Improving and extending the lives of Duchenne patientsDuchenne muscular dystrophy is the most common neuromuscular disorder of childhood with an incidence of 1 in 3,500 live male births, and although significant advances have been made in the past 25 years in our understanding of the molecular genetics of the disease, no cure has been found.
Onset of symptoms occurs early in the preschool years with definitive diagnosis around 5 or 6 years of age. The disease is characterized by progressive symmetric muscle weakness and degeneration stemming from progressive loss of contractile function. The absence of the cellular protein dystrophin is the causative factor behind the loss of contractile function.
Becker muscular dystrophy presents as a less severe form of the disease, due to the presence of altered but functional dystrophin. Current research in Duchenne is aimed at restoring the production of altered and functional dystrophin, with the goal of transforming Duchenne muscular dystrophy into a clinical presentation similar to that observed in the milder Becker muscular dystrophy.
Our immediate focus is to improve and extend the lives of Duchenne patients by funding research for therapies and facilitating the translation of the most promising research programs to the clinic that will improve and extend the lives of Duchenne patients. Our objective is to identify and promote new therapies that will transform the treatment of Duchenne from a lethal disease to a chronic disease while we continue our search for a cure. To date, eight research projects have advanced into human clinical trials with support from CureDuchenne. This accelerated push to move the most promising research from the lab into clinical trials could save the lives of those afflicted and give them hope for halting the progress of the disease. Very few health-related nonprofits have been as successful in catalyzing human clinical trials.
Duchenne muscular dystrophy presents a multitude of challenges for drug discovery and for the development of effective treatments. A number of promising therapeutic approaches have been developed which are aimed at replacing the missing dystrophin (or an alternative compensatory protein), or identifying drugs that work on molecular pathways that may reduce the severity of the disease.
|Drug Repositioning Strategy: The failure rate for clinical research projects peaks during the earliest phase of clinical development. This is due to many factors (many of which are not project specific); the most prevalent being an inability to develop appropriate safety margins in humans, inadequate exposure or an inadequate level of efficacy of the new experimental medicine. To overcome this problem, we have sponsored a number of research projects whose aim is to examine FDA approved drugs as a possible treatment of Duchenne muscular dystrophy. Because these drugs are approved, this reduces the failure risk and allows for the rapid translation of promising pre-clinical research to the clinic with drugs with an established safety profile. The FDA approved drugs sildenafil, spironolactone, ibuprofen combined with isosorbide dinitrate have shown potential to reduce the severity of the disease in pre-clinical models and are progressing to clinical studies in DMD patients.||
Protein Replacement Strategy: Antisense oligonucleotides have been designed to trick the muscle cells in Duchenne boys to produce Dystrophin by forcing the skipping of missing or faulty exons on the patient’s own DNA. A number of companies are actively pursuing this approach in the clinic. GSK, Prosensa, and AVI Biopharma are currently testing their exon-skipping drugs in Phase II and Phase III trials to elucidate their safety and efficacy profiles in Duchenne patients. The first drug approval will be for skipping exon-51 and is anticipated in 2014.
The gene encoding dystrophin is the largest identified to date, and this presents unique challenges for gene replacement therapy. Because of its size, miniaturization is required for it to be compatible with gene replacement vectors and current approaches are aimed at delivering a miniaturized dystrophin gene. AAV vector gene technology offers an alternative strategy to the antisense oligonucleotide approach, and it has the potential to target microdystrophin production in a more widespread manner that that seen with the exon skipping approaches.
Other proteins may be used to compensate for the loss of dystrophin and help support and strengthen the muscle cell environment. For example, utrophin synthesis or its up-regulation using an orally active small molecule drug are approaches that are currently being explored. Other examples include the proteins biglycan and myostatin are making their way through the preclinical process.
|Other Strategies: A plethora of approaches are currently being examined that attempt to slow the progress or reduce the severity of the disease. Examples include anti-inflammatory agents, novel differentiating steroids (with improved side-effect profiles) and anti-fibrotic agents.|