Gene-replacement therapy helping kids with neuromuscular disease

Dr. Jerry Mendell refers to a boy and a tricycle to explain how effective a new gene-replacement therapy has been in rescuing babies at Nationwide Children’s Hospital from a debilitating and deadly neuromuscular disease.

The boy, now about 2 years old, is able to ride that tricycle.

Perhaps an ordinary milestone for most children, this is remarkable for a child who was born with type-1 spinal muscular atrophy (SMA), which attacks nerve cells and can cause severe physical limitations — including the inability to breathe, swallow, talk or sit up. Typically, 92 percent of babies with the disease die or require permanent breathing assistance by the time they are 20 months old.

So this tricycle feat is a big deal. And so are the achievements of the 14 other children who have received the gene therapy as part of a first-phase clinical trial: One toddler can stand, walk and run, while others are able to sit on their own, roll over, swallow food or talk.

As Dispatch.com reports, findings of the trial were published Wednesday in the New England Journal of Medicine. The therapy could help countless children diagnosed with any number of neuromuscular diseases, said Mendell, principal investigator at Nationwide Children’s Center for Gene Therapy. SMA affects 1 in 10,000 babies and is hereditary, caused by an abnormal or missing gene that’s responsible for producing a protein essential to motor nerve cells in the spinal cord.

In the trial, 15 children with type-1 SMA received AVXS-101, an intravenous dose of a virus that carries the protein missing in the children who have the disease.

Three of the children in an initial group received a low dose, while 12 children in a second cohort received a higher dose. Each was evaluated in August, when they all were at least 20 months old.

All 15 were alive, and none required permanent breathing assistance. Of the 12 who received the high dose, 11 sat unassisted, 11 had head control, 11 could eat and speak, nine rolled over and two walked on their own.

“These are remarkable clinical observations,” said Dr. Sukumar Nagendran, chief medical officer for AveXis Inc., a Chicago area gene-therapy company that manufactures AVXS-101. “Kids with type-1 SMA never achieve these milestones.”

Nagendran said publication of the trial results will allow AveXis to approach the federal Food and Drug Administration to determine when and where the therapy will be made more widely available to patients.

Mendell is optimistic that publication of the findings also will lead to other significant changes.

First, he is hopeful it will inspire state advisory committees to add SMA to the diseases for which newborns are screened, a move that Mendell said would allow doctors to discover the disease and use gene therapy early in infancy, when the study shows it is likely to be most effective.

Second, he said, the principles of the study could be applied to any number of neuromuscular diseases.

Already, researchers at Nationwide Children’s are looking to modify the study for a trial that would treat children with muscular dystrophy. And Dr. Brian Kaspar, AveXis’ chief scientific officer, said perhaps the same science could be used to address amyotrophic lateral sclerosis (Lou Gehrig’s disease) and Rett syndrome, an autism-spectrum disorder.

“We expect that we will have a major impact on these other diseases as well,” Mendell said. “We’re very optimistic that what we’ve learned in one trial will have implications for other diseases.”

Children with type-1 SMA, caused by a mutation in a single gene, experience rapid loss of nerve cells early in life, making them hypotonic — suffering devastating muscle loss, Mendell said. By eight months old, 25 percent die; by 10.5 months, 50 percent die; by 13.6 months, 75 percent die; and by 20 months, 92 percent die.

Mendell said this study is the first time researchers have seen this level of function in SMA patients, and he anticipates that the 15 children will continue to improve.

“You’re going to see a dramatic change in this disease,” he said. “Obviously, there will still be patients who will be affected, but we won’t see this great tragedy of patients who are hypotonic.”

The study, conducted by Nationwide Children’s researchers with AveXis and the Ohio State University College of Medicine, was designed to evaluate the safety and tolerability of AVXS-101, and researchers say that additional studies are needed to further evaluate safety and efficacy. It also is not clear whether the replacement gene’s effects will lessen over time.

Four patients experienced adverse events, all involving treatable elevations of liver enzymes that were deemed related to the application of AVXS-101.

Study funding was provided by AveXis, the Sophia’s Cure Foundation and the Research Institute at Nationwide Children’s.

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