Telomere-boosting mRNA therapeutic turns back the aging clock

Rejuvenation Technologies is targeting longevity and age-related disease with telomerase-based mRNA therapies.

For the past five years, Silicon Valley biotech Rejuvenation Technologies has been quietly working on a therapeutic platform to extend telomeres in the human body, with the goal of boosting longevity and healthspan. Yesterday, the company emerged from stealth with a healthy seed funding round of $10.6 million, led by Khosla Ventures.

Rejuvenation has developed a synthetic mRNA-based approach to restoring telomeres to a “healthy length” – capable of reversing a decade of telomere shortening in a single dose. The mRNA produces telomerase, an enzyme that plays a critical role in maintaining the length of telomeres. Following positive preclinical results in lung and liver disease indications, the company is now preparing the path towards its first in-human trials.

Longevity.Technology: Telomeres are protective structures on our DNA that prevent the loss of genetic information as the cells in our bodies divide. With each cellular division, our telomeres gradually shorten and, when they become critically short, our cells enter a state of senescence or die. Research has shown that telomere length is closely associated with lifespan and healthspan, and telomere shortening is recognized as one of the primary hallmarks of aging.

While it has long been known that the enzyme telomerase extends telomeres, it was only recently that safe, rapid telomere extension has been enabled by the delivery of mRNA. To learn more about how Rejuvenation Technologies is targeting telomeres and longevity, we caught up with co-founders Dr Glenn Markov and Dr John Ramunas.

The road to Rejuvenation begins in the Stanford biology lab of Dr Helen Blau, where Markov and Ramunas first started working together, studying aging mechanisms. Professor Blau is also a co-founder of the company.

“We were both interested in exploring the bounds of biology and found a lab where we could work on longevity as part of a PhD thesis,” says Markov. “We also both had the idea in mind of developing a potential company around extending human healthspan and lifespan.”

Rejuvenation Technologies exits stealth with $10.6m for age-reversing mRNA therapeutics
Rejuvenation’s co-founders Glenn Markov (COO) and John Ramunas (CEO).

Overcoming telomerase ‘dogma’

The two founders decided to focus on telomeres, which they say are “fundamental” to aging and rejuvenation.

“Short telomeres are fundamental drivers of aging in part because they play a causal role in most other major aging mechanisms including cellular senescence, mitochondrial dysfunction, and loss of stem cell regenerative capacity,” says Ramunas.

The researchers were both keen to address a controversy around the therapeutic use of telomerase.

“A dogma arose in the 1990s that telomerase causes cancer,” says Ramunas. “This is wrong and set back the field by decades. The reality is that permanent telomerase supports cancer, whereas healthy stem cells frequently turn on telomerase transiently throughout our lives to stave off the devastating effects of short telomeres.”

“I interviewed at 19 telomere labs for my PhD before finding a lab willing to try to develop a telomere extension therapy, and that was Helen’s lab at Stanford. Helen loves overturning dogma.”

Reversing 10 years of telomere shortening

After trying various approaches, in 2015 the researchers’ efforts produced the breakthrough discovery that delivery of synthetic telomerase mRNA was able to reverse a decade of telomere shortening in a single dose. The discovery was also significant because the new mRNA telomerase treatment did not ‘immortalize’ the cells it was used on.

“Previously, telomerase was delivered in a way that would immortalize cells and so it was only really used for experiments in the lab that needed to have a model of cells that grow indefinitely,” says Markov. “It was used as a tool but wasn’t thought of as a therapeutic approach.”

Their discovery meant that the treated cells were able to divide more times, but not indefinitely.

“This was a breakthrough transient approach that still extended telomeres significantly – delaying senescence, rejuvenating old cells, and keeping young cells young for longer,” says Markov. “But crucially, it gave us a way to keep the telomeres long without having chronic telomerase activity, which could potentially be a safety risk.”

Lipid nanoparticle delivery is key

Finding a safe way to extend telomeres in cells wasn’t the only challenge; next they had to find a way to deliver the mRNA in vivo.

“Delivery in vivo is far more challenging than to cells in culture,” says Markov. “So, we tried every delivery approach we could buy or make, and sought out collaborations, including with labs at Stanford. As we learned more over the years at Stanford, and subsequently in the company, we got pretty good at it.”

Rejuvenation’s current lead formulations employ biodegradable lipids and other components.

“We use lipid nanoparticles because they tend to be a lot less immunogenic than the viral approach typically used in a gene therapy setting, so we’re able to deliver multiple doses and have that flexibility to stop when the desired effect has been achieved,” says Markov.

Targeting multiple indications

Rejuvenation started out in the renowned Y Combinator startup accelerator, which funded the fledgling company to the tune of $1 million. The company’s primary mission, says Ramunas, is to extend human healthspan.

“Ultimately, we envision treating everyone periodically to maintain their telomeres in a healthy length range,” he adds. “Since each dose reverses years of telomere shortening, the treatments could be years apart. Initially we’re focusing on fatal orphan diseases. This enables us to accelerate the clinical trials and make telomerase mRNA available to patients as soon as possible.”

The company’s lead indications are currently fibrotic age-related diseases of the liver and lung: pulmonary fibrosis and liver cirrhosis.

“We’ve had really good progress on both programs, so in the next 18 to 24 months, should investor enthusiasm and our success with grants continue as it has so far, we aim to complete our preclinical toxicology studies and then focus on clinical trials,” adds Ramunas.

Translating to humans

While the company has seen positive preclinical results in both its lung and liver programs in mice, what about making the leap to humans?

“Our primary focus has been to design a drug that will work in humans, both with respect to safety and efficacy,” says Markov. “With our lung-targeted lipid nanoparticle, for example, we haven’t just done experiments in mice, we’ve dosed rabbits and non-human primates. In each case, we’ve showing the drug is safe and is going to the right place. It’s consistent.”

In addition to yesterday’s seed funding, Rejuvenation has also raised $4.6m in grant funding, bringing the total amount raised to $15.2m. The company says the funding will be used to advance its programs to IND approval (clinical trial readiness) in fibrotic disease, as well as early research targeting the immune system.

“We believe safe telomere extension has an essential role in preserving stem cell function as we age,” says Ramunas. “We’ve recently seen a surge of interest in our mission and approach – perhaps due to the convergence of public interest in mRNA due to the pandemic, our recent breakthroughs in delivery of mRNA to stem cells, and the shift toward regenerative medicine. We’ve also recently received major grant funding and recruited world experts on the science, business, and clinical fronts, so we’ve been fortunate timing-wise.”