An Outline of Present Work on Partial Reprogramming as a Rejuvenation Therapy

Here I'll point out a good, lengthy introduction to the ongoing, suddenly very well funded work on partial reprogramming as the basis for rejuvenation therapies. Reprogramming somatic cells to induced pluripotent stem cells requires exposure to the Yamanaka factors, but is a lengthy process with low efficiency. Early in that process, epigenetic patterns in a cell are restored to a more youthful configuration without the loss of differentiated somatic cell state, and this is the goal that partial reprogramming aims to achieve: restore mitochondrial function and many other cell activities in old tissues without changing cell state. Animal data is promising, even given the issues such as DNA damage that cannot be addressed by partial reprogramming, but the challenge will be how to reach this goal in a way that does not produce a significant risk of cancer via the inadvertent creation of pluripotent cells, while still rejuvenating enough of the cells in a tissue to matter.

As a whole, partial reprogramming seems quite promising: it not only improves biomarkers across tissues, but also improves aging-related functions. Even though systemic in vivo experiments of wildtype mice only showed modest outcomes so far, it might be because the protocol has not been optimized. Low hanging fruit optimizations include starting the protocol at an earlier age as well as having a longer induction period. In addition, in vivo targeted treatment in wildtype mice demonstrated impressive rejuvenation effects, implying that non-targeted and non-universal delivery may have reduced the effectiveness of in vivo systemic studies. As a result, besides protocol optimization, technology advancement in adjacent areas like gene delivery would also be required in translating partial reprogramming.

Of course, the elephant in the room is cancer risk. We have seen that partial reprogramming inevitably dedifferentiates cells. However, dedifferentiation is not always bad - if administered at the right dosage, it is reversible and won't cause teratomas or damage to organisms. On the other hand, there are also additional efforts in finding alternative factors to the Yamanaka factors (OSKM) that are safer and more effective, both in academia and industry. It's important to optimize what works (OSKM) and discover new factors for reprogramming rejuvenation. In this sense, it is a positive sign that half of the companies in reprogramming are focusing on optimization of OSKM and the other half are focusing on new discoveries.

Because aging is not considered a disease, it's also important to think about what indications to pursue. Currently, skin and muscle stem cells are the two tissue types where partial reprogramming has demonstrated rejuvenation effects in both mice and humans, as well as being replicated in more than one study in the same species. Therefore, it makes sense that two out of three companies closest to clinical trials, Turn Bio and Reverse Bioengineering (AgeX), are pursuing dermatology indications. Another promising indication would be in immunotherapy, since approvals for cancer drugs are more risk tolerant than others.

Overall, we are still a long way from applying partial reprogramming to humans. Turn Bio is the company closest to clinical trials in this space (expected to start late this year) - it may take a decade for partial reprogramming to be approved for therapeutic use. Even then, there are still many challenges that need to be addressed, such as creating both universal and cell-specific gene therapy, before this technology can be used for whole body rejuvenation. In addition, partial reprogramming cannot completely reverse all the signs of aging.



"...Metabolic aggregates in the cell and extracellular matrix are another type of damage that partial reprogramming might not be able to fix ... it might be possible that it(partial reprogramming) could induce specific gene programs to clear these damages on its own."

Posted by: erasmus at April 25th, 2022 3:23 PM
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