As an approach to treating aging, senescent cell clearance has come of age. Rapid progress in a number of strategies has taken place in the past couple of years, UNITY Biotechnology made their big splash announcement of intent a few weeks ago, and life extension has been robustly demonstrated in mice through the removal of senescent cells. It is a great time for SENS, the Strategies for Engineered Negligible Senescence, as this one important strand of rejuvenation research - supported and advocated for more than a decade - is now energetically moving into clinical development. This pulls in previously unavailable funding from the venture community and at the same time expands public awareness of the plausibility of treating aging as a medical condition.
Today's topic is another young senescent cell clearance company that I've been enthused about since early last year: the company is Oisin Biotechnologies, founded and initially self-funded by Gary Hudson and Matthew Scholz. The Oisin researchers have what is arguably the best of current approaches to senescent cell removal and are to my eyes closer to implementation in humans than is UNITY. The early Oisin prototype work was known to the SENS Research Foundation folk soon after they started - this is a small community - but the path to getting the company seed funding in 2014 from first the Methuselah Foundation and then a few months later by the SENS Research Foundation was driven by David Gobel of the Methuselah Foundation. That funding paid for a successful proof of concept demonstration in mice, and earlier this year a new round of fundraising took place to set in motion the next stage of clinical development. I'm pleased to say that Fight Aging! participated in that round, a small helping hand for this important development project. More on that tomorrow, but for now let me turn you over to Gary Hudson of Oisin Biotechnologies to explain how they are approaching the challenge of senescent cell clearance to produce a rejuvenation therapy:
Who is Oisin Biotechnologies, how did you meet and decide that this was going to be your next venture?
Oisin was founded by two individuals, Matthew Scholz, who came up with the basic scientific approach for our first technology, and myself, who provided the initial angel funds along with the Methuselah Foundation and later, the SENS Research Foundation. I'm serving as Acting CEO while the company is in virtual mode.
Matt and I met a few years ago at one of the Bay Area Health Extension Salon evening programs (created by Joe Betts-Lacroix of Mousera). Interestingly, the primary speaker that evening was an old friend of mine, Judy Campisi of the Buck Institute. Matthew was a kick-off speaker introducing his then-new gene therapy company Immusoft. Judy was talking about exciting work that had just been published out of the Mayo Clinic that showed profound benefits of removing senescent cells in transgenic mice. Coincidentally, a follow up to this original work just published in Nature last week showing that clearing senescent cells could substantially extend life in naturally aged mice.
After the talks, Matthew and I were musing about potential ways to kill senescent cells that could be viable in humans. (By this time Matthew had spent a great deal of time researching vectors for gene therapy and was working with a non-viral suicide gene developed at Baylor and already used in humans). Matthew said he thought we could use a particular liposomal vector he'd come across in the past with the suicide gene to kill senescent cells in humans. He said he was too busy with and committed to Immusoft to take on another project, and it was so different from Immusoft's technology that it would likely be a detrimental distraction to their work if he tried to pursue it there. But the more we talked about it, the more compelling it sounded. Finally, I just said, "This has to happen. If you write this up, I'll fund it myself. I'll be the CEO and raise the rest of the money we need to see if it works." So, we licensed the liposomal vector, filed the first patent and built our prototype.
You are clearing senescent cells; what is the approach you are using, and how far along is it?
Our approach is quite different from most other attempts to clear these cells. We have two components to our potential therapy. First, there is a gene sequence consisting of a promoter that is active in the cells we want to kill and a suicide gene that encodes a protein that triggers apoptosis. This gene sequence can be simple, like the one in the Baker paper that kills p16-expressing cells, or more complicated, for example, incorporating logic to make it more cell type specific. The second component is a unique liposomal vector that is capable of transporting our gene sequence into virtually any cell in the body. This vector is unique in that it both very efficient, and appears to be very safe even at extremely high doses.
There's a subtle but profound distinction between our approach and others. The targeting of the cells is done with the gene sequence, not the vector. The liposomal vector doesn't have any preference for senescent cells. It delivers the gene sequence to healthy and senescent cells. We don't target based on surface markers or other external phenotypic features. As Matthew likes to say "we kill cells based on what they are thinking, not based on surface markers." So if the promoter used in our gene sequence (say, p16) is active in any given cell at the time of treatment, the next part of our gene sequence - the suicide gene - will be transcribed and drive the cell to apoptosis. However, if p16 isn't active in a given cell, then nothing happens, and shortly afterwards the gene sequence we delivered would simply be degraded by the body. This behavior allows our therapy to be highly specific and importantly, transient. Since we don't use a virus to deliver our gene sequence, and our liposomal vector isn't immunogenic, our hope is that we should be able to use it multiple times in the same patient.
So far we have demonstrated that our vector and gene sequence can efficiently and selectively kill senescent human cells in culture, and that we can target senescent cells in vivo in mice treated with chemotherapy. The next step is to show that our approach can achieve senescent cell clearance along the lines of the work done at the Mayo Clinic, but in a translatable model - without the use of their transgenic INK-ATTAC mice. After all, we aren't transgenic mice. As exciting as their work is, the data in those papers is purely an academic exercise; the treatment they gave the mice would be of limited value in humans. Our hope is that we will have our first data from our next studies this year.
How does your approach differ from that of UNITY Biotechnology?
I don't have any first-hand knowledge of the activities underway at UNITY; you and I have probably read the same coverage of their efforts. It appears that they are focused primarily developing small molecule drugs to kill senescent cells. As I was describing earlier, we are taking a transient gene therapy approach. Put another - less conventional - way, we're effectively killing senescent cells with a genetic computer program that we upload with our liposomal vector.
The beauty of our approach compared against a small molecule is that, if we want or need to, we can very rapidly tailor our treatment to kill a specific kind of cell under a specific circumstance, or tailor it to avoid a specific kind of cell - all by just changing the gene sequence we deliver. What we really have is a platform that allows us to selectively kill cells based on very specific and customizable genetic criteria. That kind of flexibility just isn't possible with a small molecule drug.
You just raised a funding round, what is the plan for the next year or so?
As I mentioned, all of the elements of our approach are working well, so now it is time to combine the pieces and do the work required to turn a promising candidate into a life-changing therapeutic. We hope to conduct several in vivo studies in the near future to assess the impact of the treatment on senescence induced by various means. If time and money permit, we'll also begin to try to understand what dose ranges are optimal, how many treatments might be required to dramatically diminish senescent cell body burden, and so on. We'd also like to set up for a large lifespan study in mice and maybe other animals as well. We'll be looking to make alliances with pharma partners that are focused on particular FDA indications, such as COPD, BPH, and so on.
What is your take on the bigger picture of SENS and the goal of ending aging?
I've been interested in this topic since I was a teenager, right at the time we were doing real moonshots (not the Google equivalent). When people asked me what I wanted to do with my life, I routinely and only half jokingly replied - "fly to the stars and live forever" - borrowing a theme from the science-fiction writer James Blish. But I found that it was hopeless to expect progress on the aging front in 1969, so I turned my attention to space, and became one of the first commercial space entrepreneurs. After 45 years in that "space" I'm now ready to spend some time focusing on engineering a solution to the problems of aging.
I was also the first major contributor to the SENS project. I helped fund the first SENS conferences and also the Methuselah Mouse Prize. I believe in the basic SENS notion of treating aging as an engineering problem - repair, replace, and restore function and you will both increase healthspan and move towards escape velocity.
What do you see as the best approach to getting nascent SENS technologies like this one out into the clinic?
This is a complex question. Personally, I'm not too interested in the normal "pharma" path to the clinic. That's not to say that we (or more likely some future pharma partners) won't pursue this route, but the costs have to be weighed against the need to move therapies into public view, soon. So it's necessary to examine alternative routes to the clinic. One area that is slightly orthogonal to the traditional path is to work on veterinary and companion animal treatments before a human product. Working out our strategy is a significant part of my near-term job, with the other focus being the next major raise of dollars in our Series A, sometime in 2016.
If this works stupendously well and everyone involved becomes wealthy, what next?
Essentially all of my ownership stake in Oisin will go into my nonprofit (to be announced shortly) and will be used to advance cutting edge translational medicine. But while I hope we make a profit for our investors' sake, my ambition in helping found Oisin has been to move the needle on true anti-senescence therapies. If we're successful, yes, we have a good chance to make money. But money is only important to me in that it'd allow us to move quickly onto the next aging-related problem, and that's what we'll do.
To the degree that Oisin succeeds, that success will channel funds into the Methuselah Foundation and SENS Research Foundation, as well as to a number of individuals who are already strong supporters of the longevity science cause. These are people who, like myself, are well aware that the only rational use for excess money is to fund the development of radical life extension technologies. What use is wealth to the sick and the dead? The true power of wealth in our day and age is that it can now be spent to build the technologies needed to defeat aging and illness. If only it was the case that more people realized this, we might be so much further ahead.