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Beneath muscle
cells lies dystrophin, a protein that interacts with a glycoprotein complex
spanning the muscle sarcolemma, acting as a structural link between the actin cytoskeleton and the extracellular
matrix. The
dystrophin-glycoprotein complex (DGC) promotes stabilisation and maintenance of
the integrity of the sarcolemma. In the case of mutations that cause a lack in
dystrophin production, the muscle membranes begin to leak and degenerate leading
to a muscle wastage disease known as Duchenne muscular dystrophy. This type of
muscular dystrophy is progressive and
is caused by mutations in the DMD gene, the largest in the human body
consisting of 79 exons. Find a good ending sentence Potential therapeutic methods, such as exon
skipping, or clustered, regularly interspaced, CRISPR-Cas9, aim to restore the DMD
reading frame.


In brief, Cas9, a nuclease guided by
single-guide RNA (sgRNA), binds to a targeted genomic locus next to the
protospacer adjacent motif (PAM) and generates a double-strand break (DSB). The
DSB is then repaired either by nonhomologous end-joining (NHEJ), which leads to
insertion/deletion (indel) mutations, or by homology-directed repair (HDR),
which requires an exogenous template and can generate a precise modification at
a target locus.

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In the recent paper in Scientific Reports (CITE), researchers have demonstrated
that even a single letter mutation could be targeted and corrected in muscular
dystrophy patients. The research team, used CRISPR/Cas9, a novel gene editing
approach to permanently cure Duchenne Muscular Dystrophy (DMD) by fixing their mutation. Each patient suffering
from DMD has a different type of mutation in the dystrophin gene, when the
mutation is identified it is possible to target the it with CRISPR/Cas9. Explain how it is done! Exon 50 deletion (Del-50) is
the most common DMD mutation, consequently, exon 49 will skip to exon 51, the
next exon in line. As this mutation introduces a stop codon in the reading
frame the shape of the 2 exons are incompatible, the rest of the
dystrophin protein will not be produced making it shorter than normal and
eventually fibres will disintegrate. Studies are done on humanised mouse with Del-50;
using an engineered AAV that has the gene editing components for CRISPR/Cas9,
scientists were able to successfully skip exon 51 and retain the dystrophin
reading frame. This experiment was done on mice with a single injection of AVV,
3 weeks later the cells started producing dystrophin.


dentified way of altering parts of
DNA sequencing to be used as a treatment for genetic diseases


Thus, this study has demonstrated that with
CRISPR/Cas9 it is possible to permanently cure Duchenne muscular dystrophy, as
this smart technology eradicates the mutation from the DNA of all the cells.
This presents a novel mechanism in gene editing. How it
was unknown and how it became known! Deletions of essential regions or
large deletions are not fixable by CRISPR/Cas9 gene editing. However, these types
of mutations only make 20% of all cases, which means that 80% of patients could
benefit from CRISPR/Cas9. Although the process has room to improve and is years
away from clinical trials, it is a very promising novel technology.

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