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.

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.

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

20 thoughts on “George Church and Rejuvenate Bio’s Combination Gene Therapy Paper”

  1. Brian,
    George Churches work and career in the anti-aging space is phenomenal.
    In regards to anti-aging have you looked at Dr. Charles Brenner’s research on boosting NAD+ in animal/human cells with Nicotinamide Riboside, NMN and other NAD+ precursors?

  2. Yep. The mission of Gil Hamilton’s organization had three parts, aside from “organlegging” the other two being control of unlicensed births, and suppression of dangerous technologies.

    China went whole-hog on controlling births but it doesn’t seem that will be necessary, or even desirable, in the future, either for them or anyone else, due to changing demographic trends. Funny, because growing up I was sure that birth restrictions were inevitable.

    As for suppressing dangerous technologies? I imagine a lot of countries do it. The US has over five thousand patents it has declared secret. I do wonder what happens if there is an attempt to distribute information that might otherwise be suppressed, prior to applying for a patent?

    Since there is no requirement for compensating the filer, it would seem that, if you had a patent that might be suppressed, it might be better to get the initial patent in some less restrictive country overseas, before applying for a US patent, particularly if you were attempting to patent something that could be weaponized, help defeat existing weaponry, or be related to cryptography.

    Of course, even something that might cause deep disturbances in the economy could be deemed dangerous. Reportedly, even solar panel technology was being suppressed at one point.

  3. That’s for sure: I appear to have inherited my mother’s “Excellent cardiovascular health plus arthritis” genes, which I guess are better than my dad’s “never mind arthritis, just stroke out in your late 60’s” genes.

  4. I’ve got a line on a dodgy doc, (The LEF has a directory of them!) and my own family physician apparently just decided to up and retire, so I’m kind of lacking in excuses not do so something about it at the moment.

  5. The Gil Hamilton stories still strike me as the most realistically scary dystopian future I’ve encountered in SF.

  6. Making all the old people healthier has a direct positive effect on health insurance.

    Yeah, eventually the shear number of surviving 130-year-olds might increase their costs, but they have literally decades to adjust policies and rates to match those distant needs.

  7. True, I can argue that my parents, and grandparents, developed diseases associated with aging so I probably have bad genes.

    Not that anyone has good genes in this area.

  8. Still need to find you a dodgy doc who would prescribe it for “wanting to look younger”.

    Still, our fakenewspapers are full of stories of drug addicts getting prescriptions from dodgy docs, so I guess they exist and could be found somehow.

  9. A different but similar approach I’ve been suggesting for a while is “X years of pension for Y years of work”. Much less uncertainty than the current model, more sustainable, and gives people the choice of when and how much to work.

  10. Fortunately, once a treatment is approved for one purpose, it can usually be prescribed for off label uses, though you may have trouble getting insurance reimbursement.

  11. On the “take your pension and die on schedule, or take the treatment and go back to work” part, I figured that, too, for several years after it first occurred to me.

    Now I consider it much more likely the laws will be changed and the pension and entitlement providers will simply be authorized to give people a cash out payment and then cut them off. Which they will do. I saw it happen to a Pan Am pilot after they went bankrupt, which may have helped me realize this.

    Then whether the individuals get the treatment, and whether they go back to work or try to live on the interest, that’s totally up to them. But getting back into a shrinking work force may not be easy.

  12. Of course, there are already folks worried (concerned?) about the supplies of transplant organs decreasing drastically from their already low levels due to self-driving vehicles hugely reducing the supply. (Vehicle accidents are apparently the number one source for organs to transplant, if you aren’t harvesting them from political dissidents.)

    IF they aren’t smoking dope, then the accident rate could conceivably fall below the suicide rate (which I would expect to go up as some people just get bored with life or take up more extreme sports or whatever).

    The science fiction of Larry Niven, dating back to the 1960s, has a lot of speculation on all of this (including taking organs from prisoners “Gift From Earth” and the Gil Hamilton mysteries, as well as many short stories. Near immortals getting bored and taking bigger risks “Grendel” (which features the adoptive father of the main character from “Ringworld”) and, to some extent, the main character from “Ringworld.” And even ultra-safe vehicles: “Safe at Any Speed.”

    On a side note, I expect there will be folks who, despite how well their physical body and brain is maintained, just won’t have the mental framework required to stay functional over a really extended lifespan. (Imagine amplifying the “you-kids-stay-off-my-lawn” attitude until there’s nothing else left.) Heck, it could be all of us. (Also shown rather creepily in the Niven story, “The Ethics of Madness.”

  13. “I suspect that, at some point as this stuff proves out, you’ll be presented with a choice: Either take your pension and die on schedule, or take the treatment and go back to work.”

    Exactly.  Or more European style, your placed on a waiting list for the government sponsored care, likely years in some cases awaiting your treatment.  Of Course many would die before their no. came up; unless they could afford private treatment on their own dime or private insurance.

  14. “It’s won’t be cheap, at least not initially, and is it is going to play havoc with social security, medicare, and pensions in very short order.”

    As far as SS is concerned all t he guv has to do is keep raising the retirement age to receive “full benefits” just as they are already doing as life expectancies increase.  Private pensions are already going the way of the dinosaur; although public worker pensions/benefits might become and even bigger problem.

  15. The kidney treatment sounded preventative. Maybe the others are too, or will develop into preventative treatments later. In which case, you’d only need to demonstrate increased risk of contracting the disease. So if you maintain your health, you may become eligible for treatments at an older age.

  16. Does this lead to the moral hazard of you can only get the rejuvenation treatment if you have developed one of the aging diseases?
    Work to maintain your health and you don’t get anything.

  17. You are given the choice of taking the rejuvenation treatment, but you have to also start riding a 1L Sports Motorbike.
    Square that curve good and hard.

  18. In theory it SHOULD save them a bunch of money. Anything that “squares the curve” does; Instead of dying of expensive chronic diseases, people still die, but of acute causes like auto accidents, where there’s little expense involved.

    Agreed about it playing havoc with various defined benefit pensions. I suspect that, at some point as this stuff proves out, you’ll be presented with a choice: Either take your pension and die on schedule, or take the treatment and go back to work.

    Hm, on second thought, this does provide them with a bit of a conflict of interest, as many insurance companies are also backing the non-governmental defined benefit plans.

  19. Hmm. Assuming this works even a quarter as well for humans, and even assuming this isn’t followed by a continuous stream of new wonders . . .

    . . . 2025 isn’t too bad. How much will it cost? I bet medical insurance won’t cover it unless it is well proven (insurance companies move about as fast as continental shelves) and it saves them a lot of money on payouts for other things.

    Invest your pennies wisely. It’s won’t be cheap, at least not initially, and is it is going to play havoc with social security, medicare, and pensions in very short order.

    This at a time when automation is coming on quick and companies would already rather have one highly skilled and experienced worker than several entry level ones.

Comments are closed.