Rejuvenate Bio CEO on why sourcing gene therapy targets from aging research may hold the key to treating many chronic diseases.
It’s been an interesting year for Harvard spin-out Rejuvenate Bio, which is targeting age-related chronic diseases with gene therapy and cellular reprogramming approaches. Earlier this year, the company produced some interesting preclinical data showing that its cellular reprogramming therapy improved healthspan in older mice and increased their remaining lifespan by 109% compared with control mice.
And, having recently revealed that its gene therapy candidate delivered promising preclinical results in the treatment of a rare heart condition, Rejuvenate Bio also made progress in its animal health pipeline, with a gene therapy for heart disease in dogs demonstrating positive results in a pilot study.
Longevity.Technology: Rejuvenate Bio emerged from the Harvard lab of renowned geneticist George Church in 2018, with an approach based on the fundamental idea that aging is the single largest risk factor for many chronic conditions. With programs in both human and animal health, the company is developing multiple gene therapies, each with the potential to impact multiple age-related diseases. To learn more, we caught up with CEO Daniel Oliver, who co-founded the Rejuvenate Bio along with Church and postdoctoral fellow Noah Davidsohn.
Rather than addressing age-related diseases individually, Rejuvenate Bio is focused on the “interconnectedness” of the aging process itself – particularly those genes that have been validated to play a key role in aging and longevity.
“We are essentially aiming to turn aging research into a therapeutic category,” says Oliver. “Our first programs are focused on areas like cardiac and metabolic health, but they utilize factors that have been shown in studies to extend overall lifespan in transgenic animal models.”
Focus on key longevity genes
While looking at previous lifespan and healthspan extension studies may seem an obvious place to start when seeking new gene therapies, Oliver explains that there is more to it than just the results.
“These studies are essentially long-term safety experiments where they showed durable safety, coupled with an ability to treat multiple different issues with the animal or at least prevent age related conditions,” he says. “Our focus was on how to turn transgenic interventions into therapies that would be safe and relevant for human patients. That is where we started.”
The team studied those successful genetic interventions and how to “therapize” them – selecting the genetic or transgenic interventions that best lent themselves to becoming a gene therapy. In the end, the company arrived at three key longevity genes with proven efficacy and validated safety profiles, each associated with either an upward or downward trajectory through age:
- FGF21, which regulates important metabolic and immune pathways.
- TGFβ-1, which is a known driver of fibrosis and several cancers.
- α-klotho, which is associated with cognitive performance as well as protection against heart and kidney diseases.
FGF21 in the spotlight
To illustrate Rejuvenate Bio’s approach, Oliver explains how the company’s FGF21 gene therapy is delivered via a strain of adeno associated virus that targets liver tissue.
“Even if our FGF21 gene therapy is only infecting liver tissue, we can actually see systemic effects throughout the body,” he says. “What we’re doing is turning the liver into a therapeutic bio factory, and then overexpressing this key signaling protein that then goes out through the blood stream and does its work across the body.”
This approach, claims Oliver, has advantages over gene replacement therapies, as evidenced by the company’s recent success targeting arrhythmogenic cardiomyopathy in mice.
“Because we’re utilizing a secreted protein for our delivery, we’ve shown that we’re able to hit large amounts of the cardiac tissue,” he says. “Compare that to these groups who are trying to get the gene therapy to infect every cardiomyocyte that they’d like to change. That’s a key difference.”
From a healthspan and longevity perspective, there are also wider potential benefits of the company’s approach to gene therapy.
“Levels of FGF21 in the blood tend to lower through age, and so, in some sense, what we’re doing is raising them back up and pushing it back in the direction towards what it was when you were younger and healthier as well,” says Oliver. “This is really the power of utilizing these targets sourced from the aging research space – you end up creating therapeutics that are very well tolerated, but also have broad applicability, so you end up with a lot of headroom to grow into many different possible indications.”
‘Reregulating a dysregulated system’
Speaking about Rejuvenate Bio’s work in cellular reprogramming, Oliver says that the approach underpins one of the core tenets of the company – that aging is driven by changes in gene expression throughout life.
“If you are able to not only change the gene expression of a single gene, but of the entire gene expression profile, literally the entire genome, we believe you would be able to see really robust changes in the patient,” he says. “Not only would they not experience as many age-related conditions, but they would also be able to deal with them better even if they had them. That’s exactly the goal of our epigenetic reprogramming technology – you deliver transcription factors that affect methylation and gene expression. And you’re not affecting one gene at a time, you’re literally modifying the entire gene expression profile.”
Oliver says the compelling cellular reprogramming results in mice got the company “really excited” because the data appears to demonstrate a “reregulation effect” of the gene expression profile.
“What we saw even in this elderly mouse population was that we were able to show a doubling of the remaining lifespan – a meaningful increase in lifespan in these animals,” he says. “And that was coupled with improvements in different measurements of healthspan – increased capacity for exercise, wound recovery – even the ability to regenerate damaged optic nerves and things like that as well. We’ve created a situation where we are really reregulating a dysregulated system.”
The road to the clinic
As with most longevity companies, Rejuvenate Bio has no plans for clinical trials focused on human aging or longevity, despite the lifespan-extension data generated by its epigenetic reprogramming therapy.
“I don’t think it’s necessary,” says Oliver. “I think we can rapidly expand this out into ever increasingly more prevalent indications based upon the data we’re generating in each clinical trial we’re doing, and we’ll be able to reach large amounts of patients that way.”
“That’s our philosophy. It’s partly driven by the regulatory landscape, but I also think there’s a practicality to going after specific indications. I think the best way to tackle audacious goals like aging is to have concrete milestones along the way.”
The path to human applications of Rejuvenate Bio’s technology is focused on three main programs, including a gene therapy for cardiovascular disease, another for metabolic disease, and finally its work in epigenetic reprogramming. Oliver says the cardiovascular program is the most advanced and will be the first to go into clinical trials, although exact timeframes have yet to be determined.
“We are getting pre-IND feedback before the end of the year, which will effectively provide us with a checklist that we’ll need to hit before we can launch a human clinical trial,” he says. “But this is no longer a research project – we have a world class gene therapy team, we have a defined manufacturing process, so we have everything we need to get us through these final stages.”
