EARLY GENE-EDITING HOLDS PROMISE FOR PREVENTING
INHERITED DISEASES
The technique, which uses the CRISPR- Cas9
system, corrected the mutation for a heart
condition at the earliest stage of embryonic
development so that the defect would not be
passed on to future generations.
It could pave the way for improved in vitro
fertilization outcomes as well as eventual
cures for some thousands of diseases caused
by mutations in single genes.
The breakthrough and accomplishment by American
and Korean scientists, was recently explained
in the journal Nature. It’s a collaboration
between the Salk Institute, Oregon Health
and Science University and South Korea’s
Institute for Basic Science.
“Thanks to advances in stem cell technologies
and gene editing, we are finally starting
to address disease-causing mutations that
impact potentially millions of people,”
said Prof. Juan Carlos Izpisua Belmonte of
Salk’s gene expression lab and a corresponding
author of the paper.
“Gene editing is still in its infancy, so
even though this preliminary effort was found
to be safe and effective, it is crucial that
we continue to proceed with the utmost caution,
paying the highest attention to ethical considerations.”
Though gene-editing tools have the power to
potentially cure a number of diseases, scientists
have proceeded cautiously – partly to avoid
introducing unintended mutations into the
germ line (cells that become eggs or sperm).
Izpisua Belmonte is uniquely qualified to
speak on the ethics of genome editing because,
as a member of the Committee on Human Gene
Editing at the US National Academies of Sciences,
Engineering and Medicine, he helped author
the 2016 roadmap Human Genome Editing: Science,
Ethics and Governance.
Hypertrophic cardiomyopathy is the most common
cause of sudden death in otherwise healthy
young athletes, and affects approximately
one in 500 people. It is caused by a dominant
mutation in the MYBPC3 gene, but often goes
undetected until it is too late.
Since people with a mutant copy of the MYBPC3
gene have a 50% chance of passing it on to
their own children, being able to correct
the mutation in embryos would prevent the
disease not only in affected children but
also in their descendants.
The researchers generated induced pluripotent
stem cells from a skin biopsy donated by a
male with Hypertrophic cardiomyopathy and
developed a gene-editing strategy based on
CRISPR-Cas9 that would specifically target
the mutated copy of the MYBPC3 gene for repair.
The targeted mutated MYBPC3 gene was cut by
the Cas9 enzyme, allowing the donor’s cells’
own DNA -repair mechanisms to fix the mutation
during the next round of cell division by
using either a synthetic DNA sequence or the
non-mutated copy of MYBPC3 gene as a template.
Using IVF techniques, the researchers injected
the best-performing gene-editing components
into healthy donor eggs that are newly fertilized
with donor’s sperm. All the cells in the
early embryos are then analyzed at single-cell
resolution to see how effectively the mutation
was repaired.
They were surprised by the safety and efficiency
of the method. Not only were a high percentage
of embryonic cells get fixed, but also gene
correction didn’t induce any detectable
off-target mutations and genome instability
– major concerns for gene editing.
The researchers also developed an effective
strategy to ensure the repair occurred consistently
in all the cells of the embryo, as incomplete
repairs can lead to some cells continuing
to carry the mutation.
“Even though the success rate in patient
cells cultured in a dish was low, we saw that
the gene correction seems to be very robust
in embryos of which one copy of the MYBPC3
gene is mutated,” said Jun Wu, a Salk staff
scientist and one of the authors.
This was in part because, after CRISPR- Cas9
mediated enzymatic cutting of the mutated
gene copy, the embryo initiated its own repairs.
Instead of using the provided synthetic DNA
template, the team surprisingly found that
the embryo preferentially used the available
healthy copy of the gene to repair the mutated
part.
“Our technology successfully repairs the
disease-causing gene mutation by taking advantage
of a DNA repair response unique to early embryos,”
said Wu.
The authors emphasized that although promising,
these are very preliminary results and more
research will need to be done to ensure no
unintended effects occur.
“Our results demonstrate the great potential
of embryonic gene editing, but we must continue
to realistically assess the risks as well
as the benefits,” they added.
Scientists have now demonstrated an effective
way of using a gene-editing tool to correct
a disease-causing gene mutation in human embryos
and stop it from passing to future generations.
Though this is not a full-fledged start of
a revolution of having ‘designer babies’,
the first steps, however, have been laid.
China attempted this earlier.A team of scientists
has altered human embryos using a new technique
called CRISPR CAS9 that edits genes and in
this case it helped remove a fatal mutation
that leads to heart attacks.
This now opens up an ethical ‘Pandora’s
Box’ if germline repairs and enhancements
may become a thing in vogue. As of now, the
human embryos were not implanted in humans.
But this now opens up exciting prospects of
the world having designer babies soon.
links
http://www.synbicite.com
https://www.genewiz.com
