Research Briefs: New Tools for CMT

Recent developments in Charcot-Marie-Tooth disease include CMT2E research mice, CMT1A stem cells, progress toward CMT1A gene therapy and a new pediatric disability scale

Article Highlights:
  • Three separate research teams have developed two mouse models of CMT2E.
  • A new line of embryonic stem cells with the CMT1A mutation is now available to researchers.
  • Preclinical (laboratory) research on gene therapy for CMT1A using the neurotrophin 3 gene is moving forward.
  • A new scale that reliably measures disability in children with CMT is now considered validated and ready for use in clinical trials.
by Margaret Wahl on May 4, 2012 - 9:50am

Charcot-Marie-Tooth disease (CMT) is a peripheral nerve disorder that can be caused by mutations in more than 50 different genes. Recent research has resulted in several new tools that will help advance the work of researchers in this field.

CMT2E mice developed

Mice with two different mutations that cause the type 2E form of CMT (CMT2E) have recently been developed. Both mouse "models" of CMT2E are likely to help researchers gain insight into and ultimately develop treatments for this form of the disease.

CMT2E is caused by any of several different mutations in a gene known as neurofilament light chain, or NEFL. Two research teams have developed mice with an NEFL mutation known as E397K, and a third group has developed mice with an NEFL mutation known as P22S.

The E397K mice have muscle atrophy, slowed transmission of nerve signals and an abnormal gait, all of which can occur in human CMT. The P22S mice show an abnormal clasping response and gait abnormalities, as well as some difficulties in learning a water maze. The investigators say this mouse model of CMT2E also mimics some phenomena that can occur in human CMT.

To learn more, see the following articles:

Stem cells with CMT1A mutation now available for study

The University of Michigan has made available a line of human embryonic stem cells carrying a mutation involving the PMP22 gene that causes the type 1A form of CMT (CMT1A).

The new CMT1A stem cells, which can be used to help researchers understand and develop therapies for CMT1A, have been placed on the U.S. National Institutes of Health (NIH) Embryonic Stem Cell Registry, which means they can be used in NIH-funded research.

The cells came to NIH through a collaboration between the University of Michigan and Detroit-based Genesis Genetics Institute, a provider of preimplantation genetic diagnosis (PGD). Under an arrangement between Genesis Genetics and the University of Michigan, individuals with embryos that test positive for a genetic disease who do not want to implant those embryos can choose to donate them for research.

To learn more, see the following articles:

Gene therapy for CMT1A moving forward

Neurologist Zarife Sahenk, a principal investigator at the Center for Gene Therapy at Nationwide Children’s Hospital in Columbus, Ohio, is continuing her research on gene therapy for CMT1A (a type of CMT related to a PMP22 gene mutation).

Last year, Sahenk announced that mice with a CMT1A-like disease benefited from a single injection of genes for the neurotrophin 3 (NT3) protein into a leg muscle. The gene delivery vehicle was the shell of a type 1 adeno-associated virus (AAV1).

Now, Sahenk, a former MDA research grantee, is continuing her research in NT3 gene therapy for CMT, with the eventual goal of moving toward a human trial.

"I have an NIH grant to compare two different promoters ['on switches' for genes] at different doses to assess the efficacy of AAV1-NT3 gene therapy in this CMT1A mouse model," Sahenk said recently. "Efforts such as this are an essential step towards finding therapeutics for an ultimate clinical trial."

For more information, check out NT3 Gene Therapy for CMT1A Benefits Mice, Quest News Online, April 21, 2010.

New pediatric disability scale validated

A new CMT Pediatric Scale (CMTPedS), developed in part with MDA support, has now been fully validated as a useful measure of CMT-related disability in children. A preliminary version of the scale was presented at the 2010 American Academy of Neurology meeting.

The CMTPedS measures strength, dexterity, sensation, gait, balance, power and endurance. It was developed in children with a variety of types of CMT who were 3 to 20 years old and living in the United States, United Kingdom, Italy and Australia. The details and validation of the new scale are described in the May 2012 issue of Annals of Neurology.

The final 11-item version, its developers say, can be used in clinical trials involving children with CMT to reliably measure disease progression and treatment response. They say it is well-tolerated and can be completed in 25 minutes.

To learn more, see the following articles:

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