Oisin Biotechnologies differs from other companies producing senolytic therapies, the name given to treatments that destroy senescent cells, in one very important way. The Oisin technology is highly adaptable, and can be programmed to kill any class of cell that has some distinct internal marker in the form of high levels of expression of a specific protein. The founders started with senescent cells based on the p16 marker, but as this latest interview with Gary Hudson makes clear, have expanded their efforts to effectively target cancer with p53, and beyond that they are really only limited by time, funding, and a good map of the internal biochemistry of the target cell type. The sky is the limit in the long term: any type of cell that is undesirable should have some distinctive chemistry that can be attacked, and there are many possible targets.
This update is from FightAging.org. The writer of Fightaging is also invested in the Oisin company.
When cells detect that they have been irretrievably damaged, they enter a non-dividing condition known as cell-cycle arrest, or senescence. It’s believed this occurs to prevent cells from going “rogue” and turning cancerous. Ideally, they should die by the process known as apoptosis, but in this case, they don’t. They become “zombie cells” – unable to kill themselves or resume normal function. Senescent cells secrete molecules that cause inflammation in an effort to attract immune cells that would usually clear them. But for reasons that are not fully known, as we age, persistently senescent cells accumulate, leading to a large number of age-related diseases.
Oisín is developing a genetically-targeted intervention to clear these cells. As a recent study has shown, clearing senescent cells both reduces negative effects of aging pathologies and also extends median lifespan and survival.
Oisin Biotechnologies has been hard at work for a year and a half since the last Fight Aging! interview; what has been accomplished?
Lots. In June and August of last year we demonstrated that naturally-aged, 80-week-old B6 mice, could be safely treated with our therapeutic and have their senescent cells (SCs) reduced significantly in a dose-dependent fashion. For example, a single treatment reduced senescence-associated β-galactosidase (β-gal) staining (a well-accepted marker for senescence) by more than 50% in the kidneys, and restored the tissue appearance to that of about 18-week-old animals. This reduction in SCs was also confirmed by DNA PCR analysis.
We were then challenged by one of our investors (the Methuselah Foundation) to explore the use of our therapeutic in oncology applications. Specifically, they asked us to explore our ability to target tumors with p53, in place of the p16 targeting we use in our anti-aging applications. The work was first done in immunodeficient NSG mice so the mice couldn’t reject the human PC3 prostate cancer cells that were implanted in their flanks. Surprisingly, we saw as much as 90% reductions in tumor mass in 24-48 hours of treatment. These results were astonishing and virtually unprecedented.
We subsequently repeated these studies in immunocompetent mice intravenously infused with the aggressive B16 melanoma cell line and showed a reduction in lung tumor metastases of nearly twenty-fold over controls.
Has the Oisin cell killing technology evolved significantly since we last talked, with the new focus on cancer in addition to cellular senescence?
The platform technology is evolving, but the core idea remains the same. We’ve got a hammer we can wield to 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.
It might be helpful for readers if I recap our basic technology. The technology uses two elements. First, we design a DNA construct that contains the promoter we wish to target. This promoter controls an inducible suicide gene, also called iCasp9 (no relation to CRISPR’s Cas9). 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 consider “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 and traffics to the nucleus. There 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 insures that the target cells and 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.
The adaptability of the Oisin technology seems to me a big deal. Beyond cancer, what else can usefully be accomplished in medicine by killing specific cells? Do you see further diversification of the company’s efforts ahead?
We’ve only begun to explore some of the more exotic possibilities. But clearance of immune cells that have become aberrant in some manner is on the list. No doubt many opportunities will emerge as people become more familiar with our technology. As I mentioned earlier, we only have a hammer, but it can be both powerful and yet have exquisite precision when swung properly.
If a company turns up at your door with a compelling use for the Oisin technology and the desire to license it, is that interesting? Is being a hub for many third party cell-killing efforts a viable future vision for Oisin?
Definitely. We’ve begun such conversations with several parties already and are eager for more.
Have you established any ongoing collaboration with other companies and research groups?
We’ve been talking to a number of groups, both academic and industrial, and expect to enter into collaborative agreements with several later this year.
I understand you are starting in on a larger fundraising round. How is that going?
We have begun a Series A round and have it partially filled at this time. Negotiations have begun with “the usual suspects” to fill out the subscriptions to the round. Unlike the earlier seed rounds, which were primarily filled by angel investors, it looks like this round will also have family offices, VCs, and pharmaceutical industry partners.
We’re all waiting for a successful senolytic therapy to arrive at the clinic. When do you see Oisin’s approach being tested in humans? What are the steps yet to be accomplished on that road?
The next step for us is a toxicology study. We will begin our first non-human primate toxicology studies in about six weeks, and expect results by September. This pilot study will be followed by GLP toxicology studies in multiple species, in compliance with regulatory guidance for pre-clinical studies that will allow us to embark on Phase 1 and 2 human trials. We haven’t yet picked the indication we’ll be targeting in those trials, but very likely it will be prostate cancer. Cancer is a good first indication since it provides an easier path to the clinic than is the case for more subtle aging indications. But once we have completed Phase 1 and 2, we can reuse most of the data to ease the path to the clinic for purely aging-associated indications such as COPD, atherosclerosis, or liver diseases, to name some potential targets.
I’ve previously mentioned companion animals as another possible route to early commercialization, and we haven’t lost interest in that option, but it is frankly easier to treat humans (who don’t mind holding still for a few hours while we do an infusion of LNPs) compared with a dog or cat that needs to be lightly anesthetized to be similarly treated.
The field of senolytics has certainly blossomed in the past year; putting the Oisin approach to one side for the moment, do you have opinions on the relative quality of other senolytic technologies and companies?
Oisin believes a healthy senolytic industry will require a number of different approaches to the problem of clearing SCs. We certainly don’t want to say on approach is to be preferred over another for all SC targets, at least at this stage of our ignorance. For my part, I like the “information-based” approach we are taking more than small-molecule approaches, due to the unlikeliness of off-target effects. But successful whole body repair and rejuvenation is likely to require several complementary therapies.