cas13d is largely restricted to the nucleus. Most RNA viruses only replicate in the cytosol, where Cas13d is barely active in mammalian cells and as such are protected from the antiviral effects enabled by the enzyme, wrote the study's authors, led by Christoph Gruber of the Technical University of Munich (Cell Discov, April 12, 2024, Vol. 10 [1], pp. 1-4).

The problem led Gruber and other scientists from Helmholtz Munich and the Technical University of Munich to investigate why Cas13d is largely restricted to the nucleus and explore ways to bring the enzyme into contact with replicating RNA viruses in mammalian cells.

The research revealed that the enzyme has little activity in the cytosol because the RNA that guides the CRISPR-Cas complex to specific target sequences is found in the nucleus. That finding led the scientists to explore ways to move CRISPR RNAs (crRNAs) from the nucleus to the cytosol.

Through screening and optimization of various designs of shuttling proteins, the researchers developed a system that transfers nuclear crRNAs into the cytosol. The enzyme -- nucleocytoplasmic shuttling Cas13d or Cas13d-NCS for short -- moves nuclear crRNAs to the cytosol, where the protein/crRNA complex binds and degrades complementary target RNAs.

The researchers hypothesized that Cas13d-NCS more adeptly degrades viral cytosolic RNAs than standard Cas13d and tested that idea using a self-replicating RNA from the Venezuelan equine encephalitis RNA virus. The tests showed the engineered approach "targets solely cytosolic RNA with greater efficiency compared to the current Cas13d system," the authors wrote.

To assess antiviral efficacy, the scientists targeted SARS-CoV-2, the RNA virus that causes COVID-19. The assessment showed Cas13d-NCS can completely block the replication of various SARS-CoV-2 strains, they wrote.

"Targeting conserved but weakly expressed viral-coding sequences resulted in relatively weak inhibition, whereas targeting the ubiquitous 3'UTR with a single crRNA resulted in complete inhibition of viral replication," Gruber et al concluded.

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Engineered Cas clears barrier to antiviral CRISPR therapies - LabPulse

Fort Lauderdale, FL, April 09, 2024 (GLOBE NEWSWIRE) -- The adage age is just a number embodies feeling young at any age. So whats more important when it comes to healthy aging: brain or brawn? In a recent survey of 4,100 Life Extension customers, 68% of whom were aged 61 or older, more than half ranked mental performance as the most important factor for feeling young for their age, while physical health came in a distant second place at 24%. To help people stay ahead of the aging game, Life Extension has launched Healthy Aging Powder, a triple-nutrient blend of taurine for cardiovascular health, lithium for a healthy mood, and spermidine from wheat germ extract to promote memory health. February 2024 survey of Life Extension customers.

We wanted to offer customers a way to promote a healthy aging process, so we focused on finding nutrients that support three cornerstones of aging gracefully: memory and mood health and a healthy heart, explained Life Extensions Vice President of Product Development, Glenn MacEachern, MBA.

According to Michael A. Smith, MD, Life Extensions Director of Education, aging healthily goes beyond flexing strong muscles; it also depends on heart health and, yes, cognition. Physical health is a no-brainer when it comes to healthy aging, but many dont realize that maintaining cognitive health and performance, including a healthy mood, is also crucial, Dr. Smith said. Weve come to accept our working memory slowing down and our mood souring as the norm. But we dont have to take age-related cognitive decline for granted. By tweaking our lifestyle, we can support memory health and maintain a healthy mood at every age.

Dr. Smith recommends choosing a dietary supplement that addresses the trifecta of healthy agingmemory and mood health, and a healthy heartas a proactive way to make those later years truly golden.

Healthy Aging Powder is a new addition to Life Extensions longevity supplements line, which also includes Optimized Resveratrol Elite to help protect against oxidative stress and NAD+ Cell Regenerator to support healthy cellular energy pathways. The easy-mix, unflavored powder blend contains no genetically modified ingredients.

About Life Extension For more than 40 years, Life Extension has pursued innovative advances in health, conducting rigorous clinical trials and setting some of the most demanding standards in the industry to offer a full range of quality vitamins and nutritional supplements and blood-testing services. Life Extensions Wellness Specialists provide personalized counsel to help customers choose the right products for optimal health,nutritionand personal care. To learn more, visit LifeExtension.com.

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.

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Mental Performance Is the #1 Factor for Healthy Aging, According to Life Extension Survey - GlobeNewswire

Theres a universal fact for women. If they live long enough, their capacity to bring forth children will end, and they will become menopausal. Menopause can be when the thermostat becomes their most prized possession.

But not all women have hot flashes. Some go through this period wondering why they have no symptoms. The best advice for them is, Enjoy the smooth sailing!

Other women endure needless suffering. There are treatments, and these women should see their doctors.

The medical journal The Lancet has urged women to become educated about hormone replacement therapy. Menopause should not be considered a disease. It is a natural process. Be cautious with commercial interests of pharmaceutical companies propaganda. Seek information from a medical specialist.

The authors of The Lancet report stress they are not opposed to HRT, as it can be effective in treating hot flashes, vaginal dryness, and genital urinary symptoms. Many years ago, HRT was often used by women to control menopausal symptoms. The standard treatment involved the hormones estrogen and progestin, a synthetic form of progesterone.

But a large and widely publicized study called the Womens Health Initiative identified problems with HRT. Doctors and patients concluded HRT was dangerous, and this misconception lingers today. The study had significant shortcomings, however, and subsequent studies have more nuanced conclusions. For women under 60, or for those less than a decade out of menopause, the benefits of HRT in fighting debilitating symptoms outweighed the risk. There was one other caution. Those using HRT should not have a family history of stroke, breast cancer, or coronary heart disease.

Which women suffer the most from menopause? Its those who are affected by severe symptoms. Imagine a stalwart high school principal. She has handled the tough job for years. But with the onset of menopause, the slightest provocation has her bursting into tears behind closed doors. For the first time, she feels incapable of the task. If she meets the criteria mentioned above, then she is a textbook case for HRT. Within a week, her problem would be history.

Menopause is not just one event or one symptom, such as hot flashes. A gradual decrease in the production of estrogen influences organs such as the vagina and urinary bladder. Its these organs that women are loath to discuss with their family doctor, to say nothing of their partners.

It may come as a shock to younger people to know that seniors have sexual relations. But menopause can make vaginal tissues thinner and more easily irritated. Past columns have tried to explain this with a touch of eloquence, noting that its hard for females to sing with a sore throat. Put plainly, its hard for menopausal and post-menopausal women to enjoy sex with an inflamed vagina (atrophic vaginitis). Sometimes neither the woman nor her partner knows whats causing the severe pain. Unfortunately, many women suffer silently.

Those who ask for help will find there are good remedies. Something as simple as an estrogen cream can resolve an irritated vagina within two weeks. Other consequences of menopause, like the accelerated loss of bone density, may also be treated with HRT.

Sometimes problems are missed because a vaginal examination is not done during a check-up. Or patients dont mention issues to the doctor.

The comedian Joan Rivers made a joke about news that having a dog makes you 10 years younger. My first thought was to rescue two more, she said, before adding, but I dont want to go through menopause again.

Today, women can and should get their symptoms treated.

Dr. W. Gifford-Jones, aka Ken Walker, is a graduate of the University of Toronto and Harvard Medical School. You can reach him online at his website, docgiff.com, or via email at contact-us@ docgiff.com. Follow him and his daughter on Instagram @docgiff and @diana_gifford_jones.

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The Doctor Game: What women suffer most from menopause? - The Westerly Sun

One of the most significant challenges in treating HIV is the virus ability to integrate its genome into the hosts DNA. This means that lifelong antiretroviral therapy is essential as latent HIV can reactivate from reservoirs as soon as treatment ends.

One potential technique being developed to address this problem is the use of gene editing technology to cut out and incapacitate HIV from infected cells. Currently, there is a Phase I/II Clinical Trial underway in people with HIV-1 (the most common strain of HIV)

Now, new research from another team shows that gene editing can be used to eliminate all traces of the HIV virus from infected cells in the laboratory.

The research is being presented early ahead of the European Congress of Clinical Microbiology and Infectious Diseases, which will be held from 27-30 April in Barcelona, Spain. Its been carried out by scientists from the Amsterdam Medical University in the Netherlands, and the Paul Ehrlich Institute in Germany, and has not yet been submitted for peer review.

Our aim is to develop a robust and safe combinatorial CRISPR-Cas regimen, striving for an inclusive HIV cure for all that can inactivate diverse HIV strains across various cellular contexts, they write in a conference abstract submitted ahead of ECCMID.

CRISPR-Cas gene editing technology acts like molecular scissors to cut DNA and either delete unwanted genes or introduce new genetic material, while guidance RNA (gRNA) tells CRISPR-Cas exactly where to cut at designated spots on the genome.

In this research, the authors used 2 gRNAs that target conserved parts of the viral genome this means they remain the same or conserved across all known HIV strains. This genetic sequence does not have a match in human genes, to prevent the system going off target and causing mutations elsewhere in the human genome.

The hope is to one day provide a broad-spectrum therapy capable of combating multiple HIV variants effectively. But before this dream can become a reality, the researchers had to address a number of issues with getting the CRISPR-Cas reagents into the right cells.

To delivered CRISPR components into cells in the body a viral vector, containing genes that code for the CRISPR-Cas proteins and gRNA, is used. This is the vehicle that delivers into the host cell the instructions to make all necessary components, but these instructions need to be kept as simple and short as possible.

Another issue is making sure the viral vector enters HIV reservoir cells specifically cells that express the receptors CD4+ and CD32a+ on their surface.

They found that in one system, saCas9, the vector size was minimised, which enhanced its delivery to HIV-infected cells. They also included proteins that target the CD4+ and CD32a+ receptors specifically in the vector.

This system showed outstanding antiviral performance, managing to completely inactivate HIV with a single guide RNA (gRNA) and excise (cut out) the viral DNA with two gRNAs in cells in the lab.

We have developed an efficient combinatorial CRISPR-attack on the HIV virus in various cells and the locations where it can be hidden in reservoirs and demonstrated that therapeutics can be specifically delivered to the cells of interest, the authors write.

These findings represent a pivotal advancement towards designing a cure strategy.

But the researchers stress that, while these preliminary findings are very encouraging, it is premature to declare that there is a functional HIV cure on the horizon.

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How CRISPR-Cas genome editing could be used to cure HIV - Cosmos