NASHVILLE, Tennessee—Jerry R. Mendell, MD, met his first patient with Duchenne muscular dystrophy (DMD) in 1969: an 8-year-old boy from a poor family in West Virginia whose picture he still keeps. In the more than half a century since, Dr. Mendell has established himself as one of the nation’s top experts in Duchenne, and a pioneer in neuromuscular gene therapy.
Yet despite a lifetime of research, “we have had virtually no satisfactory treatment for the disease,” said Dr. Mendell, professor of neurology and pediatrics at Nationwide Children’s Hospital in Columbus, Ohio.
That perhaps explains his determination to cure DMD, the 80-year-old scientist told Rare Disease Advisor during an interview at the Muscular Dystrophy Association’s 2022 Clinical & Scientific Conference here.
“We have done many, many clinical trials. Most of them, unfortunately, didn’t make a big difference,” Dr. Mendell said. “We tried myoblast transfer. That didn’t work. We tried follistatin or myostatin inhibition, and that didn’t work well. We even tried medications like gentamicin to upregulate dystrophin production, and that didn’t work. Now we’re finally making a difference we can see in our gene therapy studies.”
Dr. Mendell’s career took off at the US National Institutes of Health (NIH), where he joined the agency’s training program just as the Vietnam War was raging. That’s when he met the West Virginia boy with DMD, who died a few years later.
“At NIH, we had no idea about the pathogenesis of the disease until Lou Kunkel [who today directs the genomics program at Boston Children’s Hospital in Massachusetts] identified the gene and reported the results in 1987,” he said. “We then had a molecular basis for treatment.”
Phase 3 Trial Could ‘Open Up Many Doors’
However, it wasn’t until 1999 that Dr. Mendell did his first gene therapy trial—but in limb-girdle muscular dystrophy (LGMD) rather than Duchenne.
“We chose that as a starting point for gene therapy because we could deliver the entire gene,” explained Dr. Mendell, who in 2019 received a Lifetime Achievement Award from the Speak Foundation, which advocates for LGMD patients. “That means it was less than what we call 5000 base pairs of 5000 kilobases. The number’s not important. What’s important is that, for example, LGMD genes are about half that size. We can deliver that much easier than we can the Duchenne gene, which is 3 times the size of what the [adeno-associated virus (AAV)] will hold.”
For this reason, the dystrophin gene must be cut down to 1/3 of its size so it can be delivered via AAV. At Nationwide Children’s Hospital, he said, “we use a subtype of AAV called rh74. It just so happens that rh74 is derived from nonhuman primates. That’s important because it’s less likely there is previous exposure to this virus and more tolerance from the patient point of view.”
In late 2021, Dr. Mendell launched the phase 3 EMBARK study (NCT05096221) to evaluate Sarepta Therapeutics’ investigational delandistrogene moxeparvovec (SRP-9001), a gene therapy to treat DMD. A total of 120 boys aged between 4 and 8 years with a confirmed DMD mutation within exons 18-44 or 46-79 will take part. Enrollment is set to be completed later this year.
The study “represents a pivotal moment for microdystrophin gene therapy” as a treatment for DMD, said Michael Kelly, PhD, chief scientific officer at the nonprofit organization CureDuchenne.
“This is a critical and closely watched placebo-controlled trial that follows on from the much discussed results of Sarepta’s phase 2 study,” Dr. Kelly told Rare Disease Advisor by email. “If approved, this is expected to provide a significant benefit to Duchenne patients who have closely followed and participated in the development of delandistrogene moxeparvovec since its inception.”
Sharon Hesterlee, PhD, is chief research officer of the Muscular Dystrophy Association, which to date has invested more than $125 million toward developing gene therapy for neuromuscular disease in general. She said it’s clear that SRP-9001 is already providing some benefit to participants in the trial.
“But the doses used in this study, and the other 3 gene therapy DMD trials underway now, are probably at the edge of the safety margin for systemically delivered dystrophin,” Dr. Hesterlee said. “The field in general still needs to understand better immune responses to the capsid and transgene, and the longevity of the benefits that are obtained.”
Hesterlee said the MDA, CureDuchenne, and a third organization, Parent Project Muscular Dystrophy, are cosponsoring a report currently in development on these issues.
“That’s not to undervalue the progress to date, which has been miraculous,” she said. “We are just entering a period now where we have some proof-of-concept that this approach can work to treat DMD. But we need to refine it significantly to meet the hopes and expectations of the patient community.”
Upon EMBARK’s completion, Dr. Mendell said, “we hope to have approval for gene therapy—and that will open up many doors for Duchenne patients.”
Newborn Screening Could Bring ‘Unmatched Results’
That approval, he said, would be comparable in importance to the US Food and Drug Administration’s 2016 approval of Biogen’s nusinersen (Spinraza®) and its 2020 approval of the Novartis one-time gene therapy onasemnogene abeparvovec-xioi (Zolgensma®)—both to treat spinal muscular atrophy (SMA)—because that convinced many states to begin newborn testing for SMA.
“Newborn screening then led to being able to treat patients in their early infancy before the disease took hold,” he said, adding that if the same holds true for DMD, “that means we can start treating patients within the first few weeks of life. That will be a very gratifying experience for people like me who’ve been in this for how many years? I don’t even know anymore.”
In 2010, Dr. Mendell conducted the nation’s first newborn screening program for Duchenne. It showed that the incidence of the disease was about 1 in 5000 births. Using DNA from a dried blood spot from which another 35 diseases are tested, his team was able to determine a baby’s creatine kinase (CK) level, which is a biomarker for DMD.
“The advantage was that if we took that at birth, then we didn’t have to go back to the patients or back to the family. We could do the full spectrum of diagnosis from the dried blood spot and make a definitive diagnosis,” he said, noting that at present, most DMD patients aren’t diagnosed until 4 or 5 years of age, and sometimes later.
“That diagnosis delays treatment. If we can screen newborns, we are going to have unmatched results for the disease and make a difference.”
As for getting all 50 states on board for the screening, Dr. Mendell doesn’t see this as a big obstacle.
“It’ll be recognized at a national level and recommended to all the states,” he said. “Some will be resistant as they are for COVID vaccinations and everything else. That’s the beauty of living in America; they have their right. But most will approve of newborn screening for Duchenne. And once people find that this is available, you’ll see more and more people doing it.”