Harvard synthetic biology pioneer George Church generated some buzz last year when he co-founded Rejuvenate Bio with the goal of reversing aging with gene therapy. Now, he and his co-founders say they have compelling early evidence in mice that they can use the technology to reverse multiple age-related diseases at once.
The researchers gave the mice three genes associated with longevity, either alone or in various combinations. The genes were FGF21, sTGF2betaR and alpha-Klotho. In previous experiments, they had shown that mice genetically engineered to overexpress the genes experienced benefits in both their health and life spans.
This time, they used mice that were not genetically engineered but rather models of obesity, Type 2 diabetes, heart failure and kidney failure. They wanted to prove their hypothesis that giving the mice extra copies of the genes might confer similar health benefits. They found that some combinations did improve or reverse symptoms, they reported in the journal Proceedings of the National Academy of Sciences.
The Harvard team discovered that a combination of FGF21 and sTGF2betaR could treat all four diseases. FGF21 administered on its own reversed weight gain and Type 2 diabetes, and, when it was combined with sTGF2betaR in mouse models of kidney failure, it lowered kidney atrophy by 75%.
Administering all three genes together turned out to be an unsuccessful strategy, however. Mice that received that combination had worse outcomes than the other animals did, the team reported. The researchers believe there may have been an adverse reaction between FGF21 and alpha-Klotho, but they said further experiments would need to be designed to confirm that.
Rejuvenate Bio was launched from Church’s lab at Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering in 2017 but is still largely in stealth mode. It generated some attention last year, after it started reaching out to dog owners with the opportunity to enroll their pets in a trial of a gene therapy to treat mitral valve disease. The heart condition affects some breeds in outsized numbers, including Cavalier King Charles spaniels.
The potential benefits of the three genes Church’s team investigated for the newly published study are well known. FGF21, for one, has been shown to play a beneficial role in insulin resistance and fat metabolism. And last year, researchers partially funded by diabetes drug maker Novo Nordisk discovered that a variant in the gene is present in some people with naturally low levels of body fat.
Last year, Yale researchers discovered that beta-Klotho promotes weight loss, glucose metabolism and insulin sensitivity by binding to FGF21. And a separate team led by New York University published their discovery that alpha-Klotho facilitates FGF23 signaling, which in turn modulates the aging process.
Rejuvenate Bio’s Church said in a statement that a one-time gene therapy to address multiple age-related diseases could offer several benefits for patients and that the mouse trial was “a major step” toward the company’s efforts to develop gene therapies for human use.
"This research marks a milestone in being able to effectively treat the many diseases associated with aging, and perhaps could lead to a means of addressing aging itself," Church said.