With CMTA support of $225,483, researchers at the University of Miami, led by CMTA Strategy To Accelerate Research (CMTA-STAR) Advisory Board Member Mario Saporta, MD, PhD, are developing an antisense oligonucleotide (ASO) drug to treat CMT2E, an axonal form of Charcot-Marie-Tooth disease caused by dominant mutations in the NEFL gene.
ASOs are a type of drug that can target specific genes and change how they are expressed, which in turn affects how they are translated into proteins. The team’s approach uses the same chemistry as the USFDA-approved ASO treatment for spinal muscular atrophy (SMA), in use since 2016 and known to be safe and well tolerated.
In CMT2E, one copy of the NEFL gene carries a mutation while the other copy is normal. The ASO drug is designed to “silence” the mutant copy, allowing the normal copy to function without interference. This selective targeting aims to restore healthy nerve function and slow or stop disease progression.
August 2025 Update
Now completed, Dr. Saporta and colleagues targeted the p.N98S mutation, which leads to severe motor neuron damage. Using patient-derived cells, the team created a disease model that replicated key features of CMT2E and used it to test multiple ASO compounds. One candidate, known as ASO4, demonstrated the most promise.
ASO4 successfully reduced levels of NF-L, a biomarker of axonal damage, bringing them close to those seen in healthy cells. This result suggests that ASO4 helped protect nerve cells from injury. The ASO also lowered expression of the mutant NEFL gene by nearly 40%, while having only a mild impact on the normal gene copy. Additional testing found minimal off-target effects, an encouraging indicator for safety.
This project builds on earlier CMTA-funded discoveries and marks a critical step toward clinical development of gene-targeted therapies for CMT2E. The findings support continued advancement of ASO4 into animal studies and, eventually, trials in people affected by CMT2E.
