The current focus of Oisin is the targeted clearance of senescent cells through senolytics. Senescent cells are one of the hallmarks of aging, and as they accumulate, they encourage age-related diseases. Periodically removing these harmful cells has long been proposed by the SENS Research Foundation, and Oisin is taking this approach in a novel way.
The senolytic technology Oisin is using is different from other approaches, such as the small-molecule drugs being used by Unity Biotechnology, in one key way. Oisin’s approach is very versatile, and the system can be programmed to kill any particular kind of cell by targeting a specific protein that it expresses. The typical marker used to target senescent cells is p16; for cancer cells, it is p53.
Today, we have an interview with Oisin CEO Gary Hudson, who was one of the first people to support the creation of the Methuselah Foundation fifteen years ago and is working to bring one of the first SENS-based rejuvenation therapies to market. Oisin is moving forward quickly and is currently raising a series A round of venture funding to move things towards clinical trials.
1. For readers not familiar with how your technology works, could you give a brief summary of it?
We have a fairly simple implementation of inducible apoptosis. We can kill cells via apoptosis, and it’s pretty effective. Exactly which cells we choose to kill will change as we target various age-related diseases. So far, we’ve gone after p16- and p53-expressing cells.
The technology uses two elements. First, we build a DNA construct that contains the promoter we wish to target. This promoter controls an inducible suicide gene called iCasp9. Next, we encapsulate that DNA in a specialized type of liposome known as a fusogenic lipid nanoparticle (LNP). The LNP protects the DNA plasmid during transit through the body’s vasculature and enables rapid fusion of the LNP with cell membranes.
This LNP vector is considered “promiscuous”, as it has no particular preference for senescent cells – it will target almost any cell type. Once it does, the DNA plasmid is deposited into the cytoplasm. It remains dormant unless the cell has transcription factors active that will bind to our promoter. If that happens, then the inducible iCasp9 is made.
The iCasp9 doesn’t activate unless a small molecule dimerizer is injected; the dimerizer causes the iCasp9 protein halves to bind together, immediately triggering apoptosis. This process ensures that the target cells are killed and that bystander cells are left unharmed. So far, we have not observed any off-target effects.
We’ve also got some tweaks to both the promoter side and the effector side of the constructs that will provide even more interesting and useful extensions to the basic capability, but I can’t discuss those until later this year for IP reasons.
2. Senolytics have been big news for the last year or so, ever since Baker et al. first showed proof of concept. Many groups are engaged in researching small molecule drugs to remove senescent cells. What are the advantages of your system over the more traditional small molecule approach?
We’ve long thought that different populations of senescent cells might require different approaches to achieve sufficient clearance for effects to be apparent. So, the various ventures that have begun using – in some cases – wildly differing protocols for SC ablation may all have their place in the market.
I personally like our approach because of its tremendous specificity without apparent off-target effects. The latter issue is one that purveyors of the small molecule approach must always be concerned with.
3. Β-galactosidase and P16 are commonly used as targets for senolytics, but there is concern that senescent cells are not the only cells that express these factors. Stem cells for example express P16 but are not senescent. Have you examined the effect of senolytics on stem cell populations, and how would you deal with potential collateral damage?
We have not done such assessments. At the moment, we are relying upon the evidence of our eyes, so to speak. Baker et al. and others from Kirkland to de Keizer have shown health and median lifespan benefits from several different methods of senolysis. If stem cell populations were seriously adversely affected by these very different senolytic treatments (from transgene-induced apoptosis, to Dasatinib and quercetin, to FOXO4DRI peptides), we would expect to see negative consequences from the treatment, but, so far, we have not.
4. Cytomegalovirus (CMV) contributes to infectious burden and increases over time, and the immune system devotes more and more memory T cells to it, but it cannot remove it. It has been suggested that periodically purging these ineffective T cells may be useful. Have you considered using your technology for such a purpose?
Yes. We’ve made some initial efforts in this direction, and it is a favorite project of Aubrey de Grey at the SENS Foundation, but we don’t have any experiments currently planned. It is on our “to do” list along with several other immune system-related experiments.
5. On a similar note, could your system be used with things like HIV, where a payload to kill the infected cell could be deployed?
Possibly. Essentially similar solutions have been proposed by Todd Rider of the DRACO project, which was presented at SENS6 in 2013.
6. A number of experiments suggest that removing senescent cells improves healthspan, and the question still remains regarding lifespan. Have you started a mouse lifespan study to see if increased lifespan is observed, and what sort of mice are being used?
We would like to conduct a lifespan study but haven’t begun one as yet. First, lifespan studies are relatively expensive, for obvious reasons. Second, we hope to enlist an academic collaborator to participate in managing the study, but we haven’t located one yet. Finally, we are really focused on getting the treatment to the clinic and through Phase 1/2 studies in man. Doing anything that detracts from that goal means clinical delay.
I’m not sure what mouse or rodent strain might be best suited to a lifespan study, but I do know that our goal will be to test on aged animals (in mice, those that are over 70-80 weeks of age at beginning of treatment). Finding sufficient numbers of these animals is difficult, and they may have to be grown up from pups, adding to the delay.
7. How is progress going with targeting P53 rather than P16 for use against cancer?
Spectacularly well. We can ablate as much as 90% of solid tumor mass in as little as 24-48 hours and reduce metastases in both a human prostate cancer model by 10x and in a mouse melanoma model by 20x on similar timescales. Many commentators have expressed concern about targeting p53 due to its ubiquity of expression, but we haven’t found that theoretical concern to be a problem as yet in actual experiments.
8. We have seen many cancer drugs repurposed for senescent cell removal. Many of them focus on the BCL family that help the cells resist apoptosis; have you considered using BCL as a target yourselves?
We have not, but the beauty of our approach is that it is easy to try various types of promoter targets. Once we have resources to do so, we will expand our repertoire of targets.
9. We have seen increased interest lately in increasing the ratios of H1 and H2 macrophages to treat conditions such as heart disease, Parkinson’s, and peripheral nerve injury. The H1 macrophages generally cause inflammation and recruit other immune cells to an injury or infection site, while the H2 macrophages regulate and encourage healing of tissue. However, with aging, the balance gets upset and the H1 macrophages cause too much inflammation. Could your system be used to selectively destroy the H1 macrophages to favor a more healing environment?
So long as there is a promoter to be targeted, we could very likely achieve this goal. I’m not an immunologist, so someone with the necessary expertise would have to identify promoter targets and then we could have a go at it, again, if we have sufficient resources to conduct the experiments.
10. Finally, do you have a take-home message for our readers? What can the average person do to help the progress of rejuvenation biotechnology?
As I said in my recent Fight Aging! interview:
Public interest in the field of aging therapy must, sooner or later, be translated into public policy action. Letting legislators know that working on repair and regeneration is a “public good” is the first step towards getting the FDA to accept aging as a legitimate indication for treatment.
I’d like to close by saying that SENS technology is too important to be left to a handful of us who have pledged our lives, fortunes and honor to the task. We need more researchers, more companies, and more money. Get out there and do it!