Date: 7th November 2019
The world’s population is ageing and it is estimated by 2050 that 82 countries will have at least 20% of their population aged ≤65.
To this end, whilst medical advancements have increased our longevity, we are starting to see an emergence of complex health states involving multiple interconnected diseases requiring more sophisticated treatments, rather than those targeting individual diseases.
Scientists from Harvard University and Harvard Medical School, US, are now approaching the complexity of age-related diseases from a system-level point of view.
The aim to mitigate multiple diseases with minimal therapeutic treatments, treating the patient as a whole and exploring the interconnectivity of the diseases.
George Church and his team have developed gene therapies to alleviate four age-related diseases; obesity, type II diabetes, heart and adrenal failure by targeting three genes associated with longevity; fibroblast growth factor 21 (FGF21), αKlotho and a soluble form of mouse transforming growth factor βreceptor 2 (sTGFβR2).
The team starting by constructing three separate adeno-associated viruse (AAV) vectors, containing each factor. FGF21 is produced by the liver, it is a circulating factor playing roles in metabolism and glucose handling. αKlotho is also a circulating factor, produced in the kidney and it is a known regulator of intracellular calcium and provides protection in heart and kidney pathologies. Finally, in this context TGFβ1 signalling has an important role in age-related hypertrophic cardiomyopathy, immune recruitment, and extracellular matrix formation, here sTGFβR2 binds and represses TGFβ1.
Each virus was injected into mice, and all showed overexpression of its associated transgene. The blood plasma of the mice showed a significant increase of FGF21 and αKlotho and a nearly 95% decrease in TGFβ1. Side effects of the treatment were deemed minimal.
Obesity and type II diabetes
Obesity and type II diabetes is an ever increasing problem in our society and with all three factors potentially playing a role in fat or glucose metabolism or impacting the diseases they were put to the test in an established mouse model of both states (high fat diet (HFD)).
Control and HFD mice were infected with individual or combinatorial factors to assess the synergistic effect if any.
- AAV:FGF21 therapy alone completely reversed obesity within 40 days post injection.
- AAV:sTGFβR2 and AAV:αKlotho had little effect either individually or in combination together.
- The strong result from AAV:FGF21 alone made in hard to assess whether a synergistic effect from a combinatorial treatment could be detected, but the results indicated not.
To assess the question of age-related diabetes, the experiment was re-performed on older mice, on a non-restricted diet which naturally leads to increased weight.
- AAV:FGF21 alone or in combination once again seemed to support reverting the weight back to within the control range, albeit in a longer period of time.
- This time AAV:αKlotho alone, and in combination with AAV:sTGFβR2, led to a decrease in weight of up to 15%
- AAV:sTGFβR2 had no effect when used alone.
Further assessment of the AAV:FGF21 mice suggested that the weight loss was due to an increase in metabolic rate, and that changes in activity or food consumption did not occur, whilst bone and muscle density also remained unchanged.
HFD mice often acquire type II diabetes over time and several diabetic tests on the mice showed that AAV:FGF21 therapy alone completely mitigated the diabetic phenotype.
Renal disease
To assess the impact of the three factors in renal disease the team used an established means of simulating progressive renal fibrosis (unilateral ureteral obstruction (UUO)). Mice were injected with the factors a week prior to UUO, and their kidneys subsequently analysed for fibrosis and remodelling.
All three therapies showed improvement in kidney damage, although AAV:sTGFβR2 and AAV:FGF21 together showed the strongest effect.
Heart failure
The heart failure model chosen was ascending aortic constriction (AAC), again due to it being well established. One interesting observation during the surgery here was that surgery survival rates were significantly increased in AAV:sTGFbR2-treated mice and in mice receiving AAV:sTGFbR2 + AAV:αKlotho.
The team also reported that AAV:sTGFβR2 individually or combined with either AAV:FGF21 or AAV:αKlotho yielded an increased positive effect on heart function.
Future applications
The strategy presented here shows the potential for treating multiple age-related diseases with a single-combination therapeutic treatment. In this case, consisting of AAV:sTGFβR2 and AAV:FGF21.
It is important to note however, that negative interactions were also observed, suggesting that careful investigation of the underlying mechanisms of the interactions between the molecules or pathways is an important step for the future.
This holistic approach to disease management is relatively new, and this study provides an important insight into its therapeutic potential. The method offers a reduction in multiple treatments compared to traditional methods that treat individual diseases. This in turn potentially decreases the accumulative risk of side effects.
This research is part of an emerging field called geroscience. It seeks to define how the biological mechanisms that occur during the ageing process give rise to numerous age-related diseases and disorders. The question to be considered is how the ageing process affects the disease process and susceptibility, and how the conditions are interconnected.
Davidsohn, N., M. Pezzone, A. Vernet, A. Graveline, D. Oliver, S. Slomovic, S. Punthambaker, X. Sun, R. Liao, J. V. Bonventre and G. M. Church (2019). “A single combination gene therapy treats multiple age-related diseases.” Proceedings of the National Academy of Sciences: 201910073.
https://doi.org/10.1073/pnas.1910073116
