Fight Aging!

In a recent post, I suggested that is practical and useful for small organizations to run low-cost clinical trials in large numbers in order to build physician support for treatments for aging that should, by rights, already be in the clinic. The senolytic treatment of dasatinib and quercetin is the most obvious candidate, given its low cost, availability for off-label use, broad, large, and reliable benefits in animal models of aging and age-related disease, and human evidence for efficacy in clearing senescent cells to a similar degree as it does in mice.

Today I'll propose a different angle on early, small trials. In this case the goal is to fast-track access for human volunteers to whole-body partial reprogramming. In partial reprogramming, cells are exposed to Yamanaka factors for a limited time, long enough to reset epigenetic marks to a youthful configuration, but (hopefully!) not long enough for any significant number of cells to lose their differentiated state and become induced pluripotent stem cells capable of forming tumors. In mice, a variety of gene therapy approaches have been used to introduce expression of reprogramming factors, and in the short term the benefits appear interesting enough to follow.

As long-term readers might recall, I've long been dismissive of attempts to adjust epigenetic changes characteristic of aging, as (a) these changes were, in my eyes, a long way downstream from root causes, and (b) the research community was likely to try to make these changes one at a time, with limited individual benefit resulting from any given intervention. What changed my mind on this was the discovery that cycles of DNA damage and repair cause characteristic age-related epigenetic changes. That work needs expansion and replication, but it places some sizable fraction of epigenetic change very much closer to the root causes of aging than previously thought, and makes reversal of those changes a good point of intervention if there is a cost-effective way of doing it. Which there is, in principle, in the form of partial reprogramming.

A great deal of funding is now devoted to the matter of developing partial reprogramming into therapies. NewLimit will be much more nimble than the behemoth that Altos Labs has become, and Turn.bio nimbler still, but I'd still expect a decade to pass between where we are now and the first partial reprogramming therapies becoming available in the clinic in any meaningful sense. These entities will conduct a significant amount of preclinical research, and will be following the standard regulatory playbook thereafter. That takes a long time. Even then, there is a strong chance that the first therapies will be very cautious implementations, such as by being limited to the treatment of retinal diseases and only introduced into the eye.

As an alternative, I believe it would be feasible for a smaller, more agile, directed group to put together a gene therapy for most-of-the-body expression of reprogramming factors and administer it in a small trial of volunteers outside the US, accomplishing that goal in two years or so. The important challenges in reaching that milestone in just a few short years, likely consuming most of that time, are people matters rather than technical matters.

A good approach for a gene therapy capable of only short-term expression appropriate to partial reprogramming would be lipid nanoparticles (LNPs) carrying mRNA encoding the Yamanaka factors, to be injected intravenously in initially low and then ascending doses in human volunteers. The LNPs would be one of the later generation of low immunogenicity variants, while the mRNA would be optimized to reduce immunogenicity in the ways that are presently standard practice in the industry. These are existing technologies, a known sequence for expression of the reprogramming factors, and a matter of running a simple but multi-step manufacturing process that involves two distinct companies and some shipping back and forth.

This gene therapy really doesn't have to be produced using highly expensive, slow Good Manufacturing Practices (GMP) methods in order to be reasonably safe. While some medical technologies do require great care in their manufacture, in this case low-cost research grade materials will do just fine. To ensure correct manufacture at reasonable cost, one runs a quality control study for each batch in cell cultures and in mice, looking for expression of proteins, LNP size, correct sequence of mRNA, and a few other items. That data should be enough to convince anyone that the result is as expected. When injecting into humans, doses should start very low in order to assuage concerns about unexpected immunogenicity.

From a technical perspective, good options for manufacturing of the LNPs are Entos Pharmaceuticals and Acuitas Therapeutics, given what is known of the biodistribution (e.g. not passing the blood-brain barrier, so excluding brain tissue from reprogramming) and safety profiles of their products. For the mRNA there are more companies on the table, but TriLink Biotech is the leading manufacturer, owning some important process patents. The first people matter is to convince the LNP and mRNA companies to act as hands-off manufacturers for a group intending to perform human trials with research grade materials, likely outside the US. There will probably be reputational concerns amongst the leadership of companies that must work closely with the FDA.

All of the other people matters revolve around regulatory approval to perform these trials: which jurisdictions, how the regulatory bodies work in those regions, finding willing clinic owners, and so forth. The Bahamas is a favorable location for a number of groups that are presently setting up clinics for potential anti-aging therapies and would likely be interested in enabling a fast track to partial reprogramming trials. That said, given the good relationship between Bahamas regulators and the FDA I suspect they would require some form of GMP or GMP-like manufacture, significantly increasing costs.

Healthy volunteers in middle age would be a better choice at the outset of this project than those who are very old or very ill, as they will be more resilient in the case of, for example, unexpected immunogenicity. When looking for efficacy, outcomes to measure include epigenetic age, all the omics data that is shown to be rejuvenated by partial reprogramming in mice, and physical function: kidney and liver function, immune function, blood pressure, aerobic capacity, and so forth. The most important question is that of cancer risk, and regardless of how much is spent on clinical trials, or whether they are conducted by large or small organizations, that data will only emerge many years later.

Conducting this project seems to me largely an exercise in organization and finding the funding, with no major technical roadblocks. The big unknown, cancer risk, will remain a big unknown for a long time yet.