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Novel combination AAV-based gene therapy simultaneously treats several age-related diseases

Novel combination AAV-based gene therapy simultaneously treats several age-related diseasesAs one ages, the likelihood of comorbid conditions being present in a person increases. However, diseases are traditionally treated individually, largely ignoring the connection between them. The result is multiple treatments being prescribed, increasing the risk of serious interactions and decreased treatment efficacy. In a recent study in PNAS, scientists sought to depart from a non-systems approach to medicine and embarked on the development of combination AAV-based gene therapies to simultaneously treat multiple age-related diseases.

To begin creating effective multi-disease therapy, these researchers chose to target three genes that have been previously linked to prevention or reversal of age-related diseases. The three genes involved were (1) fibroblast growth factor 21 (FGF21), known for its role in metabolism and glucose handling, (2) αKlotho, an important regulator of intracellular calcium and known to be protective in heart and kidney diseases, and (3) the soluble form of mouse transforming growth factor-β receptor 2 (sTGFβR2), which sequesters TGFβ1, and is involved in age-related heart disease.

In order to deliver each gene, Davidsohn et al. engineered 3 separate AAV-based gene therapies, each expressing a different gene. In particular, they chose AAV8 serotype because of its high affinity to infect the liver. After infection, the liver cells became small factories producing large amounts of therapeutic proteins, which were then released into the bloodstream. To test the effectiveness of the therapy, each therapy was not only injected individually but in combination with each other into disease-specific mouse models for obesity, type II diabetes, heart failure, and renal failure.

What researchers found was astonishing. Individually, the AAV-based gene therapies caused an increase in heart function in a heart failure mouse model, a reduction in α-smooth muscle actin (αSMA) expression indicating a reduction in myofibroblasts, which are contributors to renal fibrosis, and a significant reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction. More importantly, they were able to completely reverse obesity and diabetes phenotypes in mice fed a high-fat diet. Interestingly, a single treatment of a therapeutic cocktail of 2 of the therapies, FGF21 and sTGFβR2, had a higher therapeutic effect in both renal and heart failure compared to individual therapies and a similar effect as FGF21 therapy alone in obesity and diabetes mouse models. However, combining FGF21 therapy with αKlotho therapy had a negative effect on each other, and elucidating the mechanism behind this interaction will aid in the development of future gene combinations.

Overall, using a combination approach to gene therapy has a more widespread effect on disease state and shows the promise of multi-gene therapies in the treatment of disease. The ability to target multiple diseases at one time, especially in an aging individual where comorbidities are common, can help to reduce serious side effects that can incur with taking multiple kinds of medicines and work towards improving overall health quicker. In turn, we will be able to gather a better understanding of how these diseases relate to each other and revolutionize the way that we think about and treat disease.


Davidsohn, N et al. A single combination gene therapy treats multiple age-related diseasese. Proceedings of the National Academy of Sciences of the United States of America. (2019).

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