The FDA approved the gene therapy Zolgensma for pediatric patients less than 2 years of age with spinal muscular atrophy, including those who are pre-symptomatic at diagnosis. Jerry Mendell, MD, principal investigator in the Center for Gene Therapy at the Abigail Wexner Research Institute led the Phase 1 clinical trial that was the first to study gene therapy for spinal muscular atrophy type 1 (SMA1), the most severe form of SMA.
SMA, the number one genetic killer of babies under two years of age, is a progressive, childhood, neuromuscular disease caused by a mutation in a single gene. Children with SMA1 fail to meet motor milestones and typically die or require permanent mechanical ventilation by 2 years of age.
In the first clinical trial to test the functional replacement of the mutated gene responsible for SMA1, the SMN gene, an intravenous injection of Zolgensma – a modified adeno-associated virus serotype 9 (AAV9) – delivered a functional copy of the human SMN gene to the patients’ cells. Almost all patients in the study who received the one-time intravenous infusion of the high dose had rapid gains in motor functions, achieving major milestones associated with childhood development, including swallowing, rolling over and sitting independently. Most of the patients who received the FDA-approved dose were able to sit and roll and a few could crawl or walk.
“Treatment of SMA1 with gene therapy has the potential to transform the disease course, in addition to improving patient and caregiver quality of life. Reduced use of ventilation and nutrition support, as well as decreased hospitalization, could significantly decrease the overall health care utilization of these patients," says Richard Shell, MD, section chief of Pulmonary Medicine at Nationwide Children's.
“The FDA’s decision is validation of decades of work to develop a treatment that alters the course of this unforgiving condition and provides a therapeutic option for the families and children with SMA,” adds Dr. Mendell. “When you see one of the clinical trial participants from our trial, some of who are now nearly four years old and the ones who are running, jumping, dancing – it is incredible.”
The preclinical work leading to the FDA approval of Zolgensma was conducted by researchers from Nationwide Children’s and The Ohio State University College of Medicine. In a key milestone toward advancing the research, Brian Kaspar, PhD, during his tenure with Nationwide Children’s, discovered that the AAV9 vector was capable of crossing the blood brain barrier when injected into the vascular system to deliver genes directly to motor neurons. Dr. Kaspar is currently the Chief Scientific Officer at AveXis, Inc.
“Nationwide Children’s Center for Gene Therapy is a national leader in gene therapy with a robust pipeline of more than 20 genetic targets in various stages of research,” says Kevin Flanigan, MD, director of the Center for Gene Therapy. “The Abigail Wexner Research Institute invested in a clinical trial infrastructure, a Good Manufacturing Practice (cGMP) facility, regulatory experts and an Office of Technology Commercialization with the goal of taking discoveries from the laboratory bench to the clinic.”