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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Gene therapy combo treats age-related diseases in mice

Harvard researchers have used a combination gene therapy approach to reverse multiple age-related diseases in mice. If proven successful in larger animal models and humans, the strategy could be a major step in treating multiple age-related diseases and aging itself.

Aging is associated with several diseases including heart failure, kidney failure, diabetes and obesity, and the presence of one lead to another. There is no single treatment that could treat all these diseases and therefore patients are required to take multiple drugs, increasing the risk of negative side effects and affecting their lifespan.

A latest study by Prof. George Church and team at Harvard University’s Wyss Institute for Biologically Inspired Engineering tested whether a combination of gene therapy using longevity-associated genes could improve age-related diseases in mice. To test this, they used three genes that had previously been shown to render increased health and lifespan benefits in mice: FGF21, sTGFβR2, and αKlotho. The team hypothesized that providing extra copies of these genes to diseased mice through gene therapy could similarly improve age-related diseases and confer health benefits.

The team first created separate gene therapy constructs for each gene using AAV8 vector, and injected them either individually or in combination with the other genes into mice models of obesity, type 2 diabetes, heart failure, and renal failure.

Results showed that a one-time administration of gene therapy with FGF21 alone could reverse weight gain and type 2 diabetes in obese, diabetic mice. Combining FGF21 with sTGFβR2 reduced kidney atrophy by 75% in mice with renal fibrosis. Heart function in mice with heart failure improved by 58% when they were given sTGFβR2 alone or in combination with FGF21 or αKlotho. This shows that a combined therapeutic treatment of FGF21 and sTGFβR2 could successfully treat all four age-related conditions, therefore improving health and survival. Interestingly, combining all three genes together resulted in slightly worse outcomes.

The study also noted that the injected genes remained separate from the animals’ native genomes and did not modify their natural DNA and could not be passed to future generations.

Findings from this study published in PNAS demonstrate the potential of gene therapy for treating diverse age-related ailments and the efficacy of combination gene therapy in improving health and lifespan by addressing multiple diseases at once.

Prof. Church commented: “Achieving these results in non-transgenic 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. 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.”

Prof. Church is developing the therapy in collaboration with Rejuvenate Bio, a biotechnology company that he co-founded in 2017. The company is pursuing gene therapy treatments for dogs.

Source: A single combination gene therapy treats multiple age-related diseases. Davidsohn N et al., PNAS, November 2019. DOI

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