A Recommended Tour of the State of Development of Senolytic Therapies

Today's article is a cut above the usual popular science standard in terms of detail and accuracy, capturing a snapshot of the present development of senolytic therapies. It is lengthy and touches on a range of present initiatives, companies, research programs, and clinical trials. Senolytics are one of the most important developments to emerge from the medical research community in quite a long time, in that they are the first rejuvenation therapy worthy of that classification. A senolytic treatment is one that selectively destroys senescent cells. These cells accumulate in old tissues, and while never rising to very large numbers, nonetheless contribute meaningfully to chronic inflammation and cell and tissue dysfunction of aging through the senescence-associated secretory phenotype (SASP).

Researchers have robustly and repeatably achieved rejuvenation in animal models via the use of senolytics, meaning reversal of measures of numerous age-related diseases, and extension of life span. Near any senolytic approach works, so long as it can remove senescent cells while avoiding harmful side-effects. Senescent cell accumulation is clearly an important process in aging, and a comparatively easy target for therapies intended to produce rejuvenation in the old.

A small number of human trials of first generation senolytic drugs have taken place in the past couple of years, some complete and published, some not. The initial trial data has been a mix of promising where it involved the use of the dasatinib and quercetin combination as a senolytic therapy, and an abject failure in the case of UNITY Biotechnology's attempt at treating osteoarthritis with a localized senolytic drug. The charitable viewpoint is that they tested the hypothesis that local administration could work, and have now demonstrated that it doesn't, because senescent cells in the rest of the body are delivering the lion's share of inflammatory signaling. The less charitable viewpoint is that the UNITY principals made poor decisions about drug choice and trial design, and that those choices looked like poor decisions ahead of time.

A single trial failure can put a damper on an entire class of treatment, causing investors to pull back, but in this case it seems quite clear that the the UNITY Biotechnology trial was not a good test of senolytics in humans. It wasn't even a good test of the ability of senolytics to treat osteoarthritis, given what we know of how it was conducted. And meanwhile, senescent cells are clearly proven in animal studies to cause the condition. Given what we know of the similar biochemistry of cellular senescence in mice and humans, the role of senescent cells in inflammation, and the role of inflammation in age-related diseases, it would be quite astounding to find that humans did not benefit greatly from clearance of senescent cells, in much the same way as occurs in mice. This is a very exciting area of development, and a very exciting time for the field of rejuvenation research.

Send in the senolytics

Unity Biotechnology was one of the darlings of the nascent anti-aging biotech sector. In August, that idea took a hit when Unity announced that its lead drug candidate had failed to beat a placebo in reducing joint pain and stiffness, according to interim results from a trial of patients with osteoarthritis of the knee. The company's stock plunged more than 60% on the news, nearly one-third of Unity staff were laid off, and its experimental drug UBX0101 - the first novel 'senolytic' agent ever to enter clinical testing - was swiftly abandoned.

That setback threw a pall over the entire senolytic field. A research note cited "substantially greater risk to the senolytic hypothesis." However, other experts were more sanguine about a class effect, highlighting issues with trial design, study population and UBX0101 itself - a small-molecule inhibitor of MDM2 designed to boost the activity of the proapoptotic p53 protein - as possible explanations for study failure. In the meantime, more than two dozen other startups continue to pursue approaches to target senescent cells - strategies that range from cell destruction and containment to senescence prevention and even reversal. "There are lots of different ways to tackle this, and I think that the initial failure of Unity's first clinical trial shouldn't be a discouragement. The field is young, it's still early, and there's a lot left to be discovered and tried," says Tim Cash, CSO of Senolytic Therapeutics.

Like Unity, most of these startups drew inspiration from a 2011 paper and a follow-up report showing the promise of senescent cell clearance to protect against age-related organ deterioration in normal aging mice as well. "I refer to those mice as the mice that launched a thousand ships," says Matthew Scholz, cofounder and CEO of Oisín Biotechnologies, a senolytics-focused gene therapy company. When it comes to raising funds, many of those senolytic 'ships' have hit rocky waters in recent months. Because of the UBX0101 trial failure, some investors - already burned once by the hype that surrounded the ill-fated anti-aging company Sirtris Pharmaceuticals and fearing a repeat with companies such as Unity - have shied away from pouring additional money into the antisenescence drug market.

Yet industry insiders say the problem with Unity's trial had more to do with the specifics of that drug and its study protocol than with the strategy of senolysis writ large. "Of course, we've been anxiously following their progress through the clinic, and we're disappointed too," says Lewis Gruber, CEO and CSO of SIWA Therapeutics, a company developing an antibody drug directed against a type of advanced glycation end product found on the surface of senescent cells. "But the actual technical results are, at least so far, not of concern to us. We don't see it as a problem for senolytics in general."

For starters, MDM2 may not have been the best target for senescent cell destruction. The protein is one of the most important negative regulators of p53, responsible for the ubiquitination and degradation of the proapoptotic tumor suppressor. As such, inhibiting MDM2 risks unleashing indiscriminate cell killing in off-target, non-senescent tissues. To avoid that kind of toxicity, Unity relied on a local delivery strategy. But according to biomedical engineer Jennifer Elisseeff from Johns Hopkins University in Baltimore, Maryland, local injections of UBX0101 are not sufficient to improve knee function in old mice with osteoarthritis. In her lab, systemic administration of another senolytic agent, navitoclax, was needed to tamp down the general inflammation in the body that was hampering tissue repair.

Then there's the drug itself. Other senescence researchers say that, in their hands, MDM2 inhibitors such as nutlin-3a have only weak senolytic activity. And there's evidence from Judith Campisi's lab to suggest that the drug could also work through attenuation of the SASP. If that mechanism predominates over cell elimination, a single dose of UBX0101, as administered in the trial, might thus offer only temporary relief before the inflammatory secretome would come flaming back.

Yet the early success of dasatinib and quercetin in human trials at least shows that the concept of senolysis is possible in patients. And it gives anti-aging researchers hope that more pronounced benefits will be seen with therapeutics rationally designed to modulate senescence in some way. "It'll happen sooner or later. The technology is just too good."

Comments

How long till the first positive in human result in a large study group?

Posted by: jimofoz at November 17th, 2020 8:01 AM

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