Mittwoch, 4. März 2015

Rapalogs and Rapamycin in the healthy?

I admit that I was skeptical at first whether the immunosuppressant rapamycin could ever be used in healthy people. A number of recent findings have changed my opinion, of which I will discuss a few (1, 3). Since I saw an enthusiastic talk by Arlan Richardson on the safety of rapamycin in animal models of age-related diseases, I have been warming up to this idea. In any case, there are three "solutions" to the major side-effect of immunosuppression: 1. design more selective rapalogs (is this possible?), 2. micro-dosing without immunosuppression may be enough to shift mTOR activity towards a healthier, lower level in vivo, 3. accepting the potential trade-offs: a 5-10% increase in life-expectancy would compare favorably to mild immunosuppression, for instance.

Study I. Familial adenomatous polyposis is a condition that leads to a massive increase in colorectal cancer incidence and it is caused by APC mutations. Rapalogs (Rapamycin analogs) have been approved for some cancers and now Faller et al. (1) found that rapamycin can protect APC deficient mice from cancer.


"...targeting mTOR and translational control may be a viable strategy for chemoprevention of colorectal carcinoma in high-risk patients, and treatment of early stage disease." (1)
"These findings suggest that targeting mTOR and translational control may represent a potential strategy for early-stage treatment and prevention of colorectal cancer." (2)

If rapalogs work for primary prevention in high-risk populations the next step will be testing them in the healthy, as well as developing and testing new (safer, improved?) rapalogs in the healthy.

Study II. Rapamycin was also tested in non-human primates (3) and appeared safe and well-tolerated; no obvious side-effects of immunosuppression were seen, although, one treated animal showed delayed wound healing and a skin infection, which was successfully treated. "It is noteworthy that there were no indications of infectious disease in this study."

"...The ability to rapidly and reliably dose socially housed marmosets with an oral form of rapamycin that is well tolerated and that demonstrates a suppression of the mammalian target of rapamycin pathway leads us to conclude that this species offers a viable model for rapamycin testing to establish safety and efficacy for long-term antiaging intervention.

The common marmoset (Callithrix jacchus) is a small monkey with a relatively short life span—the average and maximum life span for this species being roughly 50% of that of commonly used Old World monkeys such as macaques.

...a 14-month long study of daily dosing of a group of common marmosets with RAPA

The trough levels observed in both the short-term and the long-term studies that were achieved at the dose of 0.4 mg/day (roughly 1.0 mg/kg/day) were comparable with those reported in studies of C57BL/6 mice being fed a diet containing e-RAPA at a concentration of 14 ppm...
...the marmoset blood concentrations averaged 5.2ng/mL with a range from 1.93 to 10.73 ng/mL."


References
1. Nature. 2015 Jan 22;517(7535):497-500. doi: 10.1038/nature13896. Epub 2014 Nov 5. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Faller et al.

2. Cancer: mTOR inhibition curbs colorectal cancer. [Nat Rev Drug Discov. 2015]

3. J Gerontol A Biol Sci Med Sci. 2014 Jul 19. pii: glu101. [Epub ahead of print] Testing Efficacy of Administration of the Antiaging Drug Rapamycin in a Nonhuman Primate, the Common Marmoset. Tardif et al.

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