With support of $225,483 from CMTA’s Strategy To Accelerate Research (CMTA-STAR), scientists at the University of Miami have completed an encouraging study on a potential therapy for CMT2E, an axonal CMT subtype caused by mutations in the NEFL gene. The project was led by Mario Saporta, MD, PhD, and focused on a type of genetic therapy known as an antisense oligonucleotide, or ASO. See Under the Microscope to learn more about ASOs.
An ASO is like a tiny piece of genetic tape. It sticks to a faulty gene’s messenger RNA, which is the step between the gene and the protein it produces, and blocks the faulty instructions from being carried out. The team set out to see if ASOs could “silence” the harmful NEFL gene mutation that leads to CMT2E.
They focused on a specific NEFL mutation called p.N98S (also written as p.Asn98Ser), which affects peripheral nerve cells that carry signals to and from muscles. When these cells are disrupted, it can lead to progressive weakness and other symptoms of CMT2E. Using lab-grown nerve cells made from patient-donated stem cells, the researchers tested several ASO compounds to find the strongest and safest option. One candidate, called ASO4, showed the most promise.
ASO4 reduced levels of NF-L, a key protein that leaks out of damaged axons in the peripheral nerves. NF-L, short for neurofilament light chain, is a structural protein inside nerves. High levels of NF-L are a known sign of nerve injury. After treatment with ASO4, NF-L levels dropped closer to the range seen in healthy cells.
ASO4 also reduced the activity of the mutated gene by nearly 40 percent, while only mildly affecting the normal gene copy. Further testing showed that ASO4 had little effect on unrelated genes, and this is an encouraging sign for safety.
ASO therapies are already being used to treat other rare neuromuscular diseases. This research shows that a similar approach may help people living with CMT2E. The findings lay important groundwork for future testing in CMT models and bring us closer to clinical trials.
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Published on: July 31, 2025