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