Editors' ChoiceGene Therapy

One vector to rule them all

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Science Translational Medicine  04 Dec 2019:
Vol. 11, Issue 521, eaaz9764
DOI: 10.1126/scitranslmed.aaz9764


A combination of gene therapies improves age-associated diseases.

Life expectancy is steadily increasing in developed countries. However, it is not the destination but the journey that matters. The goal of current medical practice is therefore not only to increase longevity but also to improve quality of life in the eldest. Aging is a complex process frequently associated with the coexistence of different medical conditions in the same patient. The identification of methods that address at the same time multiple diseases related to aging represents the holy grail of medicine.

In their recent work, Davidsohn and colleagues treated four age-related diseases in mice by the delivery of a combination of genes in an adeno-associated virus (AAV) vector. The four disease conditions considered in the paper were obesity, diabetes, kidney failure, and heart failure. The therapeutic approach consisted of the overexpression of genes with a beneficial role in aging: fibroblast growth factor 21 (FGF21), αKlotho, and the soluble transforming growth factor–β receptor 2 (sTGFβR2). Treatment with an AAV vector expressing FGF21 either alone or in combination with the other factors demonstrated efficacy in all the disease models. There was just one exception: In the kidney failure model, the combination of FGF21 and αKlotho performed worse than individual treatment. In the mouse model of heart failure, the combination of FGF21 and sTGFβR2 improved ejection fraction and decreased development of fibrosis at 90 days after treatment. The combination of sTGFβR2 and αKlotho showed similar results. The findings suggest that a single AAV vector expressing FGF21 and sTGFβR2 may offer a treatment for the four age-related diseases of obesity, diabetes, kidney failure, and heart failure.

Although the involvement of the individual genes in the treatment of one or two of these disorders has already been demonstrated in preclinical models, the work of Davidsohn and colleagues shows that the combination of treatments may provide additive effects with better results. It also highlights the possible negative effects of the combination of treatments in specific diseases due to unknown interactions. If translated to the clinic, this approach may reduce the risk of the development of age-associated diseases, thus improving the quality of life in elder people and eventually increasing longevity.

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