Muscular dystrophy (MD) is a term used to cover several progressive muscle-wasting conditions. Ongoing research into the disease, which has no cure, aims to develop new treatments to help manage the symptoms, slow progression, and address underlying causes.
Much of this research is directed toward Duchenne MD (DMD), the most common muscular dystrophy, and some of these therapeutic candidates are discussed here.
Tackling the lack of dystrophin protein
A mutation in the DMD gene in Duchenne MD and Becker MD (BMD) leads to either a total absence of the dystrophin protein being produced by that gene (as in Duchenne) or the production of only a partially functional dystrophin protein.
Several potential treatments are aimed at promoting the production of a functional dystrophin protein.
A gene is made up of multiple small sections called exons. Some cases of DMD are caused by one or more exons missing from the gene. Their loss prevents the remaining exons from being able to fit together, so that the cell cannot produce any functional dystrophin protein. One potential therapeutic approach is to mask an exon close to the site where the others are missing, so that the remaining exons can join together. This allows the cell’s protein-making machinery to produce a shorter but still functional dystrophin protein under a treatment approach called exon skipping.
Exondys 51, developed by Sarepta Therapeutics, is the first exon skipping therapy to be approved by the U.S. Food and Drug Administration (FDA). The company is developing exon skipping candidates for other Duchenne mutations, including SRP-4045 (to skip exon 45) and golodirsen (SRP-4053), skipping exon 53. Results of a Phase 1/2 trial (NCT02310906) have been positive, demonstrating a significant increase in dystrophin protein levels in boys treated with golodirsen.
The Japanese company, Daiichi Sankyo, is also developing a therapy called DS-5141 to induce exon 45 skipping in DMD patients DS-5141 is currently in an ongoing Phase 1/2 clinical trial (NCT02667483) in Japan.
Stop codon read-through
In some cases, a mutation can create a “stop signal” in the gene that causes protein production to stop prematurely. The shorter-than-normal protein is then destroyed by the cell. Therapies are being developed to force the cell’s protein-making machinery to ignore the premature stop codon that sometimes appears in the DMD gene as a result of a mutation, and continue to make the full-length dystrophin protein.
One example is Translarna (ataluren), by PTC Therapeutics, which currently has conditional marketing approval in the EU, but not in the U.S. An FDA decision on approval is expected by Oct. 24, 2017. Another example of this type of DMD treatment is NPC14 (arbekacin) by Nobelpharma of Japan.
Ezutromid, being developed by Summit Therapeutics, aims to promote the expression of utrophin in muscle cells. Utrophin is a protein similar in nature to dystrophin, and thought able to fulfill dystrophin’s role — protecting muscle cells from damage during contractions and maintaining their integrity. Ezutromid has been investigated in multiple clinical trials and is currently being tested in a Phase 2 clinical trial across the U.K. and U.S (NCT02858362). It is thought that ezutromid could be beneficial for people with DMD and BMD.
A genome editing technique, called CRISPR/Cas9, is being investigated as a DMD therapy. It aims to fix the mutation in the patient’s muscle cells, so these cells can produce a working dystrophin protein, by adding and removing sections of DNA depending on the exact genetic mutations underlying a patient’s disease. This technology has not yet reached human clinical trials stage for MD.
Promoting muscle growth
Several potential therapies aim to promote muscle growth to combat the deterioration seen in MD patients.
Myostatin inhibitors are one such possible therapy. Myostatin is a protein that normally acts to stop muscle growth and prevent muscles from becoming excessively large. In MD patients, blocking the activity of myostatin may increase muscle mass and strength. Examples of myostatin inhibitors currently in clinical trials for DMD include BMS-98609 by Bristol-Myers Squibb, and domagrozumab (PF-06252616) by Pfizer.
Vamolorone (VBP15) by ReveraGen Biopharma, is a steroid treatment that aims to slow DMD progression with fewer severe side effects than standard glucocorticoid treatment. Vamolorone is currently being investigated in Phase 2a clinical trial (NCT02760264) and an extension study (NCT02760277) that is currently recruiting boys, ages 4 to 7, at sites in the U.S, Canada, Sweden, Israel, the U.K., and Australia.
Cardiac problems also confront DMD patients, due to heart muscle deterioration. CAP-1002, in development by Capricor Therapeutics, aims to deliver healthy heart precursor cells that contain functional dystrophin to patients to improve their heart function. Capricor has reported positive results so far from the ongoing Phase 1/2 HOPE clinical trial (NCT02485938).
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