Page 26 - 2021 Spring CMTA Report - Special Research Edition

therapy and viral vectors, reviewers from the CMTA’s
Alexis was diagnosed with CMT2F at the age of
33. She mourns the loss of wearing heels, feeling
“cute” and being able to work off pizza with an
intense workout.
STAR’s Portfolio for
Axonal CMTs - TYPE 2
(and some 4s)
Axonal forms of CMT affect the “electrical wire”
that is the nerve, which is surrounded by the protective
insulator coating known as myelin. Research specific to
axonal CMT—Types 2 and 4—includes some two dozen
projects and the CMTA Board of Directors recently
approved two new ones: a gene therapy study for CMT4A,
which researchers have identified as an ideal candidate for
this approach, and a study on CMT2A biomarkers.
GENE THERAPY AND
GENE EDITING PROJECTS
The CMTA is supporting pilot studies of gene therapy in
CMT mouse models following a gene therapy trial for one
peripheral neuropathy (GAN) at the NIH.
We are partnering with Dr. James Wilson at the University of
Pennsylvania and Passage Bio to use gene therapy to treat
CMT2A.
We are funding work with two eminent experts, Drs. Bruce
Conklin and Luke Judge of the Gladstone Institutes and
UCSF Departments of Medicine and Pediatrics, to explore
therapeutic application of genome editing technology
(CRISPR) to CMT2A, CMT2E and CMT2F.
Most recently, the CMTA Board of Directors awarded
$227,170 to two researchers who believe that CMT4A is
an ideal candidate for potential gene therapy approaches.
Noting the investigators’ extensive expertise in gene
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Scientific Advisory Board said the innovative project may
lead to the development of clinically translatable gene
replacement therapy for patients with GDAP1 (ganglio-
side-induced differentiation associated protein 1) mutations.
The prevalence of CMT4A is estimated at 1,000 out of
every 100,000 people living with CMT. Some of the patients
already enrolled in the Inherited Neuropathy Consortium’s
natural history project have this type, making it a potentially
attractive option for a biotech company to explore. One
company has already expressed some interest.
Principal investigators Steven Gray, PhD, and Xin Chen,
PhD, of the University of Texas Southwestern Medical
Center hypothesize that broad central nervous system
(CNS)-directed delivery of GDAP1 gene with
adeno-associated viral 9 (AAV9) during early life can
ameliorate CMT4A disease symptoms in GDAP1 mutant
mice, using an approach amenable to human translation.
Reviewers from the CMTA’s Scientific Advisory Board said
the clear innovative aspect of the project may lead to the
development of clinically translatable gene replacement
therapy for patients with GDAP1 mutations, advancing the
field of gene therapy for both CMT4A and CMT2K patients.
SMALL MOLECULE AND BIOLOGICAL
THERAPY PROJECTS
CMTA partners are working on developing molecules that
regulate recently identified biochemical triggers of axon
degeneration.
CMT2E is caused mutations in the neurofilament light
(NEFL) gene. The CMTA has a diverse portfolio of
approaches for 2E.
First, we are funding Dr. Mario Saporta’s work at the
University of Miami using human stem cells to develop as-
says and test additional libraries of drugs for treatment
in CMT2E.
Second, we supported a screen of FDA-approved
compounds in Dr. Ron Liem’s lab at Columbia University.
Third, the CMTA is supporting a new project to bring gene
therapy to CMT2E being conducted by Dr. Kathrin Meyer
and a leading gene therapy group at Nationwide Children’s
Hospital in Cincinnati.
UNDIAGNOSED TYPE 2
Approximately 50 percent of CMT2 patients do not yet
have a definitive genetic diagnosis. Dr. Stephan Züchner
at the University of Miami is working to change that,
spearheading an ambitious project to identify new
disease-causing mutations in patients seen in COEs
affiliated with the Inherited Neuropathy Consortium
(see related story page 30).
PREPARING FOR CLINICAL TRIALS
In partnership with the INC, we are building on their recent
successes in development of novel biomarkers and
outcome measures in CMT1A and supporting major efforts
to extend development and testing of critical biomarkers for
CMT2A in order to support the efficient design of upcoming
clinical trials.
The CMTA Board of Directors recently awarded $559,555
for a study on identifying disease biomarkers for CMT2A,
complementing the Inherited Neuropathy Consortium’s
cross-sectional analysis and evaluation of impairment in