Can We Fix the Code? A Look at Genetic Therapies for CMT

By Katherine Forsey, PhD | CMTA Chief Research Officer

Current treatments for Charcot-Marie-Tooth disease (CMT) focus mainly on managing symptoms. But new advances in genetic therapies are changing the conversation and offering real hope for the future. CMTA is investing heavily in research that targets the root cause of CMT, the genetic mutations that drive the disease.

I’m putting these therapies under the microscope because they’re going to come up more and more as research advances toward clinical trials. It’s important for all of us to stay informed, so let’s dive in.

What Are Genetic Therapies?

Genetic therapies aim to correct or modify the underlying mutations that cause diseases like CMT. These therapies can work in several ways, including repairing, replacing, turning off, or adjusting how much of a gene is expressed. Different genetic subtypes need different approaches, depending on whether there is too much or too little of the product of the affected gene, and treatments can work like the dimmer switch on a light in your living room.

You might hear “gene therapy” and “genetic therapies” used interchangeably, but there’s a difference:

• Gene therapy, which can also be called gene replacement therapy, refers specifically to inserting a healthy copy of a gene into cells to replace or compensate for a faulty one.
• Genetic therapy is a broader category. It includes gene therapy, but also includes tools like gene editing, gene silencing, and RNA-based treatments, where genes are specifically modified but not replaced.

Types of Genetic Therapies

Through CMTA’s Strategy To Accelerate Research (CMTA-STAR), we’re supporting work on a wide range of genetic therapy approaches:

• Gene replacement therapy: Delivers a working copy of a gene. CMTA is supporting work on this approach for CMT4C at the University of Texas Southwestern (UTSW) with researchers Xin Chen, MD, and CMTA-STAR Advisory Board member Steven Gray, PhD.

Other Genetic Therapy approaches

• CRISPR/Cas9: Molecular scissors to precisely cut and fix faulty DNA. We’re funding CRISPR-based studies at Gladstone Institutes with CMTA-STAR Advisory Board member Bruce Conklin, MD, for multiple types of CMT.
• Antisense Oligonucleotides (ASOs): Synthetic molecules that bind to RNA and block or modify how a gene is read. We’re supporting ASO development at the University of Miami with project CMTA-STAR Advisory Board member Mario Saporta, MD, PhD.
• Small Interfering RNA (siRNA): Silences faulty genes by interfering with the RNA before it can make disease-causing proteins.
• shRNA (short hairpin RNA): Long-acting RNA therapy that can silence gene expression
• Base editing and prime editing: Precise, next-generation tools for rewriting individual DNA letters without cutting the DNA strand.

Our CMTA-STAR investments support multiple genetic therapy programs across the spectrum from the most common type, CMT1A, to rarer subtypes like CMT4C or CMT4J. These approaches have the most potential for impact because they may directly address the underlying genetics driving CMT.

The Big Hurdle: Getting to the Peripheral Nerves

One of the biggest technical challenges in treating CMT is delivery. Most genetic therapies need to reach the peripheral nerves, which are long, delicate structures protected by something called the blood-nerve barrier. The blood-nerve barrier provides important protection to nerves by keeping harmful substances out. But that same barrier can also provide a challenge and needs to be bypassed for the delivery of therapeutic treatments to the nerve.

CMTA-funded researchers are exploring multiple delivery strategies, including viral vectors, nanoparticles, extracellular vesicles, and direct injection, to get therapies where they need to go.

What’s in the Preclinical Pipeline?

Thanks to our CMTA-STAR Alliance Partners, several CMT genetic therapies are moving closer to clinical trials:

• CMT1A: Novartis is developing an ASO, Armatus Bio is using siRNA with an AAV9 vector, Nervosave Therapeutics is exploring shRNA via local injection, and Sarepta is also working on a gene therapy approach. All aim to reduce the overexpression of the PMP22 gene. More than 200 CMTA community members helped shape one of these programs through our Patients as Partners in Research platform.
• CMTX1 (aka CMT1X or CMTX):  CMTA-STAR Advisory Board member Kleopas Kleopa, MD, has created a gene therapy that replaces the faulty GJB1 gene that has shown success in animal models.
• CMT2A and CMT1B: CRISPR-based therapies are showing encouraging signs in early research.
• CMT4C: CMTA, the University of Texas Southwestern, and the CMT4C community are working together on Project Foresee to bring an AAV-based gene therapy into an investigator-led clinical trial.
• CMT4J: CMTA is supporting Elpida Therapeutics in their work to bring gene therapy to CMT 4J patients by supporting the 4J Natural History study as the company prepares for the clinical trial in parallel.

If these strategies succeed in these types of CMT, they can be adapted for other subtypes. Once we solve the delivery challenge, the technology becomes more widely applicable.

Looking Ahead

Genetic therapies represent a transformational step forward. They don’t just manage symptoms; they aim to modify the disease itself.

While obstacles remain, particularly around delivery, the CMTA is committed to driving this science forward. We’re hopeful that within the next 5 to 10 years, several of these therapies could move into clinical trials and eventually reach patients.

How You Can Help

This research doesn’t move forward without you.

• Donate to CMTA-STAR to fuel this work.
• Join Patients as Partners in Research to help guide therapy development and be the first to hear about trial opportunities.

Together, we’re changing what’s possible for people with CMT.

Under the Microscope is a quarterly column from CMTA Chief Research Officer Dr. Katherine Forsey, offering an inside look at the science behind CMT research and what it means for the CMT community.