Commentary on Reprogramming from Yuri Deigin of YouthBio Therapeutics

Cellular reprogramming is a hot topic these days, given the vast amount of funding devoted to research and development, and the number of well capitalized new ventures focused on building therapies based on reprogramming. Reprogramming recaptures the process that takes place in the early embryo in which cells become pluripotent, but also reset their epigenetic patterns to restore mitochondrial function and other cellular processes to a youthful configuration. The primary goal of most reprogramming initiatives is to avoid pluripotency and state change in cells, while still restoring youthful epigenetic control of gene expression and cell function - a work in progress, moving ahead with enthusiasm. That said, there are a range of issues that this approach cannot address well, from nuclear DNA damage to persistent molecular waste, but it seems plausible that useful rejuvenation therapies will result from this line of work.

We are trying to translate partial cellular programming, but we have a tight focus right now on humans. Our approach is to use gene therapy to deliver reprogramming genes once into tissues of interest and then activate them with a small molecule. Ultimately, we feel that partial cellular reprogramming will need a tissue-specific approach. Different organs will probably need different reprogramming factors and definitely different dosing regimens.

Our goal is to create tissue-specific gene induction systems that, for a given tissue, can activate a specific set of genes. That platform doesn't even have to be used for partial cellular programming. It could potentially be used for any other gene therapy that needs several different gene cargoes that need to be activated in a different manner.

Eventually, we also want to move away from Yamanaka factors, because they weren't designed for partial programming. They were designed for full reprogramming, and for our purposes are too dangerous, because full reprogramming causes cells to lose their identity. This is something we obviously do not want, so we're looking for other factors that are better suited to partial reprogramming. Basically, the holy grail for us is to split the rejuvenation from the dedifferentiation. We want to just rejuvenate cells if it's possible.

To me, the beauty of partial cellular reprogramming is actually that it doesn't really matter what aging is. We're taking a very pragmatic approach. We absolutely know that a lot of epigenetic changes are driving aging. Do those changes happen in response to stochastic damage? Or because of a program? For practical purposes it doesn't really matter. We have observations that show that partial cellular reprogramming can delay aging and can reverse some hallmarks of aging on the cellular level. We also see some reversal of those hallmarks on an organ level and potentially on a systemic level. There is definitely a delay of aging in the progeric mouse model where they lived up to 50% longer and exhibited better histology of various tissues.

We are taking a pragmatic approach to translating this research to people. We're actually trying to make something useful rather than just taking a dive deep into the fundamental science, which of course is also important and interesting, but we ultimately want to create a therapy for people as quickly as possible.



The problem with partial reprogramming is that it doesn't extend telomeres. For that you need to go pretty much all the way back to IPSCs. So this in my view can only ever be a healthspan not a lifespan extending treatment.

Posted by: Mark at May 25th, 2022 6:37 AM
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