LEAF Interviews Gary Hudson of Oisin Biotechnologies

Oisin Biotechnologies is developing a gene therapy approach to the clearance of senescent cells, and here I'll link to an interview with the CEO Gary Hudson conducted by the volunteers of the Life Extension Advocacy Foundation (LEAF). Oisin Biotechnologies is very much a company of our community: seed funded by the Methuselah Foundation and SENS Research Foundation, later angel investors drawn from the audience here, and headed by by one of the earliest supporters of the Methuselah Foundation and the SENS rejuvenation research programs. As regular readers will know, the accumulation of senescent cells is one of the root causes of aging, and targeted destruction of these cells has long been a part of the SENS goal of bringing aging under medical control. Senescent cells make up only a few percent of all cells in aged tissue, but that few percent secretes a potent mix of signals that cause great harm, degrading the proper function of other cells, structures, and organs, and producing chronic inflammation. In the past few years, progress towards the goal of senolytic therapies that can destroy senescent cells has accelerated, with demonstrations of extended life and reversal of many measures of aging in mice.

A number of companies are now working on a range of therapies, aiming to bring the first practical, working rejuvenation therapy to the clinic. The Oisin approach is quite different from the therapies under development by the rest of the field, however. Companies such as Unity Biotechnology are focused on traditional drug discovery and development, in search of compounds that kill senescent cells more aggressively than they kill normal cells. It bears a great similarity to the development of chemotherapeutics, and many of the current senolytic drug candidates capable of inducing apoptosis in senescent cells are in fact chemotherapeutics, tested in past years for their ability to kill cancerous cells. In contrast, the Oisin technology involves the delivery of a programmable DNA machine into cells, triggered to induce cell death by specific aspects of internal cell state, such as high levels of specific proteins. In the case of senescent cells, the machinery is triggered by p16, the most commonly agreed upon sign of cellular senescence.

It is the programmable nature of the Oisin technology that makes this company significantly different from its competitors. This was demonstrated earlier this year with the announcement that the technology is effective against cancer when triggered by p53 instead of p16. A few moments of thought might convince you that the sky is the limit here: in principle any specific cell population can be characterized by its internal state, and a variant of the Oisin treatment delivered to destroy those cells. Think of all the varieties of unwanted cell that exist, or situations in which the balance of different types of cell could be adjusted for benefit. Aged individuals are laden with errant immune cells of numerous types, for example, from those uselessly dedicated to cytomegalovirus to those causing autoimmunity. Certain types of macrophage could be culled temporarily because they hinder regeneration. Osteoclasts could be reduced in number for a while in order to allow osteoblasts to generate greater deposition of bone and turn back the course of osteoporosis. And so forth. There is far, far too much here for any one company: if you are in the life science field and have a good idea as to how to produce benefits by destroying specific cells, then you should reach out and license the technology.

Gary Hudson - Senescent Cell Clearing and Cancer Therapeutics

For those readers not familiar with how your technology works, could you give a brief summary of it?

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.

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 senescent cells 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.

Cytomegalovirus (CMV) contributes to infectious burden and increases over time. 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 Research 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.

We have seen increased interest lately in increasing the ratios of H1 and H2 macrophages to treat conditions. 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. The beauty of our approach is that it is easy to try various types of promoter targets, and once we have resources to do so, we will expand our repertoire of targets. 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.

Have you started a mouse lifespan study to see if increased lifespan is observed with senescent cell clearance, 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.

Comments

If Oisin's fusogenic lipid nanoparticle technology works out then they will have solved the problem of delivery in gene therapy, which has been a long standing problem.

This is why I am a little bit worried about this technology. If it was so straightforward, why hasn't someone else already done it by now? Is any other group/company investigating fusion-associated small transmembrane (FAST) proteins to enable "liposome-cell fusion, bypassing the degradative endocytic entry pathway, releasing the [liposome] contents directly into the cytoplasm."?

Would a Lifespan.io fundraiser to investigate Oisin's suicide gene therapy technology against CMV be possible? How much would that investigation in an animal model actually cost?

Posted by: Jim at July 12th, 2017 5:00 AM

A fundraiser is possible for sure and its certainly the kind of project we would be interested in hosting. CMV is a really big problem in my view as it contributes to inflammaging.

Posted by: Steve Hill at July 12th, 2017 5:32 AM

@Jim Biologists get tunnel-visioned extremely easily. We have too much information and not nearly enough basic research now - just look at Yamanaka, the guy got a Nobel prize for putting a couple of proteins we've known about for 20 years in a petri dish with some cells.

Sometimes it really comes down to trying stuff until something happens.

Posted by: Anonymoose at July 12th, 2017 6:08 AM

@ Jim - I don't regard our LNP technology as the be-all and end-all transfection approach. LNPs have varying degrees of efficiency in various tissues, for example, and that needs to be taken into account. There is lots to learn yet. But I believe this tech will get us to a "first-in-man" clinical trial in the next year, and will have an important role to play in the future of regenerative aging and anti-cancer therapies.

Addressing your other question, for a proper study, something under $100K. We'd do such work in collaboration with an interested academic lab.

Posted by: Gary at July 12th, 2017 10:34 AM

Gary, can the fusogenic lipid nanoparticles penetrate the blood-brain barrier with any efficiency?

Posted by: Empirical at July 12th, 2017 1:33 PM

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