A team of researchers, including renowned geneticist Professor George Church, has published a new paper demonstrating the mitigation of multiple age-related diseases using a multi-target gene therapy.

Treating multiple age-related diseases at once

George Church is a very prominent figure in genetics and aging research, and he created quite a stir last year when he co-founded Rejuvenate Bio, a biotech company with the ambitious goal of reversing aging using gene therapies that he has been developing for many years at his Harvard lab. The company has recently stated that its initial data shows that its technology can mitigate multiple age-related diseases at once.

In its recent study, the company published data showing how it used a gene therapy to selectively and simultaneously target three longevity-associated genes: FGF21, sTGF2betaR and alpha-Klotho [1]. These targets were informed by an earlier study showing that mice modified to overexpress these genes saw increased healthy lifespans.

FGF21 was chosen as it is known to have a beneficial role in insulin resistance and fat metabolism. It is also known that beta-Klotho supports weight loss abd glucose metabolism, and it improves insulin sensitivity due to its binding action to FGF21. Alpha-Klotho is also known to modulate the aging process by facilitating FGF23 signalling.







This study used mouse models that emulate obesity, type 2 diabetes, heart failure, and kidney failure. The researchers wanted to see if their hypothesis was correct about these longevity-associated genes and whether giving mice additional copies of these genes could improve health, mitigating or even reversing these disease symptoms. Their results are indeed promising for some combinations of gene targets.

The researchers demonstrated that the combination gene therapy was able to address all four diseases at the same time. When FGF21 was the sole target, this was enough to reverse weight gain and type 2 diabetes in mouse models, and when combined with sTGF2betaR in mouse models of kidney failure, it reduced kidney atrophy by an impressive 75%.

However, it is not all good news. When the research team combined all three gene targets, the results were poor, and mice given the triple combination performed worse than the other treated animals did. The researchers suggest that this may have been due to a reaction between FGF21 and alpha-Klotho, and they intend to test this further to see if this is the case.

Comorbidity is common as age increases, and currently prescribed treatments often ignore the interconnectedness of the involved age-related diseases. The presence of any one such disease usually increases the risk of having others, and new approaches will be more effective at increasing an individual’s health span by taking this systems-level view into account. In this study, we developed gene therapies based on 3 longevity associated genes (fibroblast growth factor 21 [FGF21], αKlotho, soluble form of mouse transforming growth factor-β receptor 2 [sTGFβR2]) delivered using adeno-associated viruses and explored their ability to mitigate 4 age-related diseases: obesity, type II diabetes, heart failure, and renal failure. Individually and combinatorially, we applied these therapies to disease-specific mouse models and found that this set of diverse pathologies could be effectively treated and in some cases, even reversed with a single dose. We observed a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction and a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. Crucially, we discovered that a single formulation combining 2 separate therapies into 1 was able to treat all 4 diseases. These results emphasize the promise of gene therapy for treating diverse age-related ailments and demonstrate the potential of combination gene therapy that may improve health span and longevity by addressing multiple diseases at once.

Conclusion

Given the role of genetics in longevity and health outcomes, this research is an important stepping stone towards treating multiple diseases of aging at once. These mouse data will also serve as a good foundation for the company to develop gene therapies that address age-related diseases in humans.







Literature

[1] Davidsohn, N., Pezzone, M., Vernet, A., Graveline, A., Oliver, D., Slomovic, S., … & Church, G. M. (2019). A single combination gene therapy treats multiple age-related diseases. Proceedings of the National Academy of Sciences.