Highlights: - CRISPR gene editing tool is widely being used in
studies involving genetic diseases
- This is the first time this gene editing tool has been
used on a neurodegenerative disorder
- The symptoms of Huntington's disease were reversed on
shutting off the huntingtin gene
Huntington's disease is characterized by the
progressive breakdown of nerve cells
in the brain, and it is a fatal genetic disorder. A research team from Emory
University School of Medicine has now shown that silencing a specific gene in
the brain cells could reverse this disease condition. The study, published in
the
Journal of Clinical Investigation,
detailed how the
disease pathology was
reversed, along with restoration of motor symptoms.
The
study involved the use of the
CRISPR/Cas9 system to cut a portion of a gene that
was found to produce a toxic protein. This protein forms aggregates in the
brains of 9-month old mice. The gene editing tool was delivered using a
viral vector; a few weeks after the
introduction of the CRISPR/Cas9 system, the protein aggregates that were found
in the brain had almost completely abated. The treated mice also showed an
improvement in their motor abilities,
though they still couldn't move as well as the control mice.
‘Silencing the Huntingtin gene using a gene editing tool is an efficient technique to reverse Huntington’s disease symptoms opening up the possibility of treating the disease.’
Treating Huntington's Disease:
The
study showed a path for treating people with Huntington's disease, along with
other similar neurodegenerative diseases. Dr. Xiao-Jiang Li, who was the senior
author of the study, said that further testing was required to understand the
long-term effects of using the CRISPR/Cas9 system to treat
Huntington's disease.
Huntington's Disease:
This
disease is caused by a mutation that occurs in the Huntington gene, which codes
for the Huntington protein. The mutant variant of the gene is found to contain
additional poly-glutamine (CAG) repeats, which results in post translational
modifications, leading to a gain of function that is toxic.
The
symptoms of this condition usually occur during mid-life and are associated
with movements that are uncontrolled, along with problems of balance, changes
in mood and cognitive decline. The patients normally find it hard to carry out
daily tasks and the life span of the individual after the onset of symptoms is
10 years.
CRISPR for Neurodegenerative Diseases
CRISPR/Cas9
system is extremely popular as a gene editing tool and has been recently used
to treat
sickle cell anemia and other genetic
disorders. However, this is the first time that this tool is being used for a
neurodegenerative disease.
There
are certain considerations that need to be taken into account, like the safety
of altering genes and the risk of unwanted mutations. In the year 2012, zinc
finger nucleases, another gene editing tool, was used as a gene therapy based
approach for Huntington's disease.
The Study:
The
human mutant huntingtin gene was used to replace the mouse huntingtin gene in
mice. Such mice began to develop symptoms of Huntington's disease at around
nine months, like motor problems and aggregation of the mutant huntingtin.
The
CRISPR/Cas9 gene editing system was developed to include guide sequences that
targeted the mutant variant of the huntingtin gene as well as the normal copy.
This makes it more generic and would not require personalization to a specific
patient's genome, and so can be used on all patients' with Huntington's
disease.
Shutting Off The Huntington Gene:
Certain
genes code for specific hormones or proteins that are essential for various
metabolic processes in the body. However, earlier studies by the research team
from The Emory University had shown that mice which were older than four months
did not need the huntingtin gene to survive. This meant that when this gene was
shut off or silenced in adult mice, the mice would still be able to survive.
The
benefits of shutting off the huntingtin gene prompted the start of clinical trials,
but these trials require frequent administration of drugs that silence the
gene. However, in a treatment methodology that involves the use of a gene
editing tool, the treatment would be more durable if the methodology targets
the right number of cells.
An
adenovirus was used as a vehicle for gene therapy to guide the
CRISPR/Cas9system into the brain cells. These viral vectors, carrying the
CRISPR/Cas9 enzymes, were injected into the striatum region of the brains of
mice that had Huntington's disease, at the age of nine months. The striatum
region of the brain was targeted as this region was responsible for the
movement of the body and motor function.
The
study findings were:
- Significant reduction in the amount of the aggregated
mutant huntingtin protein within a period of three weeks.
- The ability of the brain to heal once the gene was
silenced was evidenced from the study.
- Significant improvement in motor skills like balance
and hand grip strength, though their motor movements did not prove to be
as good as that of control mice.
- Non target mutations occurred within the huntingtin
gene and did not affect other genes, addressing safety concerns associated
with frame shift mutations.
The
scientists associated with the study cautioned that the safety of injecting the
CRISPR/Cas9 system into the brain still needs to be closely monitored and
tested before it can be used to treat patients.
References:- What Is Huntington's Disease? - (http://hdsa.org/what-is-hd/)
- CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease - (https://www.jci.org/articles/view/92087)
Source-Medindia
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