Health Concerns

Muscular Dystrophy

Novel and Emerging Medical Therapies and/or Drug Strategies

Exon skipping

A promising treatment option for patients with muscular dystrophy is called “exon skipping” (Nelson 2009). This strategy is based on the idea that one could correct the errors in the dystrophin protein that result from a mutated dystrophin gene. Researchers do this by using short pieces of DNA (oligonucleotides) to “mask” the mutated region in the dystrophin RNA that is later used to instruct the assembly of the dystrophin protein. The DNA mask sticks to the defective RNA sequence and corrects the mutation so a more functional dystrophin protein can hopefully be made at sufficient levels to compensate for the genetic defect (Walter 2007; Muir 2009; Nelson 2009; Beytía 2012; Malik 2012). As a result, a dystrophin molecule that causes DMD is changed into a BMD-like protein that is expected to cause milder symptoms (Aartsma-Rus 2012).

Exon skipping in cultured muscle cells from 6 patients with DMD was successful, as dystrophin synthesis was reestablished in 75% of the cells (Walter 2007). This method has been tested in clinical trials that administered oligonucleotides locally into the muscle and showed positive results. The first systemic use of this approach was in a DMD patient in 2006. After 4 weekly intravenous injections with an oligonucleotide, low levels of dystrophin were detected in muscle biopsies, which was an improvement over the complete absence of dystrophin that existed before the treatment (Trollet 2009). Another systemic clinical trial that included 4 groups of 3 patients each was completed in 2009. In this study, dystrophin was detected in 60–90% of the muscle fibers from participants, and no serious adverse effects occurred. Three months later, the patients even had an improvement in the distances they were able to walk. Another systemic trial, conducted in 2010, included 19 patients and showed that the treatment was well tolerated, except for one patient who discontinued therapy after developing cardiomyopathy. Dystrophin was produced in several participants but, overall, a large variation in the response to treatment was observed (Aartsma-Rus 2012).

  • PTC124 is an oxadiazole compound taken orally which is designed to overrule dysfunctional translation signaling by the abnormal dystrophin gene. PTC124 is currently in phase II clinical trials for patients with Duchenne MD and cystic fibrosis (Hamed 2006).
  • AVI-4658 is a phosphorodiamidate morpholino oligomer (PMO) for potential treatment of patients with DMD. A recent open-label study in 19 ambulant patients aged 5–15 years with DMD suggested that AVI-4658 was well tolerated with no serious drug-related adverse events; AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent, but variable, manner in young males (dose escalation format: 2 mg/kg). Preliminary results suggest that AVI-4658 may be a potential disease-modifying drug for DMD (Cirak 2011). 

Proteasome inhibitors

Evidence suggests the pathology of some forms of muscular dystrophy involves the increased degradation of cellular proteins that normally act as a kind of scaffolding to support the structural integrity of muscle cells. Proteasomes are complex biomolecules that play an important role in the degradation of proteins. Therefore, proteasome inhibition is being investigated as a potential therapy. In an animal model for muscular dystrophy, an experimental proteasome inhibitor increased the production of dystrophin and other dystrophin-associated proteins. Velcade®, another proteasome inhibitor already in preclinical and clinical trials for other conditions, also increased dystrophin expression and reduced activation of the nuclear factor-kappaB (NF-kB) pathway, which is involved in the inflammatory response in DMD (Bonnucelli 2007; Gazzerro 2010).