15 Mar Exon Skipping Offers Potential for Treating Duchenne Muscular Dystrophy
Dr. Susan Apkon has dedicated her career as a rehabilitation physician to caring for boys and young men with Duchenne muscular dystrophy. Now Apkon, who serves as the Director of the Rehabilitation Department at Seattle Children’s, is at the forefront of finding a possible treatment for the disease.
With an incidence of 1 in every 3,500 male births worldwide, Duchenne is one of the most common rare diseases. It is also one of the most destructive.
The disease is caused by a mutation in the gene responsible for producing dystrophin, an essential protein involved in muscle function. Because it is caused by an X-linked recessive gene, the disease primarily affects boys.
Without dystrophin, muscle fibers break down and are replaced by fat and connective tissue until voluntary movement becomes impossible. By their teens, many boys with Duchenne become non-ambulatory. It eventually affects heart and respiratory muscles, which causes a cardiomyopathy and restrictive lung disease. Most Duchenne patients do not live past 30.
Without the PCRC, we could not have this trial because of the need for these weekly infusions and the expert care that the nursing staff provides.
There is no approved treatment for the disease. But in recent years, scientists have improved their understanding of Duchenne, and more pharmaceutical companies have begun to develop and test new drugs. When Apkon began attending a national Duchenne conference 10 years ago, “there were two or three drug companies that talked about the preclinical studies they had,” Apkon said. “Now, there is two days’ worth of conversation about the preclinical data and now the clinical data. It is in the clinics now, being used in clinical trials.”
Apkon is currently the principal investigator for three studies involving the drug eteplirsen made by Sarepta Therapeutics. The drug relies on a technique called exon skipping. Patients with Duchenne are missing one or more exons in their dystrophin genes. The remaining exons, portions of a gene that code for amino acids, cannot link together, which prevents the dystrophin protein from fully functioning.
We have pounded the pavement with these sponsors, saying we are here, we have an engaged group of kids and families, an amazing clinical research center, and the infrastructure to support clinical trials.
Eteplirsen is designed to make the cellular machinery skip exon 51 and connect to the next exon in line, restoring the gene’s ability to make a shorter, but functioning, form of dystrophin. Approximately 13 percent of people with Duchenne are estimated to have a mutation targeted by exon 51 skipping.
The goal of this treatment approach is to help patients amenable to exon 51 skipping maintain their walking ability, or, for those who are no longer able to walk, maintain upper body strength so they can continue to feed themselves and operate a powered wheelchair, Apkon added.
Once a week, the boys in the three eteplirsen trials visit the Pediatric Clinical Research Center (PCRC) at Seattle Children’s to receive an intravenous infusion of the drug. “The Pediatric Clinical Research Center has been huge in helping us,” Apkon said. “Without the PCRC, we could not have this trial because of the need for these weekly infusions and the expert care that the nursing staff provides.”
The participants, many who are into their second year of the trial, have developed close relationships with the nurses at the PCRC, Apkon said. “The PCRC nurses interact with the kids beautifully. They are able to very quickly learn who these kids are and what they enjoy,” she explained. “They are a tremendous group of nurses.”
Apkon added that conducting these trials would be impossible without the research infrastructure at Seattle Children’s and in the city of Seattle. “We have pounded the pavement with these sponsors, saying we are here, we have an engaged group of kids and families, an amazing clinical research center, and the infrastructure to support clinical trials. We have been very successful. For the families, it has been really significant.”
Eteplirsen is currently undergoing review by the U.S. National Food & Drug Administration to gain marketing approval. The next action date for FDA review is scheduled for May 2016. The outcome of this meeting will determine how future research in this area will move forward.