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Reversing Atherosclerosis With Repair Biotechnologies

Interview with Reason, Founder of Repair Biotechnologies

Repair Biotechnologies is a preclinical biotech startup in the high growth, energetic longevity
industry, focused on reversing portions of the progression of aging through repair of the
deeper underlying causes of aging and age-related disease. The lead preclinical program is a first in class approach to reversal of atherosclerosis, so far an elusive goal for the research community. The company delivers enzymes to cells that break down the toxic cholesterols that cause the

Podcast Interview

Tell us more about the Longevity industry. How big is the anti-aging marketplace and how fast is it growing?

There was no longevity industry when I first became involved in rejuvenation research and advocacy in the early 2000s. After more than a decade of a philanthropic focus, a handful of companies started popping up in the mid-2010s, when I first started investing. Now there are more than 130 biotech companies in the longevity industry, according to the Aging Biotech Info resource compiled by a fellow angel investor. Similarly, the Longevity Fund was the only industry-specific fund back in 2016, with only a few million under management. Now Juvenescence and the Longevity Vision Fund both have more than $100M under management, numerous smaller funds such as Apollo Ventures are dedicated to aging-related biotech, many existing large funds are taking positions in this industry, and I’m aware of at least three new longevity-dedicated funds that are in the process of raising $50M+ in funds from LPs.

The present anti-aging marketplace – characterized by lies, fraudulent misrepresentations of efficacy, and outright nonsense – is around $50B in size, depending on what exactly you want to include in that definition. To take another benchmark, the market size for atherosclerosis treatments is around $22B. These treatments fail to reverse the condition, and do little more than postpone mortality by a couple of years. They really are not all that much better, considered in the grand scheme of things, than anti-aging cosmetic products that claim to reverse skin aging. As Jim Mellon of Juvenescence likes to say, if these industries can be so large now, just imagine how much they will be worth when the interventions actually work in a meaningful way.

The vision of “imagine the ROI if it actually worked” is what is driving the strong investor interest in the longevity field. A variety of new biotechnologies show strong evidence of actual, real, sizable functional rejuvenation – reversal of age-related disease – in old animals, and they are new making their way towards the clinic. The target market for all of these therapies is off-label use by every human being on the face of the planet much over the age of 40. That is an eventual market of staggering size.

Age related diseases are responsible for the majority of deaths and hundreds of billions in drug sales. Tell us more about the causes for aging and the existing leading treatments.

Aging is an accumulation of damage. In practice this means broken proteins, malfunctioning cells, metabolic waste that the body struggles to break down. These are simple causes but the body is a complicated set of systems, and so the end result is a big, complex, hard to understand mess. The way to deal with this is not, as most past medical development has attempted, to start at the symptoms, the end stage of the disease, and try to figure out that mess. It is a task of unforgiving difficulty, and that this has been the strategy for the research community is why most historical treatments are marginal in effect – it is why we are all still aging and suffering, and only a little less than our ancestors.

No, the right approach is to identify underlying damage that is (a) amenable to being fixed, and (b) as close as possible to the root causes of aging. Then periodically fix it before it grows to pathological levels. The most easily grasped example of this approach in the present industry is the development of so-called senolytic therapies that selectively destroy senescent cells. Senescent cells grow in numbers with age, and they actively maintain a dysfunctional state of metabolism by secreting factors that cause inflammation, disarray in tissue maintenance, and harmful restructuring of tissues, among other problems. The more of them you have, the worse off you are. Any means to selectively kill these cells produces literal rejuvenation by allowing metabolism and tissue function to return to a younger state. It is a form of repair and maintenance for people.

The new therapy of your company successfully catabolizes cholesterol and oxidized cholesterol in cells.  Tell us about the rejuvenation therapies that Repair Biotechnologies is developing for this form of damage that causes aging and disease, and more specifically how you reverse atherosclerosis, which is the number 1 killer in the developed world.

As we grow old, we exhibit ever greater sustained background inflammation, and an ever greater disruption of the function of the cellular power plants called mitochondria. Both of these lead to a greater level of oxidizing molecules in and around cells. One important consequence, perhaps the most important consequence, is that an increasing fraction of the cholesterol molecules throughout the body become oxidized and otherwise altered, converted into toxic forms that harm cells.

Cholesterol flows through the body in the bloodstream. Some of it inevitably ends up stuck in blood vessel walls, where it is unwanted and unneeded. Immune cells called macrophages then ingest the errant cholesterol and send it back into the bloodstream to be returned to the liver. This works just fine in youth, but rising levels of oxidized cholesterols cause macrophages to become dysfunctional and die – but not before calling in reinforcements that will also become dysfunctional and die. Fatty lesions begin to form in blood vessel walls, growing as cell true and fail to remove the oxidized cholesterols that started the whole process. This is atherosclerosis. These atherosclerotic lesions grow to narrow and weaken blood vessels, causing heart failure, and eventually the fatal rupture or blockage of a stroke or heart attack.

We address this problem by providing macrophages (and other cells) the ability to break down cholesterol and oxidized cholesterol in situ. Specialized cholesterol catabolism enzymes not normally present in these cells enable the problem cholesterol to be removed directly. Macrophage cells equipped with these enzymes are essentially immune to the problems that impair and destroy their unmodified peers, and will in principle be able to carry out their jobs effectively, even in older individuals with a high burden of oxidized cholesterols. Delivering this technology into animal models and patients will in principle allow us to reverse the progression of atherosclerosis, letting the cells of the body get on with their normal task of reducing the fatty lesions, unimpeded.

Separately, in our modern culture of convenience and cheap calories, people tend to gain excessive weight with age. This has numerous detrimental effects, mediated by excess visceral fat tissue. For example, a sizable portion of the harms of fatty liver disease results from having too much cholesterol in the liver for liver cells to handle. The consequence is pathological dysfunction of that tissue. A way to get rid of this cholesterol would certainly help patients, and that is another possible application of our technology.

Further, there are a number of rare diseases caused by genetic mutation in which cholesterol processing is impeded in a critical cell population or part of the body. Our class of therapy may well allow effective management of these conditions, and we plan to evaluate this approach.

At your leading website in the aging biotech community “Fight Aging!”, you encourage the development of medical technologies & healthier lifestyles. Please explain how funding startups in this space is a necessary continuation of non-profit research.

The longevity industry is still very young, in the grand scheme of things. It is the blossoming of two decades of challenging patient advocacy and hard work in the scientific community. Starting around the turn of the century, it was a slow process of bootstrapping to convince scientists that rejuvenation research was a legitimate field of inquiry, and that addressing aging as a medical condition was both viable and something one could do without committing career suicide. Given where things stand today, it is perhaps hard to remember that 20 years ago the media ruthlessly mocked anyone working on treating aging, the leaders of the aging research community actively suppressed interest in work on intervening in the aging process, and there was very little funding for such work.

We won that battle. The research community is now firmly behind the concept of slowing and reversing aging through treating the causes and mechanisms of the aging process. But climbing the foothills is just the prelude to climbing the mountain. Yes, the research community is now turning out solid approaches that could produce rejuvenation therapies, and demonstrating rejuvenation in many ways in laboratory animals. Now we need to actually build the rejuvenation therapies, we need to convince Big Pharma and conservative biotech investors capable of funding the enormous expense of human clinical trials that this all actually works. The way to do that is to fund the startup biotech companies that perform the preclinical and clinical development. It is the necessary next stage of ensuring that we all live longer, healthier lives and that there will be ways to treat the age-related diseases that lie ahead of us all.

Having been a patient-advocate and an investor in the longevity space for 20 years, what are some of the most exciting investments you have made in this industry?

Obviously, my investment in the company I co-founded, Repair Biotechnologies, has been the most exciting for me. It is very rewarding to be a part of the hard work needed to bring a new technology to the clinic, particularly one that targets such a huge cause of death and disability in late life.

I would say that Oisin Biotechnologies is my other favorite investment. They work on senolytic therapies via a programmable suicide gene therapy approach. This is not just one of the first true rejuvenation-focused companies, building a method of repair and maintenance for old people, but their technology is particularly exciting. It is a very flexible way to destroy specific cells based on which genes they are expressing, accomplished with minimal to no side-effects anywhere else in the body. They have already adapted this into a very broad anti-cancer therapy via spin-out OncoSenX, and could in principle apply the platform to just about any situation in which someone would be better off absent a population of problem cells. There are countless age-related conditions that fall into that bucket.

How do you believe the longevity funding opportunities change / evolve over the next decade? 

The biggest near term change, on a timescale of a few years, will be the first clinical approvals of rejuvenation therapies – almost certainly senolytic treatments. The consequent widespread use and sizable, immediate patient benefits will lead to the public realization that treating aging is possible, that near all age-related conditions can be made less onerous. This will produce a huge influx of interest in the longevity field, to the point at which it is hard to predict how it will unfold and the degree to which it will spur an explosive growth of development efforts, valuations, portfolios.

On a similar time frame, two or three other very broad approaches to rejuvenation will reach a similar tipping point to that already passed for senolytic therapies. Perhaps epigenetic reprogramming, clearance of cross-links, and repair of age-damaged mitochondrial function. Perhaps others. These will each drive sizable opportunities for investment, with many competing companies and strategies, vying for a place in an industry large enough to hold them all comfortably.

One way or another, there will be an enormous expansion in the approaches to the treatment of aging and the number of organizations participating. That will bring with it the final stages of the transition from a community of passionate advocates – near everyone in the field at the moment, investor or entrepreneur, is here because they feel strongly about aging – to a more business-focused field much like the rest of biotech, except producing much better results for patients. This is a good thing. There must alway be a hand-off from the early founders of a field to those who will carry it forward for the long term.

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