Gene-replacement therapy shows promise for kids with deadly disease

Dr. JerryMendell COLUMBUS— refers to a boy and a tricycle to explain how effective a newgene-replacement therapy has been in rescuing babies at Nationwide Children’sHospital froma debilitating and deadly neuromuscular disease.

Theboy, nowabout2years old, is able to ride that tricycle.

Perhaps an ordinarymilestone for most children, this is remarkable for a childwho was born with type-1 spinal muscular atrophy, 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 diseasedieorrequirepermanent breathing assistance by the time they are 20 months old.

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

Findings of the trial were publishedWednesday in the NewEngland Journal ofMedicine. And eventually they could be applied to help countless childrendiagnosed with any number of neuromuscular diseases, saidMendell, principal investigator at Nationwide Children’s Center for Gene Therapy.

In the trial, 15 childrenwith type-1 SMA received AVXS101, 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 receiveda higher dose. Eachwas evaluated inAugust, when they all were at least 20 months old.

All 15were alive and none required permanent breathing assistance. Of the 12who 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.

“Theseareremarkableclinical observations,” said Dr. Sukumar Nagendran, chief medical officer for AveXis Inc., aChicagoareagene-therapy company that manufactures AVXS-101. “Kids with type-1 SMA never achieve these milestones.”

Nagendransaidpublication of the trial results will allow AveXis to approach the federal Food and Drug Administration to determinewhen and where the therapy will be made more widely available to patients.

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

First, he is hopeful it will inspire state advisory committees toaddSMAtothediseasesforwhichnewbornsare screened, amove thatMendell 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 appliedtoanynumberofneuromuscular diseases.

Already, researchers at Nationwide Children’s are looking to modify the study for a trial that would treat children withmuscular dystrophy. AndDr. BrianKaspar, AveXis’ chief scientificofficer, saidperhapsthesamescience couldbeusedtoaddressamyotrophic lateral sclerosis (Lou Gehrig’s disease) and Rett syndrome, an autism-spectrum disorder.

“We expect that we will have amajorimpactonthese other diseases aswell,” Mendellsaid.“We’reveryoptimistic that what we’ve learned in one trial will have implications for other diseases.”

Children with type-1 SMA, causedby amutation ina single gene, experience rapid loss of nerve cells early in life, making them hypotonic — suffering devastatingmuscleloss, Mendellsaid. Byeight 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 thefirsttimeresearchershave seen this level of function in SMA patients, and he anticipates that the 15 children will continue to improve.

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.

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