Page 31 - 2021 Spring CMTA Report - Special Research Edition

The CMT2A Gene Replacement Therapy Initiative

THE CRISPR-CAS9
INITIATIVE

CRISPR-Cas9, often referred to as
genome editing or genomic surgery,
is different from gene replacement
therapy. CRISPR-Cas9 technology uses
induced pluripotent stem cells (iPSC),
which can be reprogrammed (induced)
to become any type of cell
(pluripotent). The process typically
starts with a patient providing a skin
cell sample. From those skin cells, iPSC
are developed and reprogrammed
for use in that patient, reducing the
chances of the patient’s body rejecting
Dr. Steven Scherer, the cells.
University of Pennsylvania With support from the CMTA,
Drs. Bruce Conklin and Luke Judge of
With the CMTA’s support, Dr. Steven the Gladstone Institutes and UCSF
Scherer at the University of Departments of Medicine and
Pennsylvania is building on the Pediatrics are investigating the use of
recent breakthrough treatment for CRISPR for application to CMT2A,
spinal muscular atrophy (SMA), CMT2E and CMT2F. Working under the
which involved treating the disease auspices of the Innovative Genomics
with a first-of-its-kind gene Institute (headed by 2020 Nobel Prize
replacement therapy. Promising data winner Dr. Jennifer Doudna), the pair
from rat models suggests that the gene are investigating whether iPSC can
replacement technology developed at be used to create a gene copy, MFN2
Ohio State University for SMA could be for example, free of the CMT-causing
used to treat CMT2A and he has part- mutation.
nered with the inventors of the SMA Methods to modify DNA in the genome
treatment technology to investigate have been around for more than 30
their gene replacement application for years, but CRISPR technology has
possible use in CMT2A. brought major improvements in the
CMT2A is caused by autosomal speed, cost, accuracy and efficiency of
dominant mutations in the MFN2 gene. gene editing. CRISPR can make
With dominant types of CMT, one copy deletions in the genome and/or be
of the associated gene has a mutation, engineered to insert new DNA
and the other copy is normal. In the sequences. The CRISPR system was
case of CMT2A, only one copy of the adapted from a naturally occurring
MFN2 gene has a mutation. gene-editing system in bacteria that
Dr. Scherer is working with colleagues captures snippets of DNA from
at University of Pennsylvania and invading viruses and uses them to
Passage Bio on a treatment that would create DNA segments known as
reduce levels of the mutated copy CRISPR arrays. The CRISPR arrays
of MFN2 and provide a second allow the bacteria to “remember” the
unmutated companion copy of the viruses so that if they attack again,
MFN2 gene to restore the function of the bacteria can target their DNA.
this important gene. Remarkably, this bacterial defense
system works in human cells to edit
DNA and perhaps treat genetic
diseases.

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