Charcot-Marie-Tooth disease - Emerging treatments

PXT-3003 (baclofen/naltrexone/sorbitol)

PXT-3003 is being investigated for the treatment of CMT1A. This compound combines three drugs currently approved for other indications: baclofen, naltrexone, and sorbitol.[34] Pre-clinical trials showed decreased PMP22 mRNA levels on transgenic rats. A treatment trial of 80 patients with CMT1A found good safety/tolerability of the drug and some improvement in strength and function in the high-dose group compared with placebo. Additional trials are necessary to determine if this decreases disability in people with CMT1A, and trials are planned for the near future.[35]

Antisense oligonucleotides

A preclinical study found that the PMP22 antisense oligonucleotide (ASO) reversed CMT1A phenotypes in two different CMT1A animal models. ASOs are able to bind specific RNA and block the production of the protein related to that DNA and RNA. In CMT1A, there is an over-expression of PMP22 and the ASO may be able to reduce this expression. Preclinical and clinical trials need to be undertaken with care, because too little PMP22 production causes hereditary neuropathy with liability to pressure palsies (HNPP).[36] Although it may take a number of years to determine if this has a beneficial effect in patients with CMT1A, ASOs could potentially be the first treatment that directly attacks the cause of the disease and stops disease progression.[36] DTx-1252 is one such ASO that has received orphan drug designation by the Food and Drug Administration (FDA). It utilises a small interfering RNA (siRNA) to target the PMP22 duplication and reduce the amount of PMP22 protein produced. Mouse models show normalised myelin levels and increased functionality.

Gene therapy

Loading of a complete gene or a target gene into an adeno-associated virus (AAV) vector is being developed for multiple forms of CMT, including CMT1A and CMT1X. The goal is having a functional gene inserted into the nerves to replace the defective copy (in the case of CMT1X) or to add a different gene (e.g., NTF3) thought to increase nerve health (in the case of CMT1A).[37] NT3 is expressed by the myelin sheath and allows for survival and differentiation along the nerve. Trials are ongoing for AAV-NTF3.[38] AAV2/9 vectors are being developed for delivery of small hairpin RNAs to reduce PMP22 expression in CMT1A.[39]

Sorbitol inhibitors

CMT caused by the gene recessive sorbitol dehydrogenase (SORD) causes SORD deficiency, and people are found to have increased serum sorbitol levels, roughly 20 times normal levels.[40] Clinical trials are ongoing to reduce the sorbitol levels. Govorestat (AT-007), an experimental aldose reductase inhibitor, is being administered via oral liquid suspension in clinical trials to determine the efficacy of reduction of sorbitol levels on functional outcomes.[41]