A recent study found that a drug that helps other nerve diseases makes CMT4B1 worse, and figuring out why has opened a more promising path toward treatment, including a possible path forward for the related subtype CMT4B2. This work was funded jointly by the Muscular Dystrophy Association (MDA) and the CMT Research Foundation (CMTRF), supporting Dr. Alessandra Bolino’s lab at San Raffaele Hospital in Milan.
CMT4B1 is a severe, childhood-onset form of Charcot-Marie-Tooth disease caused by loss of MTMR2 gene function. In the absence of MTMR2 function, the insulation that wraps nerve fibers, called myelin, folds onto itself instead of forming a smooth sheath around the neuron. The small molecule drug rapamycin has been extensively tested in similar diseases of the nervous system, making it an attractive therapy to test for CMT.
Surprisingly, when CMT4B1 pre-clinical models were treated with rapamycin, myelin damage worsened consistently across multiple trials. While this was disappointing, tracking down why has given the team new insights into the biology driving CMT4B1 and the role of lipid metabolism.
Notably, the related subtype CMT4B2, caused by loss of MTMR13 rather than MTMR2, appears to respond differently. In ongoing work, rapamycin decreased tomacula (a hallmark of CMT4B2 pathology) without changing outfoldings, suggesting rapamycin may still hold promise for this subtype even as it’s ruled out for CMT4B1. These findings support the idea, previously raised by others but not fully confirmed, that CMT4B1 and CMT4B2, despite their clinical similarity and the fact that MTMR2 and MTMR13 interact in Schwann cells, don’t share exactly the same disease mechanism.
“This project is a good example of why we fund rigorous science, regardless of whether the results are positive or negative,” said Angela Lek, Ph.D., Chief Research Officer at the Muscular Dystrophy Association. “Dr. Bolino’s team has sharpened the path toward an effective therapy for CMT4B1 and CMT4B2, and the Muscular Dystrophy Association is proud to support that work alongside CMTRF.”
CMTRF CEO Laura MacNeill added, “Science is about learning. Not every project will generate a treatment, but every project can teach us a lesson that brings us closer to therapies and cures for people with CMT.”
Practically, this means rapamycin and similar drugs are off the table for CMT4B1, sparing patients a treatment that could backfire, while remaining a live possibility for CMT4B2. In its place, the team now has specific biological leads to chase in patient cells.
The lab is currently publishing this work, with more scientific details forthcoming. Dr. Bolino is also running a separate, actively funded project testing gene therapy for these same subtypes of CMT.
