SAVANNAH, GEORGIA — There’s no medical treatment for Charcot-Marie-Tooth (CMT) disease, a debilitating neurologic disorder that’s both progressive and incurable. But now, nerve specialists learned, new potential treatments are moving closer to clinical trials.
neurologists told an audience at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2024. But the neurologists also noted challenges, such as determining the best way to track disease progression — which can be slow — and the need to recruit high numbers of patients for trials.
A Common Genetic Neuromuscular Disorder
As Mario Saporta, MD, PhD, MBA, of the University of Miami, Coral Gables, Florida, explained, CMT is the most common genetic neuromuscular disorder, affecting 1 in 2500 people or about 130,000-150,000 in the United States. “Typically, it’s a length-dependent neuropathy, where your longest nerves would be affected earlier and more severely. That’s why we see foot deformities, inverted champagne bottle legs, and hand atrophy.”
Most patients with CMT in the United States have type 1A, which is linked to duplication of the PMP22 gene. All types lead to axonal degeneration, which appears to be the main cause of functional disability, Saporta said. “Patients become weaker and then progress with time, following the degree of axonal generation that they have.”
As many as 150 genes may eventually be deemed to cause CMT. The high number of genetically different forms makes diagnosis and genetic therapy difficult, he said, but that’s just part of the picture. Variations among mutations mean there’s “probably actually over 1000 different diseases” within CMT from a biologic perspective.
Genetic Therapy
In regard to genetic treatment, Bipasha Mukherjee-Clavin, MD, PhD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, said a key factor is whether the patient’s form of CMT is passed on in an autosomal dominant or autosomal recessive manner.
“Autosomal dominant conditions are typically caused by gain of function mutations. So that means the goal of our genetic therapeutic would be to reduce expression of the mutated gene,” she said. “In contrast, autosomal recessive conditions are caused by loss-of-function mutations, which means the goal of our genetic therapeutic would be to replace the mutated gene with a normal, wild-type copy.”
A tool like CRISPR could be used to directly edit the part of the genome with a CMT-causing mutation or a viral vector could deliver a healthy, wild-type copy of a gene, she said. These approaches are both being tested.
Another approach is to reduce expression at the RNA level. “RNA therapeutics are FDA [Food and Drug Administration]–approved for other neuromuscular indications, and you may well be using some of these in your own clinical practice,” she said.
Currently, about seven different projects are in the works on the RNA therapeutics front in CMT, she said, including six focusing on type 1A. Mukherjee-Clavin believes that this subtype is a “great” target because it’s so common, affecting an estimated 1 in 5000 people.
“You actually have enough patients to power a clinical trial,” she said. Also, “it’s a homogeneous population, both in terms of the genetics and in terms of the clinical presentation.”