Recalling the exploits of the Grimm brothers’ Brave Little Tailor, scientists at Harvard’s Wyss Institute showed that they could treat multiple age-related diseases with a single gene therapy. Although the scientists, based in George M. Church’s laboratory, couldn’t boast of slaying seven giants in one blow, they did help laboratory mice fare better against obesity, type 2 diabetes, heart failure, and renal failure. Yes, that’s just four diseases, but they were mitigated by therapies that delivered combinations of longevity-related genes. In some instances, the diseases were reversed by a single dose.

Details of this work are not to be found in a fairy tale, but a peer-reviewed article (“A single combination gene therapy treats multiple age-related diseases”) that appeared November 4 in the Proceedings of the National Academy of Sciences (PNAS). The article’s first author, Noah Davidsohn, PhD, said, “The results … were stunning and suggest that holistically addressing aging via gene therapy could be more effective than the piecemeal approach that currently exists.”

“Everyone wants to stay as healthy as possible for as long as possible,” added Davidsohn, who was formerly a research scientist at the Wyss Institute and is currently the chief technology officer of Rejuvenate Bio. “This study is a first step toward reducing the suffering caused by debilitating diseases.”

As the PNAS article details, Davidsohn, Church, and colleagues developed gene therapies based on three longevity-associated genes: fibroblast growth factor 21 (FGF21), soluble form of mouse transforming growth factor-β receptor 2 (sTGFβR2), and αKlotho. These genes were delivered, individually and combinatorially, using adeno-associated viruses (AAVs).

“We observed a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction, and a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet,” the article’s authors wrote. “Crucially, we discovered that a single formulation combining two separate therapies into one was able to treat all four diseases.”

Administering all three genes together resulted in slightly worse outcomes, likely from an adverse interaction between FGF21 and αKlotho, which remains to be studied. Importantly, the injected genes remained separate from the animals’ native genomes, did not modify their natural DNA, and could not be passed to future generations or between living animals.

The scientists hypothesized that providing longevity genes to nonengineered mice via gene therapy would similarly combat age-related diseases and confer health benefits. The scientists also expressed optimism that a systems-level approach to treating age-related diseases could improve overall health and lifespan.

“Achieving these results in nontransgenic mice is a major step toward being able to develop this treatment into a therapy, and co-administering multiple disease-addressing genes could help alleviate the immune issues that could arise from the alternative of delivering multiple, separate gene therapies for each disease,” said Church, who is a Wyss Core Faculty member, a professor of genetics at Harvard Medical School, and a professor of health sciences and technology at Harvard and MIT. “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.”

As we age, our bodies tend to develop diseases like heart failure, kidney failure, diabetes, and obesity, and the presence of any one disease increases the risk of developing others. In traditional drug development, a drug usually only targets one condition, largely ignoring the interconnectedness of age-related diseases and requiring patients to take multiple drugs, which increases the risk of negative side effects.

“A single-dose combination AAV therapy may also help alleviate issues associated with immune response when considering the alternative of multiple independent AAV-delivered therapies,” the authors of the PNAS article noted. “Future studies may build on the combination AAV therapy concept presented here to treat the many diseases of aging and perhaps, also as a means to address the process of aging itself.”

Sewing things up, the authors wrote, “These results emphasize the promise of gene therapy for treating diverse age-related ailments and demonstrate the potential of combination gene therapy that may improve health span and longevity by addressing multiple diseases at once.”

Church, Davidsohn, and co-author Daniel Oliver are co-founders of Rejuvenate Bio, a biotechnology company that is pursuing gene therapy treatments for dogs. Each holds equity in Rejuvenate Bio.

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