Gene Therapy for Spinal Muscular Atrophy: From Idea to Reality
On May 24, 2019, the U.S. Food and Drug Administration (FDA) approved Zolgensma® (onasemnogene abeparvovec-xioi), a first-of-its-kind gene therapy for spinal muscular atrophy which was developed at Nationwide Children’s, laying the groundwork to change the lives of children all over the world.
Harnessing the ability of a virus to deliver genetic material to a cell to treat, cure or prevent disease has been the long-time goal of researchers working in gene therapy. Over the past 30 years, the journey to gene therapy has been fraught with challenges and roadblocks. But in 2017, after countless starts and stalls along the road, the field experienced many breakthroughs.
No breakthrough received more attention than when researchers from Nationwide Children’s Hospital and The Ohio State University published the astonishing results of the phase 1 clinical trial of gene therapy for spinal muscular atrophy type 1 (SMA1) in the New England Journal of Medicine.
The SMA1 early phase trial, led by Jerry Mendell, MD, Principal Investigator in the Center for Gene Therapy in the Research Institute at Nationwide Children’s, demonstrated extended survival and increased achievement of milestones previously unseen in the natural course of the disease — a devastating, progressive neuromuscular disease that typically results in death by age 2. An intravenous injection of AVXS-101, a modified adeno-associated virus serotype 9 (AAV9), delivered the survival of motor neuron (SMN) gene.
This trial was the basis for the FDA’s approval of Zolgensma®. It builds on nearly 30 years of foundational research and collaboration. Arthur Burghes, PhD, of The Ohio State University, created the SMA mouse model that remains the standard by which all therapies are initially tested. Brian Kaspar, PhD, Senior Vice President and Chief Scientific Officer at AveXis, a clinical-stage gene therapy company developing treatments for patients suffering from rare and life-threatening neurological genetic diseases, during his appointment at Nationwide Children’s, discovered that the AAV9 vector can cross the blood-brain barrier when injected into the vascular system and can deliver genes directly to motor neurons. That landmark study was published in Nature Biotechnology in 2009.
“None of this would have been possible without the seminal discovery that AAV9 crosses the blood-brain barrier,” said Dr. Mendell, also a Professor of Pediatrics, Neurology, Pathology, and Physiology and Cell Biology at The Ohio State University College of Medicine.
The FDA approved Zolgensma for pediatric patients less than 2 years of age with SMA, including those who are pre-symptomatic at diagnosis.
“The FDA’s decision is validation of my team’s decades of work to develop a treatment that alters the course of this unforgiving condition and provides a therapeutic option for the families and infants with SMA,” said Dr. Mendell. “When you see one of the clinical trial participants – now four years old and running, jumping and dancing – it is incredible.”
Research conducted since the FDA’s approval in 2019 continues to provide evidence for the safety and efficacy for the first-of-its-kind intervention. A recent study showed that with Zolgensma, a single intravenous dose of the medicine has led to improvements in muscle strength and less dependence on noninvasive ventilation. From natural history studies that enable understanding of disease progression to clinical trials of the latest innovations in therapies, Nationwide Children’s Hospital is a model for clinical research integration. Discoveries made here are impacting the lives of children all over the world.
Pioneering breakthroughs like the Zolgensma® therapy has allowed Nationwide Children’s Hospital not only the opportunity to share the discovery with the world, but also develop the ideal clinical program to care for these unique patients and achieve the best possible outcomes.
To learn more about Nationwide Children’s Hospital and the treatment of neuromuscular disorders, visit NationwideChildrens.org/Neuromuscular-Disorders