Towards a Small Molecule Approach to Thymic Regeneration
The thymus is vital to a sustained and functional immune system. Thymocytes generated in the bone marrow migrate to the thymus, where a complex process of maturation and selection takes place, turning the thymocytes into T cells of the adaptive immune system. T cells must be capable of recognizing and reacting to pathogens and cancerous cells, without mistakenly attacking any of the normal systems of the body and its diverse cell population. That risk of self-immunity is the price of an adaptive immune system. The wide range of autoimmune conditions observed in the human population demonstrates that evolution does not produce infallible mechanisms.
The thymus atrophies with age, the active tissue replaced with fat. This reduces the supply of T cells, and in the absence of reinforcements the adaptive immune system relies increasingly on replication of peripheral immune cells to maintain its population. This leads to an aged immune system consisting of ever more harmful, senescent, exhausted, or otherwise problematic T cells. It is a sizable contribution to the age-related decline of immune function into chronic inflammation and incapacity.
There are many possible approaches to regeneration of the thymus, all of which have their issues. The thymus is a small, deep organ, which makes it hard to deliver therapies in a high enough dose without direct injection, and direct injection of that nature is probably too risky for widespread use. Mortality rates for similar procedures are around 0.1 to 0.2%. Several genes (e.g. FOXN1), recombinant proteins (e.g. growth hormone, KGF), and inhibitors (of androgens) would probably work very well to regrow the human thymus if the therapy could be delivered only to the thymus. Of these, only growth hormone can be used systemically at a reasonable cost-benefit calculation, as in the Intervene Immune protocol, but even then growth hormone isn't a treatment to be taken lightly.
Cell therapies and implantation of tissue engineered thymus organoids are presently the only obvious ways to work around the delivery issues. Several types of cell naturally home to the thymus, and researchers have demonstrated thymic regrowth in mice via delivery of such cells. It is plausible to consider the manufacture of universal cell lines that can be cost-effectively used in any patient; work on universal cells has yet to reach clinical approval, but it is quite advanced, undertaken by a number of large companies in the biotech industry. On the tissue engineering side of the fence, the company Lygenesis is built on research showing that thymus organoids can be implanted into lymph nodes, where they function in the same way a a normal thymus does. Building such organoids is presently an expensive process requiring donor tissue, however, and surgery, even minor surgery, is never cheap.
Several research groups are in search of a small molecule approach to spurring thymic regrowth, and have been for some years now. Small molecules have a different set of issues in comparison to the potential therapies noted above, in that what is known of the regulatory systems governing thymic growth does not yet present good, distinct targets. The thymus is an epithelial tissue, like the lining of the throat and intestines. As work on KGF demonstrates, there are unpleasant side-effects that attend the systemic delivery of signals to tell all epithelial tissue to grow. The path to a small molecule drug for thymus growth, if such a thing can be made, is to first search for a layer of regulation that is unique to the thymus. That is the goal of the research group responsible for today's materials.
Prior to the current study, researchers had sketched the rough outlines of the thymus' renewal processes. This included identifying molecules that orchestrated two separate regenerative pathways (one triggered by a molecule called IL-22, and another by Bmp-4), and showing that it is the damage itself that triggers the thymus to renew. They'd also discovered that damage to the thymus sparks its regeneration by temporarily destroying a normal thymic developmental process.
T cells developing in the thymus undergo a rigorous "education" process that ensures that we aren't stuck with a lot of mature T cells that either can't recognize any signs of disease, or are primed to attack our healthy tissue instead of infected cells. Most T cells don't make the cut and get weeded out, dying by the thousands. Prior work suggested that dead and dying T cells acted as a brake on regeneration. When damage to the thymus wipes out T cells - surviving and dying alike - this brake is removed, and renewal mechanisms roar in to fill the void. Though researchers knew that dying T cells somehow acted as a brake to keep IL-22 and Bmp-4 - and thymic regeneration - suppressed, they didn't know how. Outlining the molecules that made up this sensor and suppressor system would reveal potential targets they could manipulate to promote regeneration.
The cells that help the thymus refill itself with T cells aren't T cells themselves, but accessory cells that support young T cells as they clear - or miss - their developmental hurdles. Researchers found that it's these accessory cells that sense dying T cells. They then outlined the molecular relays that lead from thymic damage to Bmp-4 and IL-22 (which activate thymus regeneration), identifying several key molecules along the way. Then, the researchers tested whether they could intervene. Researchers assessed whether blocking one of the players, called Rac1, (thereby boosting IL-22 and Bmp-4) helps improve thymic function after damage. They treated mice with an experimental Rac1 inhibitor after exposing them to radiation (similar to the thymus-blasting regimen that patients receive before bone marrow transplant). Mice treated with the Rac1 inhibitor produced more T cells than either untreated mice or treated mice that lacked a molecule in the T cell-death sensing pathway.
Perhaps the biggest hurdle right now is the lack of a Rac1 inhibitor available for clinical use. But researchers are hopeful; molecules related to Rac1, collectively called Rho GTPases, have been implicated in many diseases, and are an active area of investigation by pharmaceutical companies. "To move it forward, it's really going to require a drug itself. And that's where we're at, at the moment, trying to develop compounds that could be used clinically."
I know that small molecules are the workhorse of pharma, with a super-majority of drugs being small molecules affecting signalling pathways, but with other tools in development (orgonoids, CRISPR, 3D bioprinting, etc.) and with advances in delivery (smaller CAS molecules like CAS12a and CAS 13), unless one was taking a Recursion approach (machine learning high throughput testing), small molecules feels dated. Still, pharma's data sets, pipelines, etc. are built and optimized for small molecule drug development. All the more reason that we need to have money spread on to other bets with more innovative companies/approaches. Thanks for the post, Reason.
Maybe using ultrasound to release a drug from lipid bubbles only in the thymus could work and arrive a lot sooner than cell therapies?
https://www.sciencedaily.com/releases/2020/10/201005101529.htm
" In the first step, the scientists use low energy ultrasound waves to cause the drug carriers to aggregate at the desired site within the brain. "What we're doing is using pulses of ultrasound essentially to create a virtual cage from sound waves around the desired site. As the blood circulates, it flushes the drug carriers through the whole brain. But the ones that enter the cage can't get back out," Yanik explains.
In the second step, the researchers use a higher level of ultrasound energy to get the drug carriers to vibrate at this site. Shear forces destroy the lipid membranes around the drugs, releasing the drugs to be absorbed by the nerve tissue present at the site."
There is a body of literature pointing to zinc as the agent that prevents thyme involution or reflates the thymus once it atrophies. Recent linkages between immunity and longevity points to zinc as an anti-aging agent. There is a smaller body of literature regarding vitamin D's ability to maintain thymus gland volume and function.
What is stopping us from designing an mRNA treatment that first determines if the cell is thymic and if so delivers the pro-regerative signal? Is it that it's still too difficult to get the treatment into the thymus? Is it that programming mRNA in this way is still not possible? Is it that such an mRNA complex would be too large for delivery? Is it something else?
@Neil: There are any number of much simpler gene therapy approaches that would work if you could direct the vector only to the thymus. Direct injection is the only viable way to do that at this time, an approach with a 0.1% to 0.2% mortality risk, too high to be acceptable for widespread use. One can absolutely run vectors like AAV with promoters keyed to more-or-less-thymus-specific gene expression, so that the cargo gene only expresses in thymic epithelial tissue. But to get enough vector into the thymus (a small organ) via intravenous injection would require an amount so high that it would cause excessive immune overactivation and mortality risk. That is true for LNPs as a vector as well.
Well I really hope someone figures out a good delivery method soon as once that has happened it may be a fairly short path to increased healthspan/lifespan for old and middle aged people. I imagine it could boost human lifespan as much as the introduction of vaccines or antibiotics did.
Although in mouse experiments the fibrosis of lymph nodes seemed to indicated that just rejuvenating the thymus didn't do much.
Regarding the need for toxic levels of even cell targeted LNPs to get enough to the thymus I do hope that cell targeted LNPs that are also shepherded to the thymus by ultrasound or magentic fields might be a way forward.
We can't end this thread without pointing out the thymus regeneration work of Dr. Fahy
https://www.gowinglife.com/longevity-briefs-the-drugs-that-reverse-human-ageing/
"Direct injection is the only viable way to do that at this time, an approach with a 0.1% to 0.2% mortality risk, too high to be acceptable for widespread use."
Given how much benefit a rejuvenated thymus theoretically could offer a person, a 1 in 750 risk of death for such a procedure seems reasonable. An older person probably has a higher risk than that of dying from a single case of seasonal flu.