Exon skipping

Exons are part of the gene that provides instructions to produce a working protein. Exon
skipping is the “patching” of that part of the gene with missing or mutated exons, using short
stretches of DNA called antisense oligonucleotides (AO). This can lead to the production of a
truncated, albeit functional, protein to ease some of the symptoms of muscular dystrophy.
Exon skipping is currently being evaluated in clinical trials for Duchenne muscular dystrophy
(DMD) and Becker muscular dystrophy (BMD) as these disorders are caused due to deletion of
exons at several places in the DMD gene.
Exondys 51 (eteplirsen) is an FDA-approved therapy that skips exon 51 in DMD patients, but its
approval is conditional. This means continued approval is contingent on outcomes of further
clinical trials. Other exon skipping therapies under investigation include Golodirsen (SRP-
4053) that skips exon 53, SRP-4045 that skips exon 45, and DS-5141 that binds to the mutated
site so that the gene can be read properly. 
Stop codon readthrough
Translarna (ataluren) is being studied in DMD and BMD patients to reverse the effects of a so-
called nonsense mutation that results in a premature stop signal preventing the production of a
full dystrophin protein. Translarna is approved across most of Europe, Israel, and South Korea to
treat nonsense mutation DMD, but is not approved in the U.S.
Gentamicin is an antibiotic used in the treatment of several bacterial infections and investigated
as a stop codon readthrough therapy for DMD. A study found that gentamicin was effective in
raising dystrophin levels and lowering serum creatine kinase levels.
AAV-mediated therapies
Adeno-associated viruses (AAVs) are a class of modified viruses that are commonly used as
vectors, or transport agents, to deliver functioning genes directly into specific tissues. Three such
therapies that use AAVs are currently being evaluated. 
GALGT2 introduces the GALGT2 gene in skeletal and heart muscles to increase the production
of other proteins required for muscle cell function.
SRP-9001 micro-dystrophin introduces a gene coding for microdystrophin — a protein that is
functionally similar to dystrophin but smaller in size — into the heart and skeletal muscles.
SGT-001 also aims to introduce a gene coding for microdystrophin into muscle cells.
PF-06939926 uses a so-called AAV serotype 9 (AAV9) to introduce a shortened version of the
human DMD gene and is intended to produce a comparatively shorter version of the dystrophin
protein needed for muscle health.
RNA interference
RNA interference (RNAi) is the process of inhibiting, or blocking, the function of the messenger
RNA (mRNA) produced in a gene. mRNA contains instructions from the gene ultimately
required to make a protein. BB-301 is an experimental RNAi therapy that is being investigated to
treat oculopharyngeal muscular dystrophy (OPMD).
BB-301 uses RNAi to prevent the production of an abnormal PABPN1 protein via mRNA from
the mutated PABPN1 gene. At the same time, it introduces a healthy copy of
the PABPN1 gene into a cell.
CRISPR/Cas9
CRISPR/Cas9 is a powerful method of gene editing that is being investigated for potential
applications in treating DMD. Pre-clinical studies have reported positive outcomes in a mouse
model of DMD, including restoration of dystrophin-positive muscle fibers, improved grip, and
reduced levels of serum creatine kinase.