Large deletions constitute 60% of mutations in this gene. Patients with out-of-frame deletions may potentially benefit from therapies that 'skip' an additional exon to restore the reading frame. Synthetic antisense oligonucleotides have been used to effect skipping of an additional exon. Among all patients who may be amenable to this form of therapy, those that could benefit from skipping exon 51 are the most common followed by exons 45 and 53. Consequently, skipping exon 51 is the mechanism of action for the first two agents developed for exon skipping: Drisapersen is under development by BioMarin Pharmaceutical and Eteplirsen is under development by Sarepta Therapeutics. New Drug Applications (NDAs) have been submitted to the FDA for both of these agents. Lastly, newer agents that skip other exons, including exons 45, 53, and 44, are currently under investigation in human clinical trials.
Nonsense Read-through
Another common mutation in the dystrophin gene is the nonsense mutation (premature stop codon), which results in a truncated dystrophin protein. Ataluren is an investigational drug being developed by PTC Therapeutics that allows read through of the stop codon by unknown mechanisms. Results of the Phase 2b study have recently been published. Although no significant effect was seen on the 6-min walk test (6MWT) at the higher dose of 80 mg/kg per day, the intermediate dose of 40 mg/kg per day appeared to show some benefit on the 6MWT, but the results did not meet statistical significance. This study, however, also included DMD patients of 5–6 years of age who are still improving on the 6MWT (maturation improvement), which in retrospect would confound the analysis of the results. A phase 3, double-blind, placebo-controlled study of nonsense mutation in DMD patients of 7 years of age and older is currently underway comparing 40 mg/kg per day of Ataluren to placebo utlizing the 6MWT as the primary outcome measure.
Myostatin Inhibition
Myostatin is a transforming growth factor-beta superfamily member that has been shown to inhibit muscle growth. Mice that are myostatin deficient show increased muscle mass and mice that have a mutation in both myostatin and dystrophin show improved muscle histology when compared with the dystrophin mutant mice.
Follistatin is an endogenous inhibitor of myostatin. Gene therapy with Adeno-Associated Virus (AAV1) carrying Follistatin has been injected into Becker muscular dystrophy patients with some promising results. A similar study using AAV1-follistatin in DMD is currently underway and myostatin inhibition is also being used in DMD patients for drugs that are under development by Pfizer and Bristol–Myers Squibb.
Idebenone
It has been hypothesized that idebenone, a synthetic compound that facilitates mitochondrial electron transport, may benefit DMD patients by minimizing reactive oxygen species that accumulate as a result of the degeneration process. Recently, investigators have reported a statistically significant effect of idebenone on pulmonary function (peak expiratory flow) in DMD patients ranging from the ages of 10–18 years that were not taking corticosteroids. These results will be used for the basis of the NDA that is to be submitted by Santhera Pharmaceuticals.
Gene Replacement Therapy
Adeno Associated Viruses (AAVs) have emerged as the preferred vector for gene replacement therapy. Testing has shown that AAV can only carry transcripts less than 5 kb; however, the full length open reading frame of the dystrophin gene is 11.2 kb, which is too large to be packaged into an AAV. Previous reports have proposed the use of various inframe, internally deleted forms of the dystrophin transcript (known as 'microdystrophin') as potential candidates for gene replacement therapy. Although sufficient expression of microdystrophin would likely slow the course of the disease in DMD patients, it would not fully restore the function of the dystrophin gene. Different forms of microdystrophin have been tested in mice, dogs, and humans (reviewed in[10]). Although good success was achieved in animal models, the human studies did not succeed because of likely autoimmunity to dystrophin. This suggests that successful dystrophin gene replacement therapy in humans may require concomitant immunosuppressive treatment.
More recently, Lostal et al. have proposed that co-infection of three AAV vectors with each containing different portions of the dystrophin gene. The three vector genomes are engineered to undergo recombination to form the full length of the dystrophin gene if they are co-infected into the same cell. Although the efficiency of co-infection in this report was low, this method provides a potential strategy to restore a full length of the dystrophin gene in DMD patients.
Phosphodiesterase-5 Inhibitors
Tadalafil is an inhibitor of phosphodiesterase-5 (PDE-5), which already has FDA approval for the treatment of erectile dysfunction. The mechanism of action is to prolong the half life of cyclic guanosine monophosphate, which activates protein kinase G, thus, amplifying the effects of nitric oxide on vasodilation. Reports have demonstrated that exercise induced increases in blood flow in skeletal muscle are blunted in DMD and Becker muscular dystrophy patients and that Tadalafil normalizes the response to exercise in these patients. A phase 3 study is currently underway to assess the efficacy of this approach in DMD patients.
Sildenafil is another PDE-5 inhibitor and a similar mechanism of improving blood flow to cardiac myocytes was hypothesized that would identify Sildenafil as a potential treatment for the heart failure that is seen in DMD and Becker muscular dystrophy. Unfortunately, Sildenafil was not shown to be effective in slowing the progression of heart failure in DMD patients.
Eplerinone
A recent double-blind, placebo-controlled study investigated
the potential added benefit of eplerinone in the setting of an angiotensin
converting enzyme-inhibitor (ACE-I) or an angiotensin receptor blocker
(ARB). All patients demonstrated late gadolinium enhancement in the
myocardium on their cardiac MRI, suggesting early signs of heart failure. After
12 months, there was a statistically significant reduction in left ventricular
strain in the eplerinone-treated arm when compared with that of the
placebo-treated group. These results suggest a potential benefit to receiving a
combination therapy of eplerinone with an ACE-I or an ARB.
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