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My attention was recently directed to another new group planning patient paid human trials of telomerase gene therapy. This is a company associated with Sierra Sciences and the RAAD Festival crowd, meaning the Life Extension Foundation principals. These folk have of late started to fund a number of interesting efforts, such as the Betterhumans senolytics trials. This is another in that series.

Is telomerase gene therapy a useful treatment for aging? In mice it extends life span, most likely through effects such as greater immune activity and greater stem cell activity, but possibly also via other mechanisms. Telomerase acts to lengthen telomeres at the ends of chromosomes, but it also has a range of other functions, some of which might positively impact mitochondrial function. Average telomere length in tissues falls with age: it is a function of the rate of cell division, as telomeres shorten every time a cell divides, and stem cell activity, as stem cells produce daughter cells with long telomeres. So telomere length is very much an assessment of some of the processes of aging, not a cause of aging. In turn, telomerase gene therapy is not a means of targeting the causes of aging - rather, it is one of the more effective classes of compensatory treatment identified to date, alongside forms of stem cell therapy.

Whether telomerase gene therapy will have the same sort of risk and benefit profile in humans as it does in mice is something of an open question. Mice have very different telomere dynamics in comparison to humans, and the risk of cancer may well be quite different as well. Counterintuitively, in mice that risk actually appears to be reduced by introduction of telomerase, though the mechanisms involved are not well understood. We might hypothesize that increased immune system efficiency in removing potentially cancerous cells counterbalances the telomerase-induced tendency for those cells to become more active. Still, how do you find out other than by trying? Making the attempt is the most cost-effective means of obtaining human data.

Our mission is to reverse aging and cure all age-related diseases, starting with Alzheimer's. Libella Gene Therapeutics has exclusively licensed the technology of Sierra Sciences to conduct a human research project. We believe we have the scientist, the technology, the physicians, and the lab partners, all of which are necessary to get this done. By activating telomerase, we hope to lengthen telomeres in the body's cells. To have an effective delivery system for the telomerase to reach every cell in the body, quadrillions of gene therapy particles must be produced for each test subject. The production of enough gene therapy particles to treat one person takes anywhere from four months to a year to complete. Because of the demands on production, we will have a limited number of tests available. We anticipate having around 50 spots over the next 12 months.

We believe the most expedient way to test revolutionary evidence-based technology, such as gene therapy, is a pay to play model. The FDA passed legislation in 2009 allowing for patients to pay for their care when other viable options are not available. Libella Gene Therapeutics (LGT) strongly believes an informed choice is a right, not a privilege. LGT believes that "pay to play" is ethical. The data has continued to mount that telomerase activation and lengthening of telomeres may be the most exciting and disruptional breakthrough in the history of medicine. LGT is committed to bringing telomerase therapy to the world.

Today the majority of human clinical studies are performed outside of the United States. 65% of clinical studies are performed off shore. Typically it is cheaper, quicker, and involves less regulation. LGT believes it is most ethical to conduct our studies outside of the United States where we can move faster, and at a lower cost, as long as there is no reduction in quality or safety for our study participants.

Link: http://www.libellage...cs.com/mission/

View the full article at FightAging

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Libella Gene Therapeutics is developing telomerase gene therapy as a clinical treatment, work that results from more than a decade of studies in mice that show extended life, reduced cancer risk, and improved health. Telomerase acts to lengthen telomeres, the repeated DNA sequences at the ends of chromosomes that shorten with each cell division. Average telomere length in the somatic cells making up any given tissue is a function of the rate of cell division versus the pace at which stem cells produce new daughter somatic cells with long telomeres. Since stem cell activity declines with age, it is no surprise to see telomere length shorten.

Telomerase gene therapy acts in part by extending the working life of somatic cells, and thus the prospect of active cells, burdened with damage due to a longer working life, and the attendant cancer risk has always been a concern. That telomerase gene therapy reduces cancer incidence in mice may be the result of improvements in immune function, particularly cancer immunosurveillance, that outweigh any increase in cancer risk due to increased activity of damaged cells. Mice and humans have very different telomere dynamics, however, so it remains to be seen whether or not the same balance of outcomes is the case in our species. The best way to find out, as ever, is for brave volunteers to try the therapy.

The clinical trial (NCT04133649) has just began recruitment stage. The procedure will consist of a single intravenous injection, followed by six safety and efficacy evaluations. Participants will receive adeno-associated virus (AAV) containing gene expressing telomerase reverse transcriptase enzyme. AAV is expected to move from the circulatory system to tissues, invade cells, and establish telomerase expression inside cells. Viruses will not modify the genome - AAV's genetic material normally exists separately in the cell cytoplasm (as an episome).

Formally, the study is phase I trial, which limits the main goal - whether it is successful or failed attempt - to safety only. In this case, the primary goal was declared as the incidence of adverse effects. Determination of dosing and tolerability is an important first step in all gene therapies. High doses of viral particles result in significant immunological reaction. Moreover, liver damage is a common adverse effect in early gene therapies, because of liver's participation in blood filtering. In addition, telomerase introduces additional risk on its own. In 85% cases of cancers, telomerase is found upregulated, which raises concerns about potential oncogenicity of AAVs with hTERT gene.

The trial is accompanied by two similar phase I attempts (NCT04133454, NCT04110964), which target Alzheimer's disease and critical limb ischemia. Patients participating in the trial will be enrolled in their country of origin and will travel to Colombia. Patients will stay in Colombia for a few days while the treatment is administered and hospitalized for observation. Patients will then return to their country of origin and will be followed-up per the study protocol.

Link: https://genomecontex...-of-telomerase/

View the full article at FightAging

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After Bioviva Science, Libella Gene Therapeutics is the second company to take a run at commercializing telomerase gene therapy treatments for human use. Telomerase is the enzyme responsible for lengthening telomeres, repeated DNA sequences at the ends of chromosomes, though it may have other roles. Telomeres are a part of the mechanism that limits the number of times that a somatic cell can replicate. Telomeres shorten with each cell division, and when too short they trigger programmed cell death or cellular senescence followed by destruction by the immune system. Ordinary somatic cells in humans do not express telomerase; it is only present in stem cells, which can replicate indefinitely to supply tissues with new somatic cells with long telomeres. This split between a small privileged stem cell population and the vast majority of restricted somatic cells is how higher forms of animal life keep cancer risk low enough for evolutionary success. Obviously not low enough for comfort, but evolution was never about individual happiness.

Telomerase gene therapies have been demonstrated to extend life span and reduce cancer risk in mice. The former outcome is likely largely due to increased stem cell activity, while the latter outcome is somewhat counterintuitive: if damaged cells are pushed into more activity and replication that they would not normally have undertaken, won't this raise the risk of cancerous mutations arising? It may be that improvements in immune function act to more than offset this risk - a primary task of the immune system is to destroy potentially cancerous cells before they have the chance to form a tumor. There is still some concern, in that mice have very different telomere and telomerase dynamics in comparison to humans. Will the balance of risk and improved function be the same in our species? The way we will find out is via brave volunteers trying the therapies, most likely, rather than any of the other, much slower options.

Neither Bioviva nor Libella took the standard regulatory path forward, opting for some combination of regulatory arbitrage and medical tourism to bring their therapies to patients. This sort of effort, carried out responsibly, is, I think, necessary and must spread if the present excesses of the FDA are to be reined in. The FDA sees its role as reducing risk to zero, at any and all cost, including the cost of slowing medical development to a crawl. Analyses have long shown that the cost in lives of this regulatory burden of slowed development far outweighs the benefits - but absent therapies are invisible and arouse no media outrage. Bureaucracies inevitably optimize to minimize visible problems. The only way to combat this issue effectively, given that working to change the system from within, and political advocacy to change the system from the outside, have been ongoing energetically for the past few decades, a time over which the financial burden imposed by the FDA has more than doubled, is to prove out a viable, responsible, cost-effective path to market outside the FDA system of regulation.

Libella Gene Therapeutics recently announced a patient paid trial to be held outside the US. Patient paid trials are unfairly excoriated by the research and regulatory establishment. As I have remarked upon in the past, they are an entirely legitimate approach to obtaining data. The chief objection is the lack of a control group in most such trials - but if we are only interested in large, reliable effect sizes, then the control group is the rest of the patient population, and that works just fine. In general, good therapies for aging, those that target relevant mechanisms in ways that will truly move the needle on life span, will indeed have large and reliable effects.

A second objection, more valid, is the sort of marketing that tends to accompany these trials. That is very much in evidence here, sadly. Libella should rein that in; in the long term it only harms the very necessary development of reliable, well-defined pathways for regulatory arbitrage. Telomerase gene therapies are not a cure for aging. They are a compensatory or enhancement therapy that addresses one of the downstream consequences of aging, while having little to no effect on a wide range of other important issues, such as accumulation of persistent metabolic waste in long-lived cells. No amount of telomerase will enable the body to break down harmful compounds that it cannot break down even in youth. Further, no-one has yet demonstrated that you can reverse, say, even an epigenetic clock measure by 20 years in humans using telomerase gene therapy. Even if you could, one can't say that this corresponds to 20 years of rejuvenation, given how little is known of what exactly these clocks measure. These sorts of claims are just aggravating. I understand the need for marketing, but one can carry out good marketing without having to resort to this sort of thing.

The Libella Gene Therapeutics trial will likely make waves because of the cost, at $1 million per patient. This is, however, a systemically administered gene therapy using AAV as the vector, stacked with one of the new biotechnologies that can reduce the ability of neutralizing antibodies to destroy the viral particles. If Libella is manufacturing to one of the usual Good Manufacturing Practice (GMP) standards, it is likely that the overwhelming majority of that $1 million cost is the cost of manufacture. AAV, while the most popular vector in the gene therapy development community, remains enormously expensive to manufacture. For a point of comparison, there is a systemically administered viral gene therapy for an inherited disease that is used in newborns, where it requires a 100,000 square foot facility 40 days to produce one dose. That costs more than $2 million. Everyone in the industry agrees that this situation must change and will change, that there will be disruptive advances in cost and efficiency, just as happened for monoclonal antibodies - but it hasn't happened yet.

Breakthrough Gene Therapy Clinical Trial is the World's First That Aims to Reverse 20 Years of Aging in Humans

Libella Gene Therapeutics, LLC ("Libella") announces an institutional review board (IRB)-approved pay-to-play clinical trial in Colombia (South America) using gene therapy that aims to treat and ultimately cure aging. This could lead to Libella offering the world's only treatment to cure and reverse aging by 20 years. Under Libella's pay-to-play model, trial participants will be enrolled in their country of origin after paying $1 million. Participants will travel to Colombia to sign their informed consent and to receive the Libella gene therapy under a strictly controlled hospital environment.

Bill Andrews, Ph.D., Libella's Chief Scientific Officer, has developed an AAV gene therapy that aims to lengthen telomeres. The AAV gene therapy delivery system has been demonstrated as safe with minimal adverse reactions in about 200 clinical trials. Dr. Andrews led the research at Geron Corporation over 20 years ago that initially discovered human telomerase and was part of the team that led the initial experiments related to telomerase induction and cancer.

Telomerase gene therapy in mice delays aging and increases longevity. Libella's clinical trial involves a new gene-therapy using a proprietary AAV Reverse (hTERT) Transcriptase enzyme and aims to lengthen telomeres. Libella believes that lengthening telomeres is the key to treating and possibly curing aging. On why they decided to conduct its project outside the United States, Libella's President, Dr. Jeff Mathis, said, "Traditional clinical trials in the U.S. can take years and millions, or even billions, of dollars. The research and techniques that have been proven to work are ready now. We believe we have the scientist, the technology, the physicians, and the lab partners that are necessary to get this trial done faster and at a lower cost in Colombia."

View the full article at FightAging