Observational Trial Recruiting Participants to Identify New CMT-related Mutations

A research project that is now underway and recruiting participants is intended to identify new disease-causing genetic mutations in Charcot-Marie-Tooth (CMT) disease patients.

The goal of the observational trial (NCT01193088), known as INC-6602, is to identify new genes that cause CMT, namely CMT type 2, and genes that do not cause disease but may modify patients’ symptoms. Approximately 50 percent of patients with CMT2 have no definitive genetic diagnosis.

Eligible patients must attend one of the Inherited Neuropathies Consortium (INC) clinical centers worldwide and have either CMT type 1A or an unknown form of CMT. Researchers plan to enroll 1,050 participants.

For this study, investigators will collect three tubes of blood that will be sent to the University of Miami for processing through exome sequencing, a molecular biology technique that screens protein-coding regions of the genome, which can help uncover genetic influences on disease when there is clearly a familial condition based upon multiple affected individuals.

Next-generation sequencing, a catch-all term for distinct sequencing methods including the exome approach, refers to a much faster and cheaper way to sequence DNA, enabling scientists to sequence thousands to millions of DNA molecules simultaneously.

“Next-generation sequencing has transformed the genetics field. We use clinical, bioinformatics, and molecular approaches to study the outcome of large-scale exome and whole genome sequencing projects in pursuit of identifying and understanding the function of known and novel disease genes for neuromuscular and neurodegenerative disorders,” Stephan Züchner, MD, PhD, a professor of human genetics and neurology and principal investigator at the University of Miami, said in a press release.

All generated sequencing data will be stored in the Genesis genomics analysis platform and the Inherited Neuropathy Variant Browser, both user-friendly databases that are available to CMT neurologists and scientists across the globe.

For the purpose of conducting discovery research while improving diagnostic guidelines, CMT professionals can access and analyze data, add relevant clinical information, suggest new CMT genes to be studied, and rate the harmfulness of any genetic variants.

The project is funded by the National Institutes of Health, the Charcot-Marie-Tooth Association (CMTA), and the Muscular Dystrophy Association.

“The work in Züchner’s lab aligns perfectly with the CMTA’s Strategy to Accelerate Research (STAR),” said Amy Gray, CMTA’s CEO. “Funding this project is another way the CMTA supports the development of therapies for the CMT community. As we discover more of the genetic causes of the unidentified forms of CMT, we can strategically target them with potential therapies.”

INC-6602 is related to another project called INC-6601 (NCT01193075), which was designed to determine CMT’s natural history and the correlation between the nature or location of a CMT-related mutation in a given person based on observations of affected individuals and their respective genetic makeup. INC-6601 is focused on CMT types 1B, 2A, 4A, and 4C.

Actively recruiting centers for the project include Cedars-Sinai Medical Center, Stanford University, University of Colorado Hospital, Connecticut Children’s Medical Center, University of Miami, Nemours Children’s Clinic, University of Iowa, Johns Hopkins University, Massachusetts General Hospital, University of Michigan, University of Minnesota, University of Rochester, Children’s Hospital of Philadelphia, University of Pennsylvania, Children’s Hospital of Westmead (Australia), Carlo Besta Neurological Institute (Italy), National Hospital of Neurology and Neurosurgery (U.K.), and Dubowitz Neuromuscular Centre (U.K.).

Patients participating in INC-6601 and meeting eligibility criteria for the INC-6602 study will be recruited.

INC-6601 participants are followed for a year, but participation in INC-6602 only requires a one-time blood draw. Enrollment in either of the studies includes agreement to take part in the other trial.