The future of Charcot-Marie-Tooth research and treatments rests where the disease begins: in genes.

While many new genes involved in CMT have been identified, we know as many as 40 percent of people living with CMT still don’t have a confirmed genetic diagnosis. We’re also still trying to understand the disease mechanisms of the genes already identified — why those genes cause the diseases they do. Understanding these mechanisms is the first step in the process of creating treatments.

There’s a lot of excitement around gene-targeted therapies in neuromuscular disease right now, with promising developments in trial or already on the market for spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). These include antisense oligonucleotide approaches such as Spinraza for SMA, as well as gene therapies that use viruses as shuttles to deliver missing or altered genes. There’s a lot of interest in the CMT field for gene therapies, too, and we hope we can learn from other fields on the best approaches forward.

MDA awarded a grant this year to support CMT gene identification efforts; we’re also funding research to develop better biomarkers for CMT that could help speed clinical trials. And exciting new studies aimed at uncovering how specific genetic alterations cause CMT, as well as projects focused on gene therapies for specific CMT subtypes, are underway.

The future holds promise.

Creating an open CMT genetics data resource

In December 2017, MDA awarded Dr. Stephan Zuchner at the University of Miami School of Medicine in Florida a research infrastructure grant totaling $384,967 for his work to expand and make more available resources that can streamline CMT gene identification and therapy development.

Zuchner is collaborating with the Inherited Neuropathy Consortium (INC) to establish a genomic data infrastructure platform — an open genetics data bank that will allow researchers to aggregate, archive, analyze and compare data gathered from CMT patients, potentially leading to the identification of additional genes involved in CMT.

MDA supported the early development of the INC as well; the consortium is now funded primarily by the National Institutes of Health as a Rare Disease Clinical Research Network, though MDA still provides support. More than 10,000 patients are participating in numerous INC investigations into how CMT progresses and how genetic changes affect the disease’s severity.

When scientists worldwide have greater access to this kind of comprehensive genetic and clinical data, they have the ability to improve diagnostic processes and build better clinical trials.

Identifying biomarkers to measure outcomes

Biomarkers are biological indicators — such as temperature, heart rate or the presence or absence of certain proteins in bodily fluids — that allow doctors and researchers to measure that state of a patient’s health, disease progression or reaction to a drug. MDA recently awarded Dr. Mary Reilly at the UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery in London a $1 million human clinical trial grant to develop a critical biomarker for CMT.

CMT is a slow-progressing disease, so it can be difficult to detect changes for better or worse during typical clinical trials, which don’t last very long. Dr. Reilly is hoping an MRI protocol that measures fat accumulation in thigh, calf and foot muscles over a one-year time period will prove to be a responsive biomarker. If so, this defined biomarker will also help researchers design more effective therapy trials.

Discovery through disease mechanism studies

Understanding how genetic alterations and mutations cause CMT is another key to drug discovery, and MDA awarded three grants, announced just last month, to researchers honing in on specific genes involved in CMT subtypes.

• Bogdan Beirowski at the University of Buffalo in New York is studying a protein pathway in Schwann cells, which produce the myelin nerve coating damaged in CMT. If the pathway is altered in models of CMT, it could indicate whether modulation of the pathway could be of therapeutic value.
• Alessandra Bolino at IRCCS Ospedale San Raffaele in Milano, Italy, is studying how alterations in myotubularin-related protein 2 acts on phospholipids and Schwann cells. If drugs predicted to modulate the protein are successful, the study could lead to therapies for CMT4B1 and related types.
• Vincent Timmerman at the University of Antwerp in Belgium is testing a library of drugs approved by the U.S. Food and Drug Administration and the European Medicines Agency in mouse models with mutations in a heat shock protein that causes a spectrum of diseases including CMT2L and distal SMA.

Therapies in testing

With MDA’s support, scientists are leading new gene therapy investigations for several CMT subtypes.

Dr. Robert Baloh at the University of California, Los Angeles is testing an MFN1 gene therapy in mouse models with CMT2A, and Dr. Robert Burgess at The Jackson Laboratory in Bar Harbor, Maine, is testing an adeno-associated virus therapy designed to block the altered GARS genes in mouse models with CMT2D. At the Cyprus Institute of Neurology and Genetics in Greece, and in partnership with the Charcot-Marie-Tooth Association, Dr. Kleopas Kleopa is testing whether a gene therapy given after disease onset could result in functional improvements in patients with CMT1X.

Elsewhere, Ionis Pharmaceuticals is sponsoring a study in which PMP22 (the gene responsible for CMT1A) is being suppressed with antisense oligonucleotides in rodent models of CMT1A. The PMP22 antisense oligonucleotide was able to partially reverse the signs and symptoms of CMT in rodents. Additionally, Acceleron recently presented exciting initial results from the first part of a human clinical trial. The company’s experimental drug ACE-083 aims to strengthen muscles rather than target genetic causes. If successful, the drug could be beneficial across many different types of CMT.