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Gene Therapy

An ‘anti-aging’ gene therapy trial in dogs begins, and Rejuvenate Bio hopes humans will be next

The startup, spun out of George Church’s lab, has tested an experimental therapy that treats four age-related diseases in mice

by Ryan Cross
November 5, 2019

 

20191105lnp1-dog.jpg
Credit: Wikipedia
Rejuvenate Bio plans on testing its gene therapy in a dog breed known to commonly develop heart problems, the Cavalier King Charles Spaniel.

A single shot of an experimental gene therapy could one day help stall the development of multiple age-related diseases. George Church’s lab at the Wyss Institute of Harvard University has already tested it in mice, and last month a startup called Rejuvenate Bio—founded in 2018 by Church and his former researcher Noah Davidsohn—began a pilot study testing the gene therapy in dogs. If all goes well, they hope that humans will be next.

Church’s efforts to make an anti-aging gene therapy are no secret, but he’s remained tight-lipped about exactly how it would work. Now, Church, Davidsohn, and colleagues have opened up, publishing the results of tests in mice (Proc. Natl. Acad. Sci. U. S. A. 2019, DOI: 10.1073/pnas.1910073116).

The Church group made three separate gene therapies, each consisting of a virus carrying instructions for making a protein previously linked to the prevention or reversal of age-related diseases. Those proteins were αKlotho, fibroblast growth factor 21 (FGF21), and soluble form of mouse transforming growth factor-β receptor 2 (sTGFβR2)—which sequesters TGFβ, a protein linked to aging and inflammation.

Each gene was packaged in adeno-associated virus 8 (AAV8), which has an affinity for the liver. Once the gene therapies infect liver cells, those cells are turned into small factories that produce the therapeutic proteins and secrete them into the bloodstream. The group tested the therapies individually, and in combination, in mouse models of obesity, type II diabetes, renal failure, and heart failure.

The FGF21 therapy alone helped obese mice shed weight that they gained from a high-fat diet, and restored insulin sensitivity in mice with diabetes. The FGF21 and sTGFβR2 therapies together improved heart health and kidney function when given to mice one week before the researchers experimentally caused heart failure and renal failure in the mice. Unexpectedly, αKlotho, which numerous groups have linked to anti-aging effects, hindered the efficacy of the FGF21 therapy. So the Rejuvenate team will not pursue it in their next set of studies, which will test the other two gene therapies in dogs.

The American Cavalier King Charles Spaniel Club is funding a pilot study of FGF21 and sTGFβR2 therapies in 10 dogs at the Cummings School of Veterinary Medicine at Tufts University. The breed frequently develops mitral valve disease by age eight, so the study will aim to improve the dogs’ heart health. A larger planned clinical trial will include additional breeds.

João Pedro de Magalhães, a scientist who studies aging at the University of Liverpool, and Aubrey de Grey, the chief scientific officer at the SENS Research Foundation, both reviewed the paper and say that its novelty largely lies in delivering multiple genes at once, an approach that’s conceptually simple, but has largely been deemed impractical. Grey notes that scientists have largely forgone studying combination therapies for aging, opting to focus on simpler single-target treatments. “This study is a big step towards bringing that over-caution to an end,” Grey says. Magalhães cautions that while the results are promising, the research is still in very early stages.“There’s still a huge amount of work to do before gene therapy can be applied to treat human aging,” Magalhães says.

Sebastian Aguiar, a principal at the anti-aging focused venture capital firm, Apollo Ventures, calls the study “a valiant attempt and hopefully only the opening salvo.” But most of the “heavy lifting” comes from FGF21, he adds. “There is very little ‘synergy’ between gene therapies. It’s a bit of a gimmick to make a big deal out of the combinatorial approach here.”

Matt R. Kaeberlein, a biologist who studies aging at the University of Washington, goes even farther in his critique of the work, contending that the experimental approach shouldn’t be called an anti-aging gene therapy at all because the researchers didn’t report the lifespans of the treated mice. “In the absence of this missing data, it’s impossible to know whether they actually affected the aging process or not,” he says.

“We are not focused on longevity,” Davidsohn responds. Instead, he says, Rejuvenate’s goal is to reverse diseases of aging to extend what researchers call the “healthspan,” the years of life spent in good health. Church and Davidsohn note that developing therapies that treat age-related diseases will provide a more realistic pathway towards FDA-approval, since proving that a therapy extends lifespan would require a clinical trial lasting several decades.

Church says his lab has been testing the potential of about 45 genes linked to anti-aging for gene therapies. The paper presents results of just three. His group is also looking at gene therapies that can tackle additional age-related diseases, such as neurodegeneration. “With gene therapy, we can go from an idea in the scientific literature to an experiment in the lab in two weeks,” he says. “You can’t do that with small molecules.”

David Sinclair, an anti-aging researcher and entrepreneur at Harvard Medical School, contends that since aging “is not yet considered a medical condition that’s worth treating,” anti-aging gene therapies are likely still many years away. But if Church’s gene therapy proves to be safe and effective, it “may be seen in the rearview mirror as work that led to the use of gene therapy, not just for rare diseases, but for the wider population,” Sinclair adds.

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