Request for Startups in the Rejuvenation Biotechnology Space, 2021 Edition

For a few years now, I've suggested areas of opportunity in rejuvenation biotechnology in which either (a) it seems quite viable to start a company, given what I've seen going on in industry and academia, or (b) it would be very helpful should someone step up with an approach that works, given the need for a solution. The longevity industry is still young, still small, and countless valuable programs in the aging research field remain waiting to be championed and carried forward to the clinic. The low-hanging fruit is still near all there to be claimed: what is possible is a far greater space than what is presently being attempted.

A Gene Therapy Platform that Just Works

The primary challenges in gene therapy are easily stated: express genes for (a) a controllable length of time, (b) to a useful degree in specific tissues without overloading other tissues, (c) with a high degree of coverage of cells in the tissues of interest. It would be nice to also have (d) at a reasonable cost, but cost will come down given a platform that can be used for most gene therapies and hits points (a) through (c). That there isn't a good off-the-shelf approach that can be directly and easily applied to an arbitrary gene therapy in an arbitrary tissue is hindering development.

At present plasmid delivery via more recent varieties of lipid nanoparticle, with expression made selective to cell type by use of appropriate promoters, looks like it may be able to achieve the goal of a general gene therapy platform useful for most therapies, given further advances in the technical capabilities of existing platforms. That said, near all gene therapy delivery technologies have the issue that when delivered systemically via intravenous injection, 80% or more of the injected vector will end up in the liver. Thus there must be a way to make that excess a non-event while still getting a useful amount of vector into the tissue of interest. Perhaps this could be solved by more sophisticated and much safer means of direct injection of internal organs, or more sophisticated carriers that can be steered to specific locations in the body before releasing their gene therapy cargo. Regardless, it seems plausible that there is some combination of the many approaches demonstrated in the laboratory or presently in clinical development that could result in a Gene Therapy Platform that Just Works for a majority of treatments.

Repurpose Fecal Microbiota Transplantation for the Treatment of Frailty

Repurposing an existing therapy is considerably easier than building a new one. Fecal microbiota transplantation is used to treat conditions in which the gut has been overtaken by pathological bacteria, and works quite well. The gut microbiome deteriorates with age, becoming more inflammatory, alongside a reduced production of the beneficial metabolites needed by the body. It has been demonstrated that transplanting gut microbes from young animals to old animals restores a more youthful microbiome, and as a consequence improves health and extends life span. Bringing that same approach to humans will require only modest refinement of the existing protocols, with perhaps more of an emphasis on screening out potentially harmful microbial species that a young immune system is better equipped to handle. Treating frailty by rejuvenating the gut microbiome might be a good option for a new development program, given that chronic inflammation is an important contributing cause of the condition.

Hematopoietic Cell Mobilization for Revascularization

The density of capillary networks throughout the body declines with age. This is likely quite important in loss of tissue function, particularly in muscle and brain, as these organs have a high need for nutrients and energy. The process of generating new blood vessels, particularly in response to injury, involves hematopoietic cells leaving their bone marrow niche and migrating to the area of injury. In connection with hematopoietic stem cell transplantation, a range of drugs are presently employed to provoke this exit of hematopoietic cells from the bone marrow into the circulatory system, where they can be easily harvested via drawing blood. These compounds target proteins such as CXCL12, CXCR4, CDC42, or their receptors, all involved in regulating the mechanisms that determine whether hematopoietic cells leave their niches. Can these mechanisms, and the state of the art in this part of the field, be used to increase capillary and other vessel density in uninjured individuals?

Regrow the Thymus to a Greater Degree than the Intervene Immune Approach

COVID-19 has hopefully made more people aware of the importance of age-related immunosenescence to declining health and resilience in later life. A sizable part of the decline of the immune system is the result of the atrophy of the thymus. Intervene Immune demonstrated that thymic rejuvenation is practical, and that it can measurably improve immune system function in aging humans, even when the degree of regrowth is only modest. Now we need more companies - beyond Lygenesis and Repair Biotechnologies - hard at work on better approaches that are capable of (a) producing much larger degrees of thymic regrowth, and (b) being made safe and cost-effective enough to be delivered to the entire adult population. There are many strategies that could in principle achieve the first goal, but the second is a tall order.

Make Worthwhile Treatments for Aging Accessible to the Masses

A number of possible approaches to the treatment of aging appear to pass the cost-benefit calculation, are therapies that exist today, and can be used by the medical community as off-label treatments. Examples include the first generation senolytic drugs that have undergone human trials, such as the dasatinib and quercetin combination. We might also consider periodic plasma dilution to reduce damaging signaling in the aging body. And so forth. The adoption of these approaches by physicians and clinics will be slow and patchy, and there is an opportunity here for companies that can accelerate this approach. Consider a venture like AgelessRx, for example, but with a much higher bar on the quality of treatments offered. Or physician network providers, or a chain of clinics, or a coordinated effort to make medical tourism work for senolytic therapies, wherein every older person in the US is a potential customer. There are many possibilities here in the ecosystem of medical services.

Platforms for the Destruction of Metabolic Waste

A very wide variety of metabolic waste is involved in aging. Misfolded proteins, some of which form amyloids, advanced glycation end-products, altered cholesterols, all sorts of garbage molecules that end up in the lysosome, and so on. Each of these categories contains many different molecular species, found in different places inside and outside the cell, requiring different classes of approach to find and break down. One universal platform for all unwanted molecules in the body isn't a feasible prospect, but there must still be a more efficient approach to break down or sequester or otherwise deal with the many different molecules in each specific location. Platforms are needed, approaches that can be cost-effectively customized to attack many molecules with very different characteristics. The catalytic antibody platform of Covalent Bioscience is one illustrative example. Another might be a company that uses recently developed techniques for culturing arbitrary bacterial species in order to efficiently mine soil and ocean bacteria for the tools they use to break down specific problem molecules, and which can serve as the basis for enzyme therapies.

Restore Youthful Hematopoietic Function

A complex hierarchy of hematopoietic cells in bone marrow is responsible for generating all immune cells, but this system runs awry with age. It begins to generate too many myeloid cells, and the hematopoietic cells themselves become inherently damaged, as well as dysfunctional in response to signaling changes, such as those that accompany chronic inflammation. Next to regrowth of the thymus, rejuvenation of hematopoiesis is the other important component needed to restore an aged immune system to more youthful function. The most direct of potential approaches is the transplantation of new hematopoietic stem cells. The older the patient, the more damaged the existing population, and the more likely it is that this will be necessary. But there are other approaches that might be taken earlier, such as adjusting signaling, protecting existing hematopoietic cells, changing the behavior of supporting stem cell niche cells, and so forth. This is a field which has for some years seemed on the verge of generating a viable approach to a rejuvenation therapy, and many lines of research are at the point at which they could in principle transition to clinical development. Champions are needed.

Comments

I wonder if the spiroligimers being developed by Thirdlaw Technologies to remove glucosepane could also be used to remove amyloids?

Covalent Biosciences seem to be making no progress over the years. I think their funding must have dried up for now. I hope they get some more or get to make progress soon.

Posted by: jimofoz at January 22nd, 2021 6:05 PM

Regarding Make Worthwhile Treatments for Aging Accessible to the Masses, I remember an article on fightaging about how quercetin coated onto iron nanoparticles to improve absorption might take it from an ineffective to an effective senolytic (although no animal data has been produced yet).

https://www.fightaging.org/archives/2019/10/quercetin-coated-nanoparticles-shown-to-be-senolytic-in-cell-cultures/

Once animal data is in, would these be able to be sold legally as a supplement in a lot of Western jurisdictions? If not, manufacturing them sounds challenging but not impossible, so someone might be able to do this as a scofflaw via the internet?

Posted by: jimofoz at January 23rd, 2021 4:57 AM

Ok, re-reading the article I linked to, I see the link to the fightaging article that Quercetin probably won't be useful as a senolytic:

https://www.fightaging.org/archives/2018/01/quercetin-is-probably-not-a-useful-senolytic/

How to solve the problem of there being no mass market senolytics available? The recently created artificial smart proteins could be a solution.

https://www.ucsf.edu/news/2019/07/415031/limitless-potential-artificial-protein-ushers-new-era-smart-cell-therapies

Although you'd still have to go to the expense of making a delivery system to get them into cells. And testing that they do not provoke immune reactions. Could you attach the TAT proteins that DRACO was going to use?

Posted by: jimofoz at January 23rd, 2021 6:13 AM

Does mRNA tech obviate the need for gene therapy?

Posted by: Matt at January 23rd, 2021 6:07 PM

Matt: not really. It still needs a vector to get it into cells to a meaningful degree in most scenarios. It is just another approach to achieving protein expression, with its own pros and cons. mRNA is very short lived in cells, and expression can't be constrained to cell types by promoters, for example.

Posted by: Reason at January 23rd, 2021 7:55 PM

"That said, near all gene therapy delivery technologies have the issue that when delivered systemically via intravenous injection, 80% or more of the injected vector will end up in the liver. Thus there must be a way to make that excess a non-event while still getting a useful amount of vector into the tissue of interest. Perhaps this could be solved by more sophisticated and much safer means of direct injection of internal organs, or more sophisticated carriers that can be steered to specific locations in the body before releasing their gene therapy cargo. Regardless, it seems plausible that there is some combination of the many approaches demonstrated in the laboratory or presently in clinical development that could result in a Gene Therapy Platform that Just Works for a majority of treatments. "

I can't find the news article now, but I read that modified base editors (themselves modified CRISPR Cas9 systems) had been engineered with a fusion protein to allow large precise DNA insertions.

Regarding the 80% of a therapy ending up within the liver, if you could combine this system (possibly in one lipid bubble/nanopartile) with UCSF's artifical protein that unfolds intra cellularly in response to another protein or molecule in the cell, then exposing a peptide area that carries out some function, such as activating the aforementioned CRISPR system, then you would have solved the tissue targeting problem.

And Oisin's lipid nanoparticles seem to solve the lipid nanoparticle toxicity problem, and lysosomal degredation problem.

Combine the three technologies and you have a precise gene therapy system (although that is a lot of work).

Posted by: jimofoz at January 26th, 2021 8:40 AM

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