Shedding Senescent Cells with Deciduous Therapeutics
Welcome to Molecular Ideas. We’re back today with a Startup Showcase for a cutting-edge pharmaceutical company dedicated to treating age related co-morbidities by rejuvenating immune function, as well as insights into building a company for commercial success from a serial biotech entrepreneur.
The human body is gifted with astonishing regenerative capabilities. We see them in action when we fall and scrape our knees, only to have a scab a few minutes later. We see them over the long-term when a stroke survivor re-learns how to move, or when a liver transplant patient shows a normal organ volume. These minor miracles are the result of numerous cellular and biochemical systems acting to preserve healthy tissues across the body’s many organ systems, while repairing and removing damaged cells in the process.
The immune system plays an outsized role in ensuring our body can repair and regenerate itself during times of extreme stress, from helping repair injuries to dispatching infectious diseases. However, it also plays another role: monitoring our own cells for aging or damage.
The cells in our tissues don’t last forever. Most cells in our bodies can only divide a maximum of 40 or 50 times (known as the ‘Hayflick limit’). As they approach this threshold, they are programed to commit suicide and make way for the next generation of cells to take their place. Failing that, cells can become senescent.
How Senescence Arises© Molecular Ideas | Created with BioRender.com
What do Zombies & Cellular Biology Have in Common?
Senescent cells are more commonly known as ‘zombie cells’. While they are metabolically active, they’ve become irreversibly damaged and therefore do not fulfill their predesignated function. Anyone who has ever seen a zombie film knows that one zombie isn’t much of a problem, but they often present a problem in numbers.
Senescent cells are the same. They release inflammatory signals that can damage surrounding healthy tissues. Moreover, the immune system fails to accurately identify and dispose of these cellular zombies. The tissues around them age prematurely, which ultimately gives rise to dozens of specific diseases. These range from Type 1 Diabetes and ocular disease to fibrosis, osteoarthritis and many more. Further, it has been shown in a number of peer reviewed journals that removing these pathogenic ‘senescent’ cells is a highly effective way to treat diseases that are poorly managed today.
Fortunately, I had the chance to sit down with Robin Mansukhani, CEO of Deciduous Therapeutics to learn more about how they are harnessing the immune system to shed senescent cells – just like trees shed their leaves in the Fall.
Senolytic's Promise: Making a Fresh Start
Senescence in the anti-aging space represents one of the uncharted frontiers of the pharmaceutical industry. Major efforts have been made to better understand the underlying effects of these cells on tissues. Legacy pharmaceutical companies like Bristol-Myers Squibb have attempted to reposition cytotoxic oncology drugs to attack these obstinate cells directly, but with limited success.
By comparison, Robin’s company is taking a more endogenous or natural route. Their platform-based portfolio is based on rejuvenating the immune cells that specifically scan, recognize, and eliminate senescent cells, but become less functional as we age, therefore opening the door for certain diseases to develop. These are our Invariant Natural Killer T Cells (iNKTs).
Invariant Natural Killer T Cells (iNKTs) Attacking Senescent cells | Image Source: Shutterstock
“To date, the core function of iNKT cells has been poorly understood and thus improperly positioned therapeutically. However, when you look at the epigenetics of senescent cells, they have a clear cross talk with iNKT cells .” Robin says. “Experimentally, we can take diseased and older mice who have impaired iNKT function, and remobilize these [immune] cells with our small molecules to help them carry out their natural function [of eliminating senescent cells].”
So, What’s the Endpoint?
So, what happens to the spaces in the tissue left by the departure of the senescent cells, and how does it affect disease progression? Since senescent cells release inflammatory biochemicals into surrounding tissues, they cause chronic damage that can exhaust the body’s regenerative abilities. This drives fibrosis – the formation of scar tissue in place of healthy tissue. While a scar on your skin may be a minor inconvenience, internal scars can reduce the ability of organs to perform critical functions.
Ideally, this enables the body’s incredible regenerative abilities via stem cells to regain their natural function. By removing the senescent cells, the space becomes free for healthy stem cells to fill the gaps in your tissues to resume normal functions. Of course, that’s optimistic; chronic damage is hard to undo. However, even slowing the progression of disease can make a massive difference.
The most important thing to Robin is to generate paradigm shifting data. He also articulated a key point that all biotechnology entrepreneurs should take to heart: “I tend to favor measuring success through quantitative, irrefutable endpoints over glorifying mechanisms. I think mechanism is fascinating to talk about, but at the end of the day, it's the endpoints that are quantitative and define the ultimate utility of our medicines for patients.”
Image Source: Shutterstock
One of the current challenges in this space is that the FDA does not recognize aging as a formal indication. This is due primarily to the heterogeneity of “aging”, lack of clinical diagnostic tools and quantitatively validated biomarkers, rather than underlying basic research. However, it places even greater importance on the Deciduous Therapeutics platform: if you have a core molecule that can be used to modulate iNKT cells in certain tissues, there’s a chance you can tailor it for other tissues without altering the underlying the core mechanism of action. Using this philosophy, the company is exploring a wide range of indications for their technology, including multiple disorders within the fibrosis, ocular, and metabolic disease classes.
Thus far, preclinical data and animal models have begun to show causal links between the biology and technology. By working with the FDA to define appropriate surrogate endpoints, Robin plans to move Deciduous’ lead molecules into IND enabling studies and Phase I trials.
Follow (Some of) the Money
Developing and commercializing new compounds is a Herculean task without having to convince the FDA of your platform’s underlying clinical value. With the benefit of a decade of experience, Robin has seen more and more venture capital funding flowing towards biotechnology and the anti-aging space. That said, he recommends proceeding with caution.
“There's some ‘funny money’ out there looking for anti-aging startups [because it is an untapped field] but the value prop is easy to digest for most anyone.” Robin told me. “Therefore, you really have to be conscious of who you select as your investors. Traditional biotech investors may be moored to traditional approaches. I believe the investors best equipped to play in the field have strong scientific underpinnings but also the vision to see how we can more effectively treat the co-morbidities of aging with systemic, multi-indication targets.”
Image Source: Shutterstock
We’ve spoken previously about the founder’s ‘fit’ to investors on a quantitative and qualitative basis. Financing biotechnology startups is inherently complex due to unique combination of large capital investments over long and risky development horizons alongside exceptionally technical products.
The idea that hype can influence investments with this degree of importance felt nonsensical, so I asked Robin how he learned to tell the difference through his experiences as a serial entrepreneur.
His reply: “Above all, your investors need to be educated about what you're doing and should be able to help materially when needed. Further, they will sometimes be your microphone and speak about the company when you're not there. There are a number of investors who have taken the time to really learn the diseases underlying the risk to longevity and aging in immune cell targets – they are the ones who are best equipped to play in the field.”
Of course, that trust goes both ways. “They're putting their faith and trust in us to be good stewards of their capital. I feel very deeply that I owe them our best effort and our best everything to get it done for them.”
The flipside of evaluating whether an investor is a good fit for you is establishing whether you are a good fit for investors. Given the irregular progression that pre-clinical science often takes, I asked Robin for any tips he could share about planning well. Simply put, focus on the critical path. There are endless studies you can run and papers you can publish, but all that really matters is the impact to the patient and keeping them safe. With respect to development, he told me: “Once your development candidate shows strong efficacy and safety profiles, then the timelines become well defined.”
Leafing Through Technologies
We left our interview discussing how Robin got started as a biotech entrepreneur and how he evaluates new project ideas. Ironically, he began his career as a venture capitalist (VC) – the endpoint for many successful entrepreneurs. However, Robin and I share the need to be hands-on, but the way he says it is too elegant to paraphrase:
“I ask myself what I really care about doing, and then start reading. Eventually I find things that just fire me up to the point where I can't rest. To start a company without any promise of funding, you need to be in it for more than just having a job. You need to be emotionally and intellectually invested in this to be successful. From there, I look at the recent research, find out who's doing it just reach out. I don't care about whether or not I know the person, I will gladly just send them an email or give them a phone call. When I come upon groundbreaking science, no matter how early, there’s an innate desire to enable an opportunity for that work to see the light of day.”
Of course, connections help. Between being integrated into UCSF’s technology transfer office and many acclaimed research laboratories, Robin has no shortage of friends to help him evaluate technologies. What stands out about all of this is the metaphor of senescence is antithetical to building startups. As we go through life, some of us become habitual, even inflexible. When we shed preconceptions about what can’t be done, it’s easy to find that spark that helps us feel - and even be - young again.
Image Source: © Molecular Ideas
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