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“Moscow Buyers Club” of anti-aging therapy - research plan

AIDS activists in the 1980s

According to the results of my previous post, some readers reproached me with the fact that I did not describe a plan in it, but only a hypothesis. Although there was one and the other. Just the plan was in general terms, from the height of bird flight. And the hypothesis is very simple: epigenetic coil is epigenetic rejuvenation . Consequently, by rolling back in any way the gene methylation profile, we also roll back the biological age of the organism, which means we rejuvenate it.

If someone is interested in a detailed plan of my research, I will present it below. But first I want to answer another objection I heard: “Isn’t it easier to wait for Belmonte?” It’s certainly easier. Sit and wait until others solve all your problems are really easier. But when it comes to fatal illness, this is not the best strategy.

If HIV-infected people in the 80s sat silently and waited, I think a much smaller percentage of them would live to life-saving anti-retroviral cocktails. They understood this very well, and therefore organized many thousands of demonstrations , demanding to find a cure for HIV as soon as possible, and also created " Dalassian clubs of buyers " in order to try various experimental therapies on themselves.

I believe that HIV 2.0 should be treated the same way. To do everything possible for the speedy development of at least some effective therapy. Because otherwise, our parents will not live to such therapy.
And I'm not sure that Belmonte is obsessed with this idea as much as I am obsessed with it. But even if he, too, is actively pursuing research in this area, there is nothing wrong with several teams doing this. In any case, Belmonte is primarily a scientist. And I am a practitioner. Only the end result in the form of life-prolonging therapy is important to me, and even its commercial value is secondary to me. Although if everything works out, I am sure that commercial success will also come. But money is not an end in itself, it is only a tool for achieving a much more important goal.

Actually, the research plan


First, a little teaching mother. So, the key hypothesis: in order to reliably rejuvenate the entire body, we need to roll back the epigenetic clock of most cells of the body, if not every cell at all. Thanks to the work of the Belmonte group, we know that this is possible by delivering OSKM factors (or other transcription factors) into the cell. At the same time, the process is subject to the “Goldilocks problem”: rolling back too weakly, we will not get a significant rejuvenating effect; rolling away too much, you can get cancer, because the cells lose their phenotype and return to the stem, pluripotent state.

Do not forget that it was the ability to effectively return cells to a pluripotent state and served as the main selection criterion for selecting 4 OSKM factors from the original 24 candidates by Yamanaka. Therefore, although the OSKM factors have shown their effectiveness for rejuvenation through partial rollback and constitute a bird in the hand, they are far from ideal for safe rejuvenation. So, it is worthwhile to continue the search for safer ways of epigenetic recoil. It makes sense to start by checking the remaining 20 factors from the original 24 factors of Yamanaki , and also try to use the Oct4 factor alone, as there is evidence that he alone can roll back epigenetic and generally is the main “guardian of epigenetic gates."

Also worth checking out are other reprogramming methods developed in recent years. For example, look at the method of replacing the transcription factors Oct4, Sox2, c-Myc with antibodies, which was published literally this week . If this approach works, then gene manipulations may not be needed at all, and periodic administration of antibodies will suffice. Although repeated administration may cause problems with a secondary immune response.

In any case, while for me the main hypothesis of therapy is the gene, with the help of certain factors of rollback. But finding the best factors is only half the battle. The other half is how to deliver them safely and, ideally, cheaply. The epigenetic aging program is quite stubborn even in the face of weekly kickbacks, as the work of the Belmonte group showed. Therefore, in order to achieve significant rejuvenation in people, most likely, it will be necessary to activate rollback factors monthly or even weekly.

I see the most economical way to do this is to integrate a special, default inactive gene cassette (containing the genes for rollback factors) into almost every cell of the patient, presumably using lentiviruses or another integrative delivery method. Further, such a cassette will have to be periodically activated by a unique and inert agent that can be developed separately and will make such therapy patentable. Today, such cassettes are activated, for example, by tetracycline or doxycycline . With this approach, the cost of weekly induction of anti-aging factors will be determined only by the cost of the induction agent (presumably a small molecule or peptide) - that is, it will be relatively cheap.

The optimal plan seems to me to be a step-by-step, iterative improvement of the already proven approach (induction of OSKM factors with doxycycline; such a cassette with OSKM factors can be delivered to the body using lentiviral carrier available on the market today) and the parallel development of ideal therapy (maximum safe and effective activated by a unique, inert, patentable agent).

Thus, the research can be divided into three parallel tracks:


Next, I will describe in more detail all three areas of research.

Research track 1 (“tit in hand”): develop an optimal dosing regimen using 4 initial factors OSKM


The Belmonte group found that mice begin to die after 3 consecutive days of OSKM induction:


Therefore, they used the 2/5 protocol, in which mice (with only the 1st copy of the OSKM cassette allele is important, since teratomas were formed in mice with 2 copies) OSKM (using doxycycline) inducted 2 days in a row and then received a 5-day break before repeating the treatment cycle.

However, the weight of the mice began to decline already from the 2nd day of induction:


This suggests that two-day sequential induction is not optimal. Moreover, the 5-day break seems too long, based on what I know about cell cycles. I think the 1/2 or 1/3 treatment regimen has the best long-term potential (1-day induction, and a 2- or 3-day break).

To test these assumptions, the following steps are necessary (these studies are best ordered from large CROs, for example, from Charles River):



Research Track 2 (“cranes in the sky”): search for safer factors of epigenetic recoil (not leading to complete de-differentiation)



Research track 3: delivery vehicle (carrier) and patentability



Prices, terms


Here's what I got at prices and terms:


Major mileston project:


The project duration of 5–6 years means overhead costs in the amount of 7.5–12 million US dollars, based on the above 1.5–2 million US dollars per year. Thus, the total amount of expenses up to the IND stage is: 24–37.5 million US dollars.

If the project successfully reaches the IND stage, then Big Pharma companies will tear it off with arms and legs, which will then begin clinical trials of such therapy (first from atherosclerosis, Alzheimer's disease, diabetes, or other age-related nosologies for which aging drugs have to be tested today) as aging itself is not yet classified by WHO as a disease).

Summary


Such is the project of the Moscow Buyers Club crystallized in my head. Or even a “club of self-rescuers”. Let's see what happens. If we manage to find financing for him, I think it will be a glorious hunt. I hope that, as a result of it, HIV 2.0 will suffer significant losses, and we will be able to win at least several decades of healthy life for us and our loved ones.

Source: https://habr.com/ru/post/406721/

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