Investigational CMT1A Gene Therapy Eased Myelin Loss in Mice

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A potential gene therapy for Charcot-Marie-Tooth disease type 1A (CMT1A) has shown promising results in a two-year study using a mouse model of the disease.

According to a press release from the CMT Research Foundation, which is funding the study, the gene therapy led to marked reductions in the levels of PMP22, the protein involved in CMT1A, in peripheral nerves compared to untreated mice, used as controls. Peripheral nerves send sensory and motor information from the brain and spinal cord to the rest of the body.

Microscopy analysis of the nerve cells revealed that mice given the gene therapy had far fewer signs of demyelination (loss of myelin), a hallmark of CMT type 1. Myelin is the fatty substance that surrounds nerve fibers, and is important for sending electrical signals throughout the nervous system.

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In addition, parameters of nerve function, strength, and balance improved significantly in treated animals, frequently to levels similar of mice without the CMT1A-causing mutation.

The benefits of the gene therapy were seen in young mice, but also in older ones that already had significant loss of strength and balance.

Overall, these preclinical findings support the potential of a genetic therapy for CMT1A, according to the Foundation.

Kleopas Kleopa, MD, at the Cyprus Institute of Neurology and Genetics, is leading the project along with Scott Q. Harper, PhD, at Nationwide Children’s Hospital in Columbus, Ohio.

CMT1A is caused by having an extra copy of the PMP22 gene, leading to elevated levels of PMP22 protein and myelin abnormalities and dysfunction.

The gene therapy project was developed based on the hypothesis that reducing levels of PMP22 protein may prevent symptom onset and potentially rescue nerve damage in people with CMT1A.

First, the researchers tested different sequences targeting the PMP22 gene in lab-grown cells. The best sequence was then packed into harmless viruses used to deliver gene therapies — adeno-associated viruses — and injected into the mice’s cerebrospinal fluid (the fluid surrounding the brain and spinal cord).

Early this year, the Foundation granted additional funding to this project, which also explores potential biomarkers for CMT, including neurofilament light chain (NfL) and other blood and skin markers that may be useful in gauging the effectiveness of gene therapies.

Notably, NfL levels are typically elevated upon nerve cell damage, which makes it a potential biomarker for diseases of the nervous system.