Exon Skipping Medication is Safe and Effective in the Treatment of Duchenne Muscular Dystrophy

by Dr Sam Girgis on July 24, 2011

Duchenne muscular dystrophy is a recessive X-linked disease that results in muscle wasting, muscle degeneration, ambulatory problems, and ultimately death of the affected males.  The approximate incidence is one in every 3,500 newborn males.  The disorder is caused by mutations in exon 51 of the dystrophin gene which results in almost absent levels of the protein.  A mild form of the muscular dystrophy called Becker muscular dystrophy occurs due to deletion of exon 53 of the dystrophin gene.  In Becker muscular dystrophy, the mutation causes a shortened and truncated form of the dystrophin protein which is still functional.  The dystrophin protein functions as a structural element at the surface of muscle cells.  Recently, the use of oligonucleotides to treat Duchenne muscular dystrophy has shown good results in human cultured muscle cells and in animal models of the disease.  The oligonucleotides cause exon skipping of the mutated exon 51 and thus result in a shortened protein and a mild form of the disease as seen in Becker muscular dystrophy.  Researchers lead by Dr. Francesco Muntoni have recently shown that a specific exon skipping oligonucleotide was both safe and effective for the treatment of Duchenne muscular dystrophy.  The results of their research were published online in the journal The Lancet.  The researchers performed a phase 2 dose escalation clinical trial of an oligonucleotide named AVI-4658 in patients with Duchenne muscular dystrophy to assess the safety and tolerability.  There were 19 participants in the study and they ranged in age from 5 to 15 years of age.  The participants had muscle biopsies performed at the start of the study and after 12 weekly intravenous infusions of the experimental exon skipping oliogonucleotide AVI-4658.  There were no serious adverse events reported and the drug was well tolerated.  The experimental medication successfully resulted in exon 51 skipping in all participants and was able to induce expression of new dystrophin protein in a dose dependent manner at doses of 2mg/kg and above.  Of the 19 participants, seven patients had good responses to the medication and showed a mean increase of dystrophin from 8.9% to 16.4% of normal controls.  The three patients with the greatest response had 21%, 15%, and 55% dystophin positive fibers in the muscle biopsies.  Several proteins that are associated with dystrophin also had their levels increased and markers of inflammation were decreased in the muscle biopsies after treatment.  The authors wrote, “On the basis of our data and recent preclinical data, we expect that extended administration of AVI-4658 at doses of 10 mg/kg or higher will result in sufficient dystrophin expression to have a positive effect on the prevention of muscle degeneration in Duchenne muscular dystrophy… AVI-4658 has the potential to ameliorate the progressive natural history of Duchenne muscular dystrophy and now needs to be investigated in clinical efficacy trials”.  Dr. Akinori Nakamura and Dr. Shinichi Takeda wrote in an editorial comment that, “This study is a milestone in the feasibility of systemic exon-skipping therapy for Duchenne muscular dystrophy, especially with respect to clinical safety and biochemical efficacy”.


Sebahattin Cirak et al. “Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open label, phase 2, dose escalation studyThe Lancet Published Online July 25, 2011 DOI:10.1016/S0140-6736(11)60756-3

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Chris Bergstrom July 25, 2011 at 3:28 pm

This is amazing! You find the best stories!


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