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While many clever quips about gaining grace and wisdom with old age abound, aging, at its core, involves the progressive decline of numerous physiological processes. Over time, cells lose their ability to function, leading to the deterioration of tissue and organs. These declining functions leave individuals less able to handle various stresses and more vulnerable to disease.
Research over the last decade plus has sought to understand the specifics of why aging happens. In 2013, molecular biologist Carlos López-Otín and colleagues attempted to categorize the cellular and molecular drivers of aging by proposing nine (later expanded to 12) common hallmarks of aging.
The hallmarks can be divided into three groups: primary, antagonistic and integrative. The primary hallmarks of aging, such as genomic instability or epigenetic alterations, start the process, producing damages that accumulate with age. The antagonistic hallmarks, such as mitochondrial dysfunction and cellular senescence, start out beneficial but over time increase in intensity and become harmful. Finally, the integrative hallmarks, such as stem cell exhaustion and chronic inflammation, make their appearance after damage from the first two groups overrides the body’s homeostasis mechanisms.
While these hallmarks are not definitive, Otin’s research has reinforced the idea that there isn’t a singular cause of aging. Understanding the interconnectedness of these various drivers can help unlock the key to treating aging through an emerging class of drugs collectively referred to as longevity therapeutics.
“We strongly believe that longevity therapeutics could shift the focus from treating symptoms of aging to addressing its root causes, potentially reducing the prevalence of multiple age-related diseases,” says Thomas Solbach, partner at Strategy&, PwC’s strategy consulting business.
But in doing so, drug developers would upend the pharma industry’s conventional approach to treatment of age-related diseases — which has, for the most part, been one chronic disease at a time.
Solbach describes it as a “paradigm shift in health care,” — the idea that conventional therapies that individually target chronic disease could be replaced by longevity therapeutics that would markedly improve healthspan by simultaneously going after multiple chronic diseases.
Research published in 2019, led by Rejuvenate Bio co-founders Noah Davidsohn and George Church, sought to acknowledge the interconnectedness of age-related conditions by creating adeno-associated virus (AAV)-based anti-aging gene therapies for simultaneous treatment of several age-related diseases in mice.
“Noah and George were able to show that one treatment could have efficacy across a model of cardiac disease, renal failure and induced diabetes and obesity,” says Daniel Oliver, CEO and co-founder of Rejuvenate Bio. “That initial paper confirmed the idea that one treatment could, by generally making your patient healthier, be able to treat multiple chronic diseases across multiple classes. And it became really intriguing to try to create a new therapeutic class.”
If the idea of a mega-treatment, capable of making people healthier by attacking multiple conditions at once sounds familiar, it’s because the industry currently has a wildly successful example of this concept.
“If you look at the GLP-1 drugs, almost all of them started in the metabolic space and now they’re moving into cardiac and renal as well,” says Oliver. “GLP-1s are paving the way for an interest in this type of technology where people do believe that you could create one therapy that is able to treat multiple different indications and really change the health of the patient, not just a very specific disease or a specific problem.”
As research continues to unlock these interconnected biological drivers of aging, the potential for therapeutics that address chronic disease multimorbidity becomes increasingly tangible.
Crawl before you run
Despite encouraging preclinical progress, the longevity space has suffered its share of snake oil promises from bad actors, which has only muddied the waters for those offering legitimate science. Both regulators and investors require evidence, and for drug developers, that means traversing the so-called ‘valley of death’ — the perilous gap between preclinical research and clinical applications.
“We have cured every mouse on earth of every disease known to humankind. The only way to learn how to treat disease is to treat people with the disease,” pointed out Fyodor Urnov, co-founder of epigenomic therapy biotech Tune Therapeutics, in a recent podcast.
But the path to simultaneously treating multiple-age related conditions starts by picking a target to aim for in the clinic, whether age-related or not, that can have the biggest impact on patient populations.
“A big part of all of this is proof. When we started, we absolutely were utilizing factors that have been demonstrated in aging studies, but we didn’t know if they were going to be a game-changing cardiac therapy,” says Oliver. “And so, for instance, our initial programs, and you could have classified those as anti-aging gene therapies, but we’re now working in partnerships with animal and human health companies on a cardiac-focused gene therapy with label expansion opportunities.”
Rejuvenate Bio is currently working to establish the safety and commercial viability of its preclinical drugs in areas of unmet need. Rejuvenate’s pipeline consists of treatments in both the human and animal health space, and the company is utilizing a similar approach to development in both areas.
Building on research conducted at Harvard Medical School and the Wyss Institute by co-founder George Church, Rejuvenate is developing a AAV gene therapy treatment for the leading type of heart failure in dogs, mitral valve disease. The company has partnered with Phibro Animal Health for the development and commercialization of the therapy, RJB-01, which they hope will provide an early revenue stream to further develop the company’s human clinical programs.
“This is particularly illustrative of the power of the type of technology we are working with. One of the things this partnership implies that is intriguing for the general market is that these types of therapies can work for these blockbuster indications. We’re not talking about a specific genetic niche; the manufacturing costs and the scale that we can manufacture these on are relevant for millions of patients,” says Oliver.
There are an estimated 90 million dogs in the U.S. and about 10% of the canine population has some sort of cardiac condition, meaning there are millions of potential furry patients for Rejuvenate’s treatment.
Similar to its animal health drug, Rejuvenate’s most advanced human candidate, RJB-0402, is a liver-directed AAV gene therapy delivered as a one-time intravenous injection. The company shared preclinical data for the treatment last year, demonstrating efficacy in a mouse model of arrhythmogenic cardiomyopathy (ACM), an inherited disease caused by mutations in one of several genes encoding proteins in parts of the cardiac muscle known as desmosomes.
While not a disease typically associated with aging, ACM presents a profound unmet medical need, as there are no disease-modifying treatments, other than cardiac transplant for late-stage disease.
“I think it’s important to take really logical steps, attack particular indications, in particular organs or tissue areas, to understand what we’re doing and start moving that forward. But these things have a way of accelerating,” says Oliver.
Rejuvenate has already completed a pre-IND meeting with the FDA for RJB-0402 in ACM. Beyond this specific type of cardiomyopathy, Rejuvenate believes its gene therapy could expand into other cardiac indications, such as heart failure, and both the metabolic and renal space.
Tune Therapeutics, launched in 2021 by a veteran team that includes co-founders Akira Matsuno, Fyodor Urnov and Charles Gersbach, is taking on hepatitis B (HBV) with its experimental treatment, TUNE-401, which the company hopes to bring to the clinic by the end of the year. TUNE-401 represents a fundamentally new approach to HBV treatment in that it utilizes the company’s precision genetic tuning platform, TEMPO, to inactivate viral DNA integrated into host chromosomes, while simultaneously silencing the extra-chromosomal ‘viral factories,’ known as covalently closed circular DNA (cccDNA), necessary for sustained HBV infection.
Although an effective vaccine for HBV exists, it’s estimated that 296 million people worldwide are living with the virus. For most HBV patients, current standard of care treatments have proven insufficient to clear infection, leading to a lifelong, chronic condition. Tune’s therapy, however, could offer the first functional cure.
“A low percentage of patients can actually get a functional cure without drug intervention through epigenetic silencing of the hepatitis B virus DNA,” explains Jennifer Kwon, founding principal scientist at Tune. “And we can mimic that same type of process by sending our epi-editing tool to target that particular sequence.”
Since there is no large animal model available to study HBV, Tune used a surrogate target, PCSK9, to demonstrated durable, liver-directed epi-editing in non-human primates. In the liver, the PCSK9 gene provides instructions for making a protein that regulates cholesterol level; repressing it reduces elevated LDL-cholesterol (aka ‘bad cholesterol’) levels.
“We were able to dose monkeys one time with the epi-silencer, reducing the PCSK9 levels and subsequently lowering their cholesterol levels for over a year, with measurements still ongoing,” says Kwon.
The breakthrough research, led by Kwon, demonstrated that genetic tuning can drive the stable repression of PCSK9 following a single treatment, showcasing the potential to develop genetic tuning into a robust therapeutic modality for the treatment of other common chronic diseases.
The epigenetics leap
The epigenetics-based treatment undertaken by Tune forays into the area of longevity therapeutics that has captured significant public attention. Although often accompanied by splashy headlines teasing an ‘ageless future’ or the ‘pursuit of immortality,’ recent advances have backed the validity of new epigenetic reprogramming tools and the possibility of using targeted therapeutic interventions to influence the epigenetic regulation of specific genes.
The concept of epigenics dates back to the work of British biologist Conrad Waddington in the 1940s, who used the term to discuss the impact of genetic and environmental influences on cell type and tissue formation during embryonic development. It is now understood that the epigenome, a multitude of chemical tags attached to DNA and its surrounding proteins, directs gene expression and behavior.
But as we age, gene expression can go awry, leading to silent genes becoming activated and healthy genes being silenced. Many common diseases, such as cancer, are caused or made worse by this epigenetic regulation mechanism malfunctioning.
“Now that we have developed tools that can precisely alter the epigenome, it’s become almost an obvious way to utilize these tools to treat diseases that have these epigenetic bases. That’s why epigenetics and treating age-related diseases go hand-in-hand,” says Kwon.
Apropos to its name, Tune aims to effectively orchestrate different gradiations of the epigenome. Using its TEMPO genetic tuning platform, the company can turn up the volume on genes required for healthy cells and tissue or turn down the volume on genes that cause or contribute to disease, ultimately rebalancing levels of gene expression.
In 2006, Japanese physician and researcher Shinya Yamanaka — who later went on to win the 2012 Nobel Prize in Physiology or Medicine for his work — discovered a set of four specific genes that can reprogram mature, differentiated cells into a pluripotent stem cell state. These ‘Yamanaka factors’ work together to reset the cell’s developmental clock, effectively turning specialized cells, such as skin cells, back into a state of pluripotency, where the cell has the ability to develop into almost any type of cell.
Earlier this year, Rejuvenate published preclinical research detailing how researchers were able to double the remaining lifespan of elderly mice by delivering these Yamanaka factors via gene therapy.
“The idea here is not necessarily just delivering particular genes that encode for a protein or two, but really creating a therapy that changes the epigenetic state of a patient such that their cells, and more importantly, the gene expression profile that’s driving how their body is acting, is changed back to what it was when that patient was healthier,” says Oliver.
Importantly, the study results may have implications for the development of partial reprogramming interventions to reverse age-associated diseases in elderly humans and potentially extend human lifespan.
“And this really illustrates the excitement around epigenetic reprogramming, which is this idea of reversal. Can we reverse the state of these patients such that their body’s operating a way that’s more akin to what it was when it was younger/healthier?” says Oliver.
Making the golden years shine
While excitement alone does not a market make, the urgent unmet needs related to chronic disease and multimorbidity faced by the aging population are increasingly difficult to ignore.
The U.S. is experiencing unprecedented growth of the 65 and older population. And while more people are living longer lives, they aren’t necessarily living healthier lives. By 2030, an estimated 83.4 million people in the U.S. will have three or more chronic diseases, compared with 30.8 million in 2015. This shift will invariably affect federal assistance programs for the aging population, such as Social Security and Medicare. Fifty years ago, Social Security and Medicare spending accounted for 20% of the federal budget; those programs now account for more than one-third of federal spending.
One analysis of the economic value of targeting aging with treatments found that improving health by “compressing morbidity” — a concept put forth by healthy aging pioneer James Fries that hypothesizes that delaying the onset of illness can compressed disease burden into a shorter period — is more valuable than simply increasing life expectancy. The study used a statistical model to assign a monetary value to healthy aging, claiming that a slowdown in aging that improves health and increases life expectancy by one year is worth $38 trillion, and by 10 years, $367 trillion.
Despite what appears to be an urgent imperative, the broader pharma industry is moving tentatively when it comes to treatments that target the biological drivers of aging. “Large pharma still seems hesitant to invest,” says Solbach. “But entering the nascent longevity market offers significant advantages for large pharma companies and investors, such as first-mover advantage, substantial market share, and potential for high returns.”
Theoretically, this longevity treatment market would comprise several multi-billion dollar markets — one for each chronic disease that affects the aging population — and, since aging is currently inevitable, it would consist of close to 8 billion potential customers.
The space is not entirely without investment from multinational pharma companies, however. AbbVie has had a partnership in place with Alphabet-founded Calico Life Sciences since 2014 focused on the biology of aging and first-in-class targets for age-related diseases. In 2016, precision medicine company Human Longevity signed a 10-year deal with AstraZeneca to sequence and analyze DNA samples from AstraZeneca clinical trials. The San Diego-based venture also signed similar deals with Roche’s Genentech and Celgene. In 2020, Fountain Therapeutics, a biotech focused on treating diseases by reversing cellular age, was selected by Eli Lilly to move its corporate headquarters to the Lilly Gateway Labs in San Francisco. More recently, Genentech signed a licensing deal with Sangamo Therapeutics to develop intravenous genomic medicines to treat certain neurodegenerative conditions, including Alzheimer’s disease.
While epigenomic reprogramming to reverse age-associated disease or proactively prevent it is likely still years away in humans, savvy biotechs navigating this exciting space are taking a practical approach to tackling the looming public health crisis of an aging population.
“When they say ‘fountain of youth,’ that just sounds like a myth, but in reality it’s about treating the cardiovascular diseases, trying to prevent diabetes and eventually treating these age-related diseases sooner. That’s the practice of it,” says Kwon. “I think all of these things are feasible and look forward to being a part of developing them.”
