Page 6 - 2021 Spring CMTA Report - Special Research Edition

Cross-Type Initiatives

Nerves are bundles of many nerve fibers,
most of them wrapped in myelin.
Myelin is an insulating and protective coating,
formed by Schwann cells, which also makes
nerve impulses much faster (from 1 to >50
meters/second). Myelin problems cause
demyelinating CMTs (CMT1). Problems with
nerve fibers, or axons, cause axonal CMT
(CMT2). Type 4s can be either.
Mutations in more than 100 different genes
cause CMT neuropathies. The mutations have
diverse cellular functions, resulting in many
disease mechanisms.
Mutations in genes expressed by Schwann
cells mostly cause demyelinating CMT,
though eventually this damages the axons
as well. Mutations in genes expressed in nerve
cells and their axons mostly cause axonal
types of CMT.
GENE THERAPY
Gene therapy involves the introduction of
genetic material (DNA or RNA) into the cells
and tissues of an individual instead of drugs
or surgery.
There are several approaches to gene
therapy: replacing a faulty (missing or
mutated) gene that causes a disease with
a healthy copy of the gene; deactivating or
“silencing” a mutated gene that is functioning
improperly; or editing part of a mutated toxic
gene using a “cut and paste” method.
How does gene therapy work? Essentially,
a virus, or “vector,” delivers the therapeutic
gene to the target cell and inserts the genetic
material. Once the healthy gene enters the cell,
it restores proper functioning.
Gene therapies have to address the disease
mechanism. That means that for CMT
neuropathies caused by loss of function
(mostly CMT 4 and X) mechanisms, we can
deliver the healthy gene to restore the function
(gene replacement). For CMT neuropathies
with a toxic gain of function (mostly CMT 1
and 2) mechanism, we can either silence
(reduce) the toxic gene or try to repair (edit)
the mutation.
The CMTA sponsors gene therapy
development for many types of CMT,
including CMT1A, CMT1X, CMT2A, CMT2D,
CMT2E, CMT2F, CMT2K, CMT4A and CMT4C,
utilizing a number of different technologies,
including AAV delivery, gene silencing, gene
replacement, genome editing using CRISPR-
Cas9 and antisense oligonucleotides (ASOs).

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