Gene therapy is a promising experimental approach that uses genes (the fundamental units of heredity) to treat disorders that result from genetic mutations. Gene therapies involve replacing, silencing, or knocking out a mutated gene, or introducing new genes to confer additional function or protection.
Muscular dystrophy refers to a group of more than 30 inherited diseases that result in progressive weakening and wasting of muscles. These diseases are caused by mutations in genes that are involved in the production of proteins required for muscles to work properly.
Currently, several kinds of gene therapies are being investigated to treat muscular dystrophy, and possibly offer the chance of a cure. These approaches are summarized below.
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.
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.
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 (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).
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.
Gene therapy is very much a developing field, and as such carries elements of risk that can include the possibility of toxicity, inflammation, and cancer. Regulatory agencies like the U.S. Food and Drug Administration (FDA) carefully regulate and monitor gene therapy clinical trials for these reasons and because changes introduced by gene therapy, unlike a medication, are lifelong.
Last updated 07/12/2019
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