None approved; multiple ASO programs in preclinical development
Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy, accounting for approximately half of all CMT cases. It is caused by a 1.5 Mb duplication on chromosome 17p11.2 that includes the PMP22 gene, which encodes peripheral myelin protein 22. The duplication results in three copies of PMP22 instead of the normal two, leading to overexpression of PMP22 protein. This excess protein disrupts the structure of the myelin sheath that insulates peripheral nerves, leading to progressive demyelination and axonal degeneration.
CMT1A typically presents in childhood or adolescence with slowly progressive distal muscle weakness and atrophy, starting in the feet and legs (leading to foot drop and high-arched feet) and later affecting the hands. Patients also experience sensory loss and reduced deep tendon reflexes. While not life-threatening, CMT1A causes significant disability and there is currently no disease-modifying treatment.
Because CMT1A is a gene dosage disease — three copies of PMP22 produce too much protein — gene silencing is a rational therapeutic approach. The goal is to reduce PMP22 mRNA levels by approximately one-third, bringing protein levels back to the range produced by two copies. This requires precision: reducing PMP22 too much would cause hereditary neuropathy with liability to pressure palsies (HNPP), the disease caused by PMP22 deletion.
ASOs targeting PMP22 mRNA for RNase H-mediated degradation have shown promising results in preclinical models of CMT1A. In animal studies, ASO treatment reduced PMP22 mRNA levels, improved myelination, and restored nerve function. The challenge is delivering ASOs to Schwann cells (the myelinating cells of the peripheral nervous system) at sufficient concentrations while managing the dosage precision required to reduce but not eliminate PMP22 expression.
Several pharmaceutical companies are developing ASO approaches for CMT1A. The relatively slow progression of the disease means that even modest reductions in PMP22 overexpression could provide meaningful clinical benefit over years of treatment.
Pequliar designs gene-silencing ASO candidates for CMT1A, targeting PMP22 mRNA for RNase H-mediated degradation. The platform identifies optimal binding sites on the PMP22 transcript, scores candidates for binding affinity and off-target safety, and provides synthesis-ready sequences with full chemistry assignment. The design is optimized for efficient target engagement while maintaining the specificity needed for a gene where dosage precision is critical.
Describe your mutation and get ranked, synthesis-ready ASO candidates in minutes. $399 per design.
Start a designPequliar is a computational research tool for informational purposes only. All sequences are computationally predicted candidates that have not been experimentally validated. Pequliar does not prescribe, recommend, or administer any compound. Independent validation by qualified professionals is required.