Scientists have been studying a potential treatment option for CMT by inhibiting (blocking) a protein called histone deacetylase 6 (HDAC6). They have found that HDAC6 plays an important role in regulating the pathways involved in breaking down proteins and transporting proteins along the axons (the long parts of the nerves that conduct the electrical impulse from one end to the other). Inhibiting HDAC6 has shown promising results in reversing these dysregulated processes in CMT models.
In this study funded by CMTRF, researchers from Oryzon evaluated the effects of a new and potent HDAC6 inhibitor called ORY-4001 in a mouse model of CMT1A. The mice were 8 weeks old at the start of the study and were showing clear signs of CMT disease compared to control mice without CMT. The mice were treated with ORY-4001 by mouth twice a day for 6 weeks. There was also a positive control group of mice that received a mixture of baclofen, naltrexone, and sorbitol, which is a new drug cocktail currently being studied in a Phase 3 clinical trial for CMT1A. The researchers measured the mice’s grip strength, their performance on a rotating rod, and the electrical activity in their sciatic nerve before and after the treatment. They also examined the health of the sciatic nerve tissue using a staining method called toluidine blue.
The results of the study were positive. ORY-4001 significantly improved the speed of nerve conduction and muscle response, which led to improved strength and coordination in the mice. The treatment also resulted in a significant increase in body weight compared to mice with CMT who did not receive any treatment. When the researchers examined the sciatic nerve tissue, they found that the number of axons had increased, and the protective myelin covering around the axons had improved in health.
The mice that received ORY-4001 treatment looked very similar to the mice in the positive control group that received a mixture of baclofen, naltrexone, and sorbitol. The doses used in this study were safe and below the maximal tolerated dose, which allows room for dose increases in additional studies to further deepen the therapeutic benefit of ORY-4001.
These results suggest that ORY-4001 has the potential to improve the symptoms of CMT and prevent disease progression. Based on the data generated in this study and other data, Oryzon has selected ORY-4001 as a candidate for clinical development and is now planning to perform pre-clinical studies to enable an investigational new drug (IND) application.