George Church and Rejuvenate Bio’s Combination Gene Therapy Paper

Nextbigfuture has been eagerly awaiting the publication of the research paper on the scientific results of the combination gene therapy experiments by George Church and the team at Rejuvenate Bio.

There was a video over one year ago where George Church mentioned being able to double the lifespan of mice. This would be three times better than any single antiaging therapy on mice. Rejuvenate Bio has 60 aging reversal gene therapies. They have been testing aging reversal in dogs in 2018-2020. Human treatments could be available on a general basis by 2025.

[about 8:40 in the video] He says the organ longevity has also been done successfully with entire mice. They have mice that live twice as long. He says this means that if this had a linear effect and worked in humans then humans could live 160 years.

Rejuvenate Bio is currently offering antiaging age reversal treatments to dogs. Successful age reversal for dogs could be $70 billion per year market. This would fund the development of antiaging treatment for humans.

Here are the highlights of the paper on combination gene therapy.

* Combo gene therapy works against multiple aging diseases
* They have shown success reducing age-related obesity, reduced kidney degradation, and improved heart health
* People have multiple chronic age-related diseases when they are old
* They will get FDA approval against specific diseases instead of against overall aging.
* This paper talks about 4 combined gene therapy treatments but Rejuvenate Bio has been testing over 40 gene therapies in combination

Beginning with the obesity model, they tested multiple therapeutic combinations and found that AAV:FGF21 together with either 1 or both of the other 2 gene therapies was able to mitigate the obesity phenotype in the HFD model as well as the aged ND model, although with a slightly diminished (nonsignificant) effect. Proceeding to the type II diabetes model, we observed that all therapeutic combinations that included AAV:FGF21 rescued the HOMA-IR levels in the treated HFD mice. Next, we applied the individual therapies and their combinations to the UUO model and found that all therapies elicited a positive effect on medullary deterioration and αSMA compared with control mice. Finally, the therapies were applied to the AAC heart failure model and corroborated the results from the other 3 models, with the largest effect observed for the combinations of AAV:sTGFβR2 with either AAV:FGF21 or AAV:αKlotho. Collectively, these data show that a single-combination therapeutic treatment consisting of AAV:sTGFβR2 and AAV:FGF21 can successfully treat all 4 age-related diseases at once. This combination had a higher therapeutic effect in both renal and heart failure compared with the individual gene therapies and maintained therapeutic effectiveness similar to the AAV:FGF21 therapy regarding obesity and diabetes, allowing for a better treatment overall for the 4 diseases involved in this study.

They initially thought that the combo AAV gene therapies would provide positive or possibly, additive effects against the 4 tested diseases. Indeed, an increased therapeutic effect was observed for AAV:sTGFβR2 combined with AAV:FGF21 or AAV:αKlotho in the renal and heart failure models. However, they also found an unexpected negative interaction between AAV:FGF21 and AAV:αKlotho. These 2 gene therapies performed worse when combined compared with their individual results for all 4 diseases, especially with regard to renal and heart failure. It will be interesting to investigate the underlying mechanistic interactions that led to this outcome in future studies to better inform their understanding of the responsible signaling networks and help determine suitable gene combinations in future experiments.

Their approach attempts to increase the overall wellbeing of the individual by eliciting a widespread effect, mitigating multiple disease states at once, compared with traditional therapeutics that narrowly perturb a particular single gene/pathway. Importantly, this strategy also presents a more attractive path toward FDA approval by focusing on the treatment of age-related diseases, which have defined quantitative end points, whereas measuring an increase in longevity would require a lengthy (over 20 years) and expensive clinical trial. The safety and health benefits of the expressed genes together with the low-risk profile of AAV-mediated gene delivery yield an approach that may avoid the risk of negative, off-target effects associated with small molecule therapies. While they have used the expression of 3 secreted factors as a proof of concept to avoid issues related to the codelivery of cell-autonomous factors (such as telomerase), they believe that, as AAV capsids are continually engineered to enhance their infectivity, more cell-autonomous genes may be successfully used in combination in order to achieve similar if not improved results. Crucially, they have also demonstrated that individual longevity gene therapies can be easily combined into a single therapeutic mixture. This serves as an alternative to the traditional therapeutic approaches that, when concurrently treating multiple diseases, require multiple interventions with unrelated substances, which in turn, increase the accumulative exposure to negative side effects. A single-dose combination AAV therapy may also help alleviate issues associated with immune response when considering the alternative of multiple independent AAV-delivered therapies. Future studies may build on the combination AAV therapy concept presented here to treat the many diseases of aging and perhaps, also as a means to address the process of aging itself.

Reduced Age Related Obesity

They evaluated if their therapy could mitigate age-related obesity, 18-mo-old aged mice on an ad libitum ND were used. These mice tend to naturally experience increased adiposity and weighed on average 40 g. We injected all 3 constructs individually or in combination into these mice, resulting in a return to a lean body weight of 30 g for mice that received AAV:FGF21 alone or in combination within 100 d postinjection, which was maintained until at least the 150-d mark (Fig. 1E). Interestingly, we witnessed a decrease in weight in all therapy groups that received AAV:αKlotho as well. AAV:αKlotho alone and in combination with AAV:sTGFβR2 was able to achieve up to 15% weight loss in naturally occurring age-related obesity but did not show any weight loss effects in middle-aged mice fed an HFD.

Reduced Kidney Degradation

Kidney failure and renal fibrosis are a major concern regarding the aging population in the United States, with more than 661,000 people either on dialysis or recipients of a kidney transplant.

They injected mice with single and combination gene therapies 1 wk prior to disease induction via UUO, and kidneys were harvested and analyzed for fibrosis and remodeling 1 wk after the UUO procedure.

Surprisingly, the largest mitigation of medullary atrophy was due to the combination AAV:sTGFβR2 and AAV:FGF21, which performed significantly better than AAV:αKlotho at preventing renal medullary atrophy, with only 6.4% atrophy compared with 22.5%.

Improved Heart Health

Heart failure is responsible for 425,000 deaths per year in the United States, with a prevalence of over 5.8 million people

Six-month-old mice were injected with AAV:sTGFβR2, AAV:αKlotho + AAV:sTGFβR2, AAV:FGF21 + AAV:sTGFβR2, or all 3 therapies combined 1 wk prior to measuring baseline echocardiograms (ECHOs) and performing AAC surgeries. Although the baseline ECHO did not reveal any influence of these therapies on normal heart function, the surgical survival rates were 77% for AAV:sTGFbR2-treated mice and 87% for AAV:sTGFbR2 + AAV:αKlotho compared with only 50% for control mice. This result suggests that there may be an increase in stress resistance that merits further investigation in future studies.

Significance
Human and animal longevity is directly bound to their healthspan. While previous studies have provided evidence supporting this connection, therapeutic implementation of this knowledge has been limited. Traditionally, diseases are researched and treated individually, which ignores the interconnectedness of age-related conditions, necessitates multiple treatments with unrelated substances, and increases the accumulative risk of side effects. In this study, we address and overcome this deadlock by creating adeno-associated virus (AAV)-based antiaging gene therapies for simultaneous treatment of several age-related diseases. We demonstrate the modular and extensible nature of combination gene therapy by testing therapeutic AAV cocktails that confront multiple diseases in a single treatment. We observed that 1 treatment comprising 2 AAV gene therapies was efficacious against all 4 diseases.

Abstract
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.

Proceedings of the National Academy of Science – A single combination gene therapy treats multiple age-related diseases

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