Further research will be needed to see whether the same mechanisms are at play in human disease. Of note, this study was done using cells in dishes and in mice. In both cells in dishes and living mice, this treatment significantly reduced abnormal myelin production, the team found.Ĭollectively, these data suggest that modulating mTORC1 activity - whether via rapamycin or other pharmacological strategies - may represent a viable therapeutic strategy in CMT4B.

Rapamycin was tested to determine whether it could prevent abnormal myelin production caused by a lack of Rab35. This medication - which is well-studied in humans - works by blocking mTORC1. Food and Drug Administration for several uses, including reducing immune system activity during organ transplants and treating certain types of cancer. That led the researchers to investigate rapamycin, a medication approved by the U.S. If MTMR dysfunction (as seen in CMT4B) leads to myelin defects by affecting mTORC1, then blocking the activity of mTORC1 could be a therapeutic strategy for CMT4B, the team hypothesized. “These data suggest that Rab35 and its associated MTMRs may regulate mTORC1 activity,” the researchers wrote. Furthermore, the inhibition of lysosomal function by addition of. Its derivative drug, GDC-0349, demonstrates pathway modulation and dose-dependent efficacy in mouse xenograft cancer models. Additional experiments suggested that this was a direct result of changes in the lipids regulated by MTMRs. dMtmr6 is a member of the myotubularin-related (MTMR) family of proteins and is most. Description: IC50 Value: 1.5nM (Ki) GDC-mTOR inhibitor is a potent and selective ATP-competitive inhibitor of mTOR. For instance, when the researchers decreased the activity of Rab35 or its associated MTMRs, mTORC1 activity decreased. Subsequent experiments supported this hypothesis. This would explain the overproduction of myelin observed upon a lack of Rab35 functionally, the lack of Rab35 would be “cutting the brakes” on mTORC1, leading to its overactivation and subsequent myelin production. Thus, the researchers hypothesized that Rab35 could - through the MTMRs it recruits - help limit the activity of mTORC1. Notably, mTORC1 is known to be regulated by some of the same lipids that MTMRs regulate. Previous research had shown that the protein mTORC1, when overactive, could lead to similar myelin defects. These mice’s neurons had areas of myelin overproduction and myelin out-folding, or improper folding - characteristic myelin defects of CMT4B.

Mtmr inhibitor