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 symptoms, slow progression, and address underlying causes.

Much of this research is directed toward Duchenne MD (DMD), the most common muscular dystrophy. Some of these therapeutic candidates are discussed here.

Tackling the lack of dystrophin protein

A mutation in the DMD gene in Duchenne and Becker muscular dystrophy (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.

Exon skipping

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, and the cell cannot produce a 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) into golodirsen have been positive, demonstrating a significant increase in dystrophin protein levels in treated boys.

The Japanese company, Daiichi Sankyo, is also developing a therapy called DS-5141 to induce exon 45 skipping in DMD patients. DS-5141 is being evaluated 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., where the FDA again rejected a request for Translarna’s approval in October 2017. A long-term Phase 3 trial (NCT03179631) is now underway. Another example of this type of DMD treatment is NPC14 (arbekacin) by Nobelpharma of Japan.

Utrophin modulation

Utrophin is a protein similar in nature to dystrophin that is thought to be able to fulfill dystrophin’s role — protecting muscle cells from damage during contractions and maintaining their integrity.

Summit Therapeutics was developing ezutromid, which aimed to promote the expression of utrophin in muscle cells. Ezutromid was investigated in multiple clinical trials, but results from Phase 2 clinical trial (NCT02858362), called PhaseOut, suggested that the treatment did not provide a significant benefit to patients. Further development of ezutromid has been discontinued, but the company still believes that utrophin modulation could be a way forward for DMD treatments.

Biglycan (TVN-102) is another utrophin modulator being developed by Tivorsan Pharmaceuticals for DMD patients. It has not been tested in clinical trials yet, but positive results from pre-clinical studies in mouse models of DMD have been published in the journal Human Gene Therapy in 2017. Biglycan was granted orphan drug designation by the FDA in 2016.

CRISPR/Cas9

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 gene mutation 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 myostatin activity 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.

Another potential therapy, DT-200 by Akashi Therapeutics, uses a different mechanism in pursuit of the same goal — it aims to promote muscle growth by activating androgen receptors.

Other medications

Raxone (idebenone), being developed by Santhera Pharmaceuticals, was seen in a Phase 3 clinical trial (NCT01027884) to significantly slow the decline of respiratory function of DMD patients. Another Phase 3 clinical trial (NCT02814019) is recruiting at sites in the U.S., Israel, and across Europe.

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 has been investigated in a Phase 2a clinical trial (NCT02760264) and an extension study (NCT02760277). A Phase 2b clinical trial (NCT03439670) is currently recruiting boys, ages 4 to 7, at sites in the U.S and Canada.

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 heart function. Capricor has reported positive results in the Phase 1/2 HOPE clinical trial (NCT02485938), and has begun recruiting patients for the Phase 2 HOPE2 trial (NCT03406780).

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