As we age, our bodies tend to develop diseases such as heart failure, kidney failure and diabetes, and the presence of any one disease increases the risk of developing others.
A drug usually targets only 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 new study from Harvard Medical School and the Wyss Institute for Biologically Inspired Engineering at Harvard University reports that a single administration of an adeno-associated virus (AAV)-based gene therapy delivering combinations of three longevity-associated genes to mice dramatically improved or completely reversed multiple age-related diseases, suggesting that a systems-level approach to treating such diseases could improve overall health and extend life span.
The research was reported Nov. 4 in PNAS.
“The results we saw were stunning and suggest that holistically addressing aging via gene therapy could be more effective than the piecemeal approach that currently exists,” said first author Noah Davidsohn, a former research scientist at HMS and the Wyss, who is now the chief technology officer of Rejuvenate Bio. “Everyone wants to stay as healthy as possible for as long as possible, and this study is a first step toward reducing the suffering caused by debilitating diseases.”
The study was conducted in the lab of senior author George Church, the Robert Winthrop Professor of Genetics in the Blavatnik Institute at HMS and a Wyss core faculty member, as part of Davidsohn’s postdoctoral research into the genetics of aging.
Davidsohn, Church and their co-authors homed in on three genes previously shown to confer increased health and life span benefits in mice genetically engineered to overexpress them: FGF21, sTGF𝝱R2 and 𝛂Klotho.
They hypothesized that providing extra copies of those genes to nonengineered mice via gene therapy would similarly combat age-related diseases and confer health benefits.
To test this hypothesis, the team created separate gene therapy constructs for each gene using the AAV8 serotype as a delivery vehicle, injecting them into mouse models of obesity, type II diabetes, heart failure and renal failure, both individually and in combination with the other genes to see if there was a synergistic beneficial effect.
FGF21 alone caused complete reversal of weight gain and type II diabetes in obese, diabetic mice following a single gene therapy administration, and its combination with sTGF𝝱R2 reduced kidney atrophy by 75 percent in mice with renal fibrosis.
Heart function in mice with heart failure improved by 58 percent when given sTGF𝝱R2 alone or in combination with either of the other two genes, showing that a combined therapeutic treatment of FGF21 and sTGF𝝱R2 could successfully treat all four age-related conditions, therefore improving health and survival.
Administering all three genes together resulted in slightly worse outcomes, likely from an adverse interaction between FGF21 and 𝛂Klotho, which remains to be studied.
It is important to note that 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.
“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. “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, 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.
“The finding that targeting one or two key genes has therapeutic effects in multiple diseases makes enormous sense from the perspective of pathophysiology, but this is not how drugs are normally developed," said Wyss founding director Donald Ingber, the Judah Folkman Professor of Vascular Biology at HMS and Boston Children’s Hospital and professor of bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.
“This ability to tackle several age-related diseases at once using gene therapy offers a potential path to make aging a more manageable and less debilitating process," he said.
"We are excited to see how this research progresses in the future,” he added.
The research was supported by the National Institutes of Health (grants R37DK039773 and R01DK072381) and the Merkin Family Foundation.