Page 4 - 2019 Fall CMTA Report

STAGE SET FOR TYPE 2

BREAKTHROUGHS

WHILE BREAKTHROUGHS ARE TYPICALLY VIEWED further tested, and human stem cell longest axons are lost in a process
AS SUDDEN, DRAMATIC DISCOVERIES, they are in fact cultures are being developed for called axon degeneration. CMTA
the result of relentless hard work and determination. larger chemical screens. partners are working on devel -
That’s what has been going on with Type 2. Despite the diversity of oping chemical inhibitors of
genetic causes of CMT2, there recently identified biochemical
o recap, CMT2A is caused are encouraging signs that a few triggers of axon degeneration.
by dominant mutations in types of therapy may have broad The CMTA plans to explore the
Mitofusin 2 (MFN2). The application. The three major ther- applicability of this recent tech-
STAR team has developed apeutic approaches that can be nology to the multiple forms of
T two excellent rat models for used to bring CMT2 therapies to CMT2 using the many models of
CMT2A that are being made avail- clinical trials (and that may also CMT that have been generated
able to the research community apply to undiagnosed Type 2s) are: within our network.
and represent an important tool to GENE THERAPY Next Phase: Test the applicability
to CMT2A and CMT2E by the
test potential new modulators of
2 2 mitofusin activity. Stem cell models Progress: One of the most exciting end of 2019, leading to phase 1
clinical developments has been the
clinical trials by 2021.
of CMT2A have also been devel-
development of gene therapy for
oped for CMTA-sponsored
Spinal Muscular Atrophy (SMA),
SMALL MOLECULE THERAPIES
research in the laboratory of Dr.
2 Robert Baloh at Cedars-Sinai Med- which affects the same motor neu- Progress: The most common cause
of CMT2A is mutation of the
rons that are affected in CMT2.
ical Center. In partnership with
Mitofusin 2 gene. Researchers have
The CMTA has supported pilot
several companies, therapeutic
recently identified custom-designed
studies of gene therapy in CMT
approaches under study include
mouse models and convened a
molecules that can stimulate the
inhibition of axon degeneration
2 and gene therapy. Other candidate meeting of gene therapy experts to activity of mitofusin proteins. We
are seeking to promote develop-
outline the next steps in bringing
molecules have emerged from acad-
this therapeutic strategy to CMT2.
ment of this therapy by testing for
emic research, with planning
underway to test these as well.
gene therapy field to our scientific
rat models of CMT2A.
CMT2E is caused by We have recruited leaders in the efficacy in our recently developed
dominant mutations in the Neuro- advisory board, who are guiding Next Phase: Complete the first
filament Light Protein (NEFL) our efforts in this area. We are also evaluations of these compounds in
2
gene. With support from the partnering with an eminent expert our CMT2A rats by 2020, leading
CMTA, one of the best mouse in the new technology of genome to phase 1 clinical trial as early as
models of CMT2E, made by editing to explore the application 2021.
2 University, has been extensively CMT2A and CMT2E. a host of ancillary efforts—stem
These three strategies require
of this therapeutic approach to
Dr. Ronald Liem at Columbia
Next Phase: Support the first sin-
cell studies to make human neu-
characterized in collaboration with
rons based on cells obtained from
gle-patient clinical trial of gene
Dr. Steven Scherer at the University
CMT2A and CMT2E patients,
therapy for CMT2 in 2020, and
of Pennsylvania. Both human and
mouse stem cells containing
the 50 percent of CMT2 patients
mon forms of CMT2 by the end
CMT2E mutations have been dif- extend this therapy to more com- definitive genetic diagnoses for
ferentiated into motor neurons and of 2021. who don’t yet have them and the
are being used in drug screens to development of effective biomark-
identify therapies that prevent INHIBITION OF AXON ers and outcome measures for
aggregations of neurofilaments seen DEGENERATION clinical trials that will make CMT
in CMT2E. Candidate compounds Progress: The progression of all an ideal target for therapeutic
have been identified and are being types of CMT occurs as the development. h
4 THE CMTA REPORT FALL 2019