CMT2A damages nerves in an unusual way. In this subtype, the mitochondria that power the cell can’t provide enough energy to the body’s longest nerve fibers, causing them to slowly break down. This differs from the more common subtypes of CMT, which damage the myelin that insulates the nerves. A new research project is testing an unconventional way to protect nerve fibers in CMT2A by switching on a backup gene – MFN1 – that affected cells aren’t using.
To pursue the idea of using MFN1 to power nerves, CMTA invested $110,500 in a new partnership with La Jolla Labs, led by CMTA Scientific Advisory Board Chair John Svaren, PhD, of the University of Wisconsin-Madison. La Jolla Labs is a biotechnology company specializing in a class of genetic medicines called antisense oligonucleotides (ASOs).
What causes CMT2A? The MFN2 gene and your nerves
Caused by mutations in the MFN2 gene, CMT2A is an axonal form of Charcot-Marie-Tooth, meaning it damages the long fibers (axons) that carry signals along peripheral nerves. MFN2 provides instructions for a protein called mitofusin 2, which sits on the surface of mitochondria, the “powerhouses” of the cell that convert food into energy. Mitofusin 2 helps mitochondria stay healthy and move to where they are needed in the body.
This movement is important to healthy nerve cells. Peripheral neurons are among the longest cells in the body; a single nerve can run from the spinal cord to the foot. To power the far ends of the nerve, mitochondria must travel the entire length of the fiber. When MFN2 is faulty, energy delivery fails first at the most distant points, which is why CMT2A symptoms often begin in the feet and move upward over time.
Could enabling MFN1 treat CMT2A?
Our cells carry a close relative of the MFN2 protein called MFN1. These two genes overlap in function, and in most of the body MFN1 is active enough to cover for problems with MFN2. Peripheral nerve cells are the exception. They naturally make little to no MFN1. This missing backup is thought to be a key reason why peripheral nerves are so vulnerable in CMT2A.
This project aims to activate that backup. Researchers believe prompting nerve cells to produce more MFN1 could compensate for faulty MFN2, keeping mitochondria healthier and more mobile in people with CMT2A.
What is an ASO (antisense oligonucleotide)?
Genes are instructions stored in DNA, but a cell can’t use them directly. It first makes a working copy of a gene, called RNA, and reads that copy to build a protein.
An ASO is a short strand of genetic material built in a lab to match one specific RNA copy, so the two lock together like the two halves of a zipper. Once an ASO attaches to its target, it changes how much protein the cell makes from that copy.
ASOs are best known for turning down a gene to reduce a protein that harms cells. They can also be used to turn a gene up. In this project, La Jolla Labs will design an ASO to increase MFN1 in nerve cells. There is precedent for this approach. An approved therapy for spinal muscular atrophy, another inherited disease involving the nervous system, uses an ASO to increase a protective protein that patients cannot make on their own. This project tests whether a similar tactic can work for CMT2A.
A potential treatment for many MFN2 mutations
More than 200 distinct MFN2 mutations can cause CMT2A, making any approach that targets a single mutation slow and narrow. Because this ASO targets MFN1 instead, it could, in principle, help people with CMT2A regardless of their specific MFN2 mutation.
Building on CMTA’s CMT2A research
This project builds on CMTA-funded CMT2A studies and tools, including an AI imaging platform and patient-derived nerve cells for measuring mitochondrial movement in neurons, plus a rat model that mimics disease symptoms. Other CMTA projects are testing CRISPR to silence the faulty MFN2 copy and developing improved measures of disease progression to accelerate drug development in CMT2A.
People living with CMT2A play a vital role in shaping research that reflects the community’s needs. To learn about ways to contribute, join CMTA’s Patients as Partners in Research.
The information provided here is for informational purposes only and does not constitute medical advice. The CMTA does not endorse any specific products or treatments for CMT. Please consult your doctor before making any healthcare decisions.
