Hi @Max_Unfried, I have just reflected the changes on the IP-NFT minting and ownership and included the senior review digest, with the quantitative part here and the full digest in a linked file, because very long.
Thanks for adding some of the changes.
Donât wanna be overcritical, but given the rather weak conviction scoring by senior reviewers, and the comments in the reviewer report I think it might be appropriate to redo voting, so that everyone who is voting is aware of it and votes just not get grandfathered in. Especially as some reviewer comments contradict what is written in the proposal.
Strongest point seems to be the team.
After checking with the governance squad, because there were material changes in the Discourse proposal after the votes, namely the change in ownership and the review results, the poll has to be reset.
I agree the IP-NFT fractions for the PI and PM on this tRNA project are too steep in relation to the precedent that was set with VITA-FAST. Personally, I would love to see @mykalt45 and @aschwartzphd get a large % ownership because I think they will do a great job and will deserve it. However, that is the old mentality of equity and company formation. We want to do something different because we think it will be better. The IP-NFT fractions create a mini DAO and a DAO should not be controlled so strongly by any one person. This is the case for VitaDAO where any one person will likely not control more than 1% when everything is said and done. Note, unlike equity these fractions will not be diluted. Therefore, it is hard to compare %s but one couldnât claim the IP-NFT fraction %s are for sure lower than what the equity %s would ultimately be after dilution. cc @Paolo @tylergolato @benji @EliMo for visibility.
Please vote on what the IP-NFT fractional ownership should be for the PI and PM for this tRNA project:
- #1 Keep the same (PI-20%; PM-25%)
- #2 Like VITA-FAST (PI-10-15%; PM-3-5%)
- #3 in between 1 and 2
- #4 higher than 1
- #5 lower than 2
0
voters
Thanks, Tim, for bringing this forward. I did want to double-check my understanding of how IP-NFTs work. Whatever the starting %, wouldnât it get diluted if more funds are raised through the sale of the mini DAO tokens (VITA-Mutant) as the project matures? In that case, isnât the above statement not accurate? Thanks for clarifying for me.
No the % fractions would NOT get diluted.
Can you please point me to any guidance around what youâre saying so I can better understand? I donât see how that works. Thanks.
I donât have the documentation but thatâs my understanding of how VITA-FAST worked. @benji @tylergolato can you help please?
I do know VITA-FAST has a fixed amount of tokens, 1M. So if you own 10%, you own 100K VITA-MUTANT. Capping the total token supply is how this is different from equity.
VITA-FAST does not have a fixed amount of tokens. More can be minted as needed. You will have complete tokenomic engineering freedom here @mykalt45. You can mint a fixed amount and put into governance that the token supply should be capped; however the smart contract enables unlimited minting, like shares of a company. There is certainly an element of trust here that is still required, as the tokenholders would be reliant on the holder of the IP-NFT to not mint more IP Tokens if they promised not to, but this is something we hope to make trustless over time so that tokenholders cannot be further diluted without an on-chain vote.
Short answer: mint as many IPTs as you want. Dilute, or not, but if you choose to make a fixed number of tokens, your tokenholders will be trusting you to not dilute them further, for now.
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I would prefer to lower the USDC pay to the PI/PM instead of lowering the equity so that VitaDAO bears less of the risks. I donât mind the PI having a large share of voting control over their own IP.
Some of the confusion may be that individual VITA-FAST token holders (i.e. VitaDAO) could sell some of their tokens to the public without needing to mint more tokens. But the VITA-FAST DAO has control of how many more tokens could be minted.
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Agreed, this is reasonable â more equity than cash for the PI and PM because that incentivizes them more strongly.
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@Paolo nice job on structuring this proposal, itâs very methodical and clear. I donât think this MoA is very relevant for VitaDAO however, even if weâd like to support our dear friends Michael and Anthony on this project â itâs likely that their formidable combined intellectual firepower could identify a therapy in academia or biotech that is more relevant to LongBio than this initial proposal.
Missing relevance to longevity:
There is only one citation provided suggesting any connection to longevity, and itâs rather a tenuous and speculative one â looking through the genome and finding potential mutant stop codons in genes that are linked to age-related diseases (note: not lifespan, but specific diseases of interest). This is a bioinformatics exercise.
There was no actual lifespan data shown in support of this MoA. Meanwhile, there are many dozens of drug targets and MoAs (which can be addressed with small molecules, mAbs, or cell therapies) which have very compelling rationale for lifespan extension.
Modality is impractical:
Another significant challenge is the modality of using a gene therapy, especially an AAV, which have shown significant toxicity and manufacturing expenses. AAVs and gene therapies broadly are reserved for life threatening diseases, usually Mendelian âinborn errors of metabolismâ i.e., genetic diseases in which a gene is missing or malfunctioning. Not as a prophylaxis against aging or any specific age-related disease.
Tissue tropism issues:
AAVs also do not generally deliver payload to many tissues, with AAVs commonly delivering 90% of payload to the liver, or specific tissues rather than broadly. They also generally have poor tropism into the CNS (which is probably a good thing!)
Gene therapy is quite far away from being relevant to longevity because the vectors are toxic, elicit a strong immune response, have poor delivery, and are expensive to manufacture. For gene therapy to apply to longevity, we need an entirely different form of vector. (Or ex vivo delivery to specific cell types to be re-infused). The Entos Pharma vector is quite promising, along with other non-viral vector technologies.
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Hi Sebastian,
Thanks for the comments. I appreciate the perspective. Iâm surprised by the debate around what constitutes longbio and what strategies may address anti-aging. VitaDAO seems to be heavily weighted to the same categories over and over. Autophagy, cell rejuvenation, senolytics. None of these have been proven to address anti-aging. Do I know if suppressing arginine mutations will prove to be effective? No, but is it different than what VitaDAO is funding, and could an asset be developed with value? Iâd argue yes. This is an interesting concept that Iâd love to see explored, and given the economics, this could be a win for VitaDAO, Molecule, and the broader community.
âGene therapy is quite far away from being relevant to longevity because the vectors are toxic, elicit a strong immune response, have poor delivery, and are expensive to manufacture. For gene therapy to apply to longevity, we need an entirely different form of vector. (Or ex vivo delivery to specific cell types to be re-infused).â
Iâd argue there is a lot of nuance here. Gene therapy continues to be a mainstay. While there have been toxicity issues, it is far from unviable. Strategic and VC investment say otherwise. Certain AAVs like 2 and 9 have broad tropism. The number of CDMOs with GMP vector manufacturing continues to increase, driving the price down. Academic groups are submitting INDs and performing trials with GMP AAV-based therapies. Lastly, given the time it takes to age, I imagine chronic treatments will have the biggest impact.
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Hi Michael,
We value your contribution to VitaDAO and I think you would be very much appreciated for assessing and managing projects which have very clear relevance to aging biology.
This particular project appears to be a prior personal interest of yours that was âpivotedâ to have some relevance to aging if you really squint at it and suspend disbelief, but a single citation of a speculative bioinformatics paper is not the standard of evidence that we generally look for.
Given that there are many MoAs that definitely extend healthy lifespan across species, we should focus on the ones that have the strongest evidence.
(e.g., see: Hallmarks of Aging: An Expanding Universe. Hallmarks of aging: An expanding universe - ScienceDirect ).
We should pick the âlow hanging fruitâ that is well-established before pursuing purely theoretical MoAs. Academia is a good place for âblue skyâ R&D, but VitaDAO has an obligation to finance projects which are closer to translation into the clinic.
Lack of lifespan data, cellular health, or animal model data for the codon approach
The stop codon suppression approach just doesnât have any lifespan data, and indeed not even any data in cellular or animal models of disease. Is there any evidence for rejuvenating cells in vitro? Thatâs the basic minimum.
Most academic IP at least has the animal model of disease evidence and some indication of toxicity/therapeutic window.
There are thousands of projects sitting on the shelf in academia â some even near clinical-stage but stranded for lack of capital. The idea of going back to the drawing board for an entirely theoretical therapeutic approach is irrational, given the abundance of well-validated assets in academia and biotech just waiting to be advanced. Especially now that capital has become scarce â assets go on sale!
Hallmarks of Aging / 7 Deadly SENS as attractive MoAs to pursue
Are we focusing on the âsame categoriesâ of LongBio: this would be an interesting analysis â of the projects weâve funded, how do they cluster across MoAs? I think weâre fairly diversified and if weâre investing multiple times in the same Hallmark, thatâs probably because that hallmark has enough evidence to justify doubling-down on it. We havenât done enough deals to probably achieve âstatistical significanceâ on any analysis of the portfolio yet, but it would be interesting to take stock of this.
The premium we place on lifespan extension data
âNone of these have been proven to address agingâ â actually, yes, they have. By extending lifespan across multiple species, reversing the epigenetic, histological, and behavioral phenotypes of aging.
For example, genetic autophagy enhancement extends mouse lifespan >15%, makes the animals better at physical and cognitive tasks â and rapamycin and other autophagy enhancers have similar effects. Senolytics can reach 20% lifespan extension. Heterochronic bone marrow transplant up to 30%. And they work for many age-related models of disease, in addition to WT mouse aging.
The Interventions Testing Program of the NIA, run by my colleague Richard Miller, standardizes these lifespan studies to compare apples-to-apples and has a list of about a dozen which work well. Here is a helpful summary compiled by my friends at Apollo Health Ventures: The Most Promising Longevity Drugs To Date | by Apollo Health Ventures | Apollo Health Ventures Insights | Medium
AAVs are toxic, expensive, and unsuitable for repeat dosing to treat chronic diseases or aging: theyâre not safe enough to be dosed prophylactically to slow aging or as a preventive therapy.
AAVs as a âmainstayâ â there are <10 approved AAV gene therapies and theyâre all for rare genetic diseases (often life-threatening ones) or other gene therapies for ex vivo engineering of cells for re-infusion.
In some patients, the AAVs cause a severe immune response or they cause liver failure. This is not the standard of safety we would need to prevent or treat slow-moving diseases of aging, much less aging itself.
Even if we were all convinced of the merit of this tRNA codon approach for longevity, we would have to wait some decades until the gene delivery technology has solved the fundamental problems of viral vectors (delivery, toxicity, manufacturing cost, repeat dosing), before this therapeutic approach could be theoretically applicable to aging.
Meanwhile, we have small molecules, mAbs, and cell therapies which work in multiple animal models of disease, extend healthy lifespan, and can be in the clinic within 3 years. From a triage perspective, it makes sense to focus on the therapies that can reach patients quickly and where we have strong evidence for their efficacy.
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Thanks, Sebastian. I appreciate the long reply. It looks like weâre at a philosophical impasse regarding what VitaDAO should fund. Thatâs okay. We will see what tokenholders say. It may not make it past snapshot. I do have to clear up some inaccuracies, though for the sake of public disclosure.
âprior personal interest of yours that was âpivotedâ to have some relevance to aging if you really squint at it and suspend disbelief, but a single citation of a speculative bioinformatics paper is not the standard of evidence that we generally look for.â
I worked on tRNA as my postdoc project. I donât think where a project originated from should have any bearing on the viability of it. Additionally, I am not sure what your bar for what enough evidence should be. I personally, donât believe a concept must have X number of papers for it to be valid.
âHallmarks of Aging / 7 Deadly SENS as attractive MoAs to pursueâ
While I see the rationale in this, I think it is short-sighted to be so dogmatic about where to find interventions. In my Ph.D. training, I was taught to not be so narrow-focused and to not be tied down by what the literature says, a lot of which isnât reproducible.
âWe should pick the âlow hanging fruitâ that is well-established before pursuing purely theoretical MoAs.â
Again, this is philosophical. No one actually knows what the âlow-hangingâ fruit actually is. This statement should be retired as Iâm not sure how well this strategy actually plays out, despite its use across many industries.
âFor example, genetic autophagy enhancement extends mouse lifespan >15%, makes the animals better at physical and cognitive tasks â and rapamycin and other autophagy enhancers have similar effects. Senolytics can reach 20% lifespan extension. Heterochronic bone marrow transplant up to 30%. And they work for many age-related models of disease, in addition to WT mouse aging.â
In mice, with no clear human data to support. My definition being a highly-powered randomized placebo controlled trial. What FDA requires to approve a drug.
" AAVs are toxic, expensive, and unsuitable for repeat dosing to treat chronic diseases or aging : theyâre not safe enough to be dosed prophylactically to slow aging or as a preventive therapy."
This is conjecture. We simply donât know. One can guess and have an opinion, but the statement above is opinion not fact. There is some truth that AAV or viral vectors have safety issues. Peptides, RNA, small molecules, all have issues. There are black-box warnings for every modality. I donât disagree that safety is an important factor, but itâs short-sighted in my view to âthrow the baby out with the bath waterâ.
"In some patients, the AAVs cause a severe immune response or they cause liver failure. This is not the standard of safety we would need to prevent or treat slow-moving diseases of aging, much less aging itself.
Even if we were all convinced of the merit of this tRNA codon approach for longevity, we would have to wait some decades until the gene delivery technology has solved the fundamental problems of viral vectors (delivery, toxicity, manufacturing cost, repeat dosing), before this therapeutic approach could be theoretically applicable to aging."
*Some patientsâŚagain, âsomeâ, is not all.
" we would have to wait some decades until the gene delivery technology has solved the fundamental problems of viral vectors (delivery, toxicity, manufacturing cost, repeat dosing), before this therapeutic approach could be theoretically applicable to aging."
Just not true. If there were fundamental problems, the viral vector space would not look like this:
This is an underrepresentation, of course, and the speed of development is getting quicker and quicker. Neurogene, an AAV9-based company actually made news this week for going public. This is an active space. https://www.neurogene.com. The CMDO market is strong: https://www.forgebiologics.com.
Again, I totally get your big-picture view. At the end of the day, this may not pass, but I needed to call out whatâs opinion and whatâs fact. DeSci is fun!
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âI worked on tRNA as my postdoc project. I donât think where a project originated from should have any bearing on the viability of it. Additionally, I am not sure what your bar for what enough evidence should be. I personally, donât believe a concept must have X number of papers for it to be valid.â
The idea for this project did not come from your unbiased review of the aging literature and decision that this is the most attractive approach of all possible options.
Itâs an idea you worked on previously, unrelated to aging, and now suspect there might be an application to aging. Itâs a matter of convenience.
When the possibility space for VitaDAO includes all possible geroscience R&D, to focus on this one is like the drunk looking for his lost keys under the lightpost â because thatâs where the light is â not because of any other reason than prior familiarity.
Thereâs a difference between being âdogmaticâ and requiring some shred of evidence to justify spending 100k on a basic research question with little connection to aging. Itâs the kind of thing that would be a good side project during a PhD or Postdoc.
âIn mice, with no clear human data to support.â If your standard requires human clinical data, then the codon approach is quite far from that as well. Thatâs a strange double standard to invoke.
Having animal lifespan data, cellular rejuvenation, or some animal model of disease data â this is better than having no data at all.
Itâs a false dichotomy to suppose that either an MoA has clinical RCT data vs. none at all. Thereâs a third option: strong preclinical evidence.
Iâd always support the project that has preclinical evidence above one that has no evidence, not even in vitro. Itâs too early to suppose that this MoA would have beneficial effect in the aging context.
It is not âconjectureâ that AAVs are toxic and had poor tissue tropism: https://www.frontiersin.org/articles/10.3389/fimmu.2022.975803/full
The graphic you show lists companies developing gene therapies, and theyâre almost all for life-threatening rare genetic diseases. Where local administration or liver tropism is sufficient. Many of them are also ex vivo.
Yes, there are companies developing gene therapies. But they are used in narrow indictions where the risk/reward is justified. Also â just because there are companies operating doesnât mean itâs a good idea â the amyloid hypothesis comes to mind. Or all the funding for CRISPR companies â (CRISPR canât be delivered in vivo without immunogenicity).
There is a lot of unjustified hype around AAVs and the world is recognizing their toxicity now that the hype is fading a bit. Hereâs a recent example of two patient deaths in an AAV trial: High-dose AAV gene therapy deaths | Nature Biotechnology
AAVs simply are not suitable to dose people with unless they have a life threatening disease, often a Mendelian one where we can be quite certain that delivering a functional copy of a broken gene will work.
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This stop codon tRNA approach has virtually zero evidence. In aging or in any animal models. Not even in cellular aging. Theoretically this MoA could be a cause or consequence of aging â to have these premature stop codons appear â but we donât have compelling evidence for that yet (e.g., create a mouse model with more stop codon malfunctions â does it cause progeria? Create a mouse (or even a cell line) with enhanced tRNA fidelity â does it slow aging? These are questions for basic research, not the risk capital from our DAO participants.
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Even if there were a connection to aging proven in the future, thereâs still the modality problem. Itâs a gene therapy that would need to be delivered to many tissues to slow aging. And it would need to be preventatively dosed â because the stop codons occur prior to the onset of any specific disease. There is currently no gene therapy vector type that is safe enough for preventive dosing, nor with efficient tropism to enough tissues in the body to address a complex multi-tissue disease (much less aging). The same problem applies to Yamanaka transient reprogramming â and hence the pivot to chemical reprogramming agents (which will only be useful ex vivo anyway, since in vivo cocktail stoichiometry has never been achieved).
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Please, kindly vote on ownership options, poll will close in about 24 hours.
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