Page 8 - Fall 2020 CMTA Report

CMT1A Research Agenda

Fuller than Ever

ack at the dawn of the Strat- maintained at a specific level to ini- OVERALL NEXT STEPS
egy to Accelerate Research tiate the degeneration program. INCLUDE:
(STAR), the CMTA decided Several approaches have emerged l The progression of all types of
to focus its initial research to try to prevent axon degeneration CMT occurs as the longest
Befforts on CMT1A because and preserve nerve function. axons are compromised in a
it affects more people than any Second, the maintenance of process called axon degenera-
other type. While the CMTA’s myelin around the long axons in tion. We are working with
focus has expanded in the decade the peripheral nervous system partners to develop chemical
since, it is not neglecting Type1A. depends on a number of meta- inhibitors of the triggers of axon
In fact, the 1A agenda is fuller bolic pathways. For example, the degeneration. We are currently
than ever before. formation and maintenance of the testing the applicability of this
In addition to the recently myelin sheath are tightly coupled approach to multiple models of
funded projects outlined on p. 7, to lipid synthesis pathways. More- CMT1A and collaborating with
The CMTA the CMTA has formed research over, as documented in several several companies on candidate
is actively alliance relationships with compa- studies (including a recent lecithin drugs to promote axon survival
engaged in nies specializing in small molecule, study from Dr. Michael W. and preserve nerve function.
therapeutic biological and genetic therapies Sereda’s laboratory at the Max Additional studies to validate
Planck Institute for Experimental
and is now actively engaged in
testing therapeutic testing alliances with Medicine in Göttingen, this as a legitimate target for
alliances with organizations interested in creating Germany), one of the metabolic CMT1A are needed.
organizations new therapies for CMT disorders aspects of CMT1A neuropathy l Target screens for CMT1A have
interested in or in re-positioning therapies is the downregulation of lipid identified some pathways that
regulate PMP22 levels, and can-
creating new developed for other diseases. production that is required for didate compounds from these
Apart from enabling com-
therapies or pany-sponsored efforts, we are maintenance of axons and myelin. screens are being tested using
Therefore, the maintenance of
repositioning also actively identifying novel Schwann cell metabolism and sup- cell-based assays in preparation
ones developed approaches and opportunities to port of axon health is likely central for animal model testing.
for other develop therapies for CMT1A. to CMT1A and other types of l Recent studies have shown
diseases. There are a number of new initia- CMT. Some studies have employed that lipid metabolic pathways
tives and opportunities in the cholesterol or lecithin as ways to are affected in CMT1A, and
works. restore myelination, but these strategies to stimulate the neces-
Studies of peripheral nerve involve agents that likely do not sary production of lipids to
and CMT neuropathy have completely rescue metabolic maintain myelin and axons are
revealed the central role of metabo- defects in CMT1A Schwann cells. ready for testing once we secure
lism in maintaining the energy of On another front, while the the needed funds for animal
axons that conduct nerve impulses. CMTA has initiated several studies model testing.
The energy source for nerves to advance anti-sense oligonu- l Finally, new therapeutic
comes from mitochondria and cleotide (ASO) and adeno- approaches are being developed
mitochondrial defects cause neu- associated virus (AAV) genetic to manipulate the levels of over-
ropathy. There are two approaches therapies for CMT1A, delivering expressed proteins. These are
for addressing the metabolic issues them to Schwann cells remains a being tested in CMT1B with
of neuropathy affecting myelin in fundamental issue. Depending on possible application to CMT1A.
CMT1A. First, the critical factor the results of ongoing pilot studies
driving CMT progression is axon and emerging ideas, the CMTA The CMTA has established a
degeneration, which has been will likely need to increase invest- unique capability to develop new
shown to involve a critical metabo- ments to make these types of therapies directly with companies
lite, NAD, that must be therapies safer and more efficient. and to expertly test those potential

8 THE CMTA REPORT FALL 2020