James Wilson, MD, PhD, recalls being struck by the devastating toll of rare diseases as a young physician in the 1980s. He set out on a path to correct the genes that cause these conditions, including spinal muscle atrophy (SMA), the most common inherited fatal disease in infants.
"Knowing that most of these diseases are caused by mutations in single genes suggested to me that a generic approach would be to fix the disease at its root -; to correct the genetic defect through what is now called gene therapy," said Wilson, who serves as director of Penn's Gene Therapy Program and Orphan Disease Center, and is a professor of Medicine and Pediatrics in the Perelman School of Medicine at the University of Pennsylvania.
Today, Wilson and his team are celebrating a major milestone in the field: approval by the U.S. Food and Drug Administration (FDA) of a gene therapy known as Zolgensma for SMA. The therapy is based on a delivery vehicle that his team discovered and developed over the past decade as part of a wide-ranging portfolio of research to advance gene therapy.
SMA is caused by a mutation in the survival motor neuron gene 1 (SMN1), which affects nerve cells in the spinal cord. Normally, this gene produces a protein necessary for nerves that control the muscles. Over time, the mutation diminishes a young child's ability to walk, eat, and breathe. The infant form of SMA has a 90 percent mortality rate by one year and is almost completely fatal by two years. Made by Novartis, Zolgensma is a one-time treatment for SMA that is designed to restore production of a full-length SMN protein in motor neurons by delivering a functional, non-mutated copy of the SMN1 gene.
A primary goal of Wilson's research has been developing methods for delivering genes to cells. His laboratory discovered a family of viruses found in primate tissues called adeno-associated viruses (AAVs) that can be engineered to ferry healthy DNA into the correct cells; they have proved to be safer and more effective than older viruses Wilson and others had used.
"This is the first drug based on an adeno-associated virus vector to be approved by the FDA that stops the progression of a lethal disease," Wilson said. "Of the more than 100 new AAVs that we discovered, it was AAV9 that stood out. Vectors based on this virus have remarkable properties, with the ability to deliver genes across anatomical obstacles such as the blood-brain barrier."
In 2009, REGENXBIO, a clinical-stage biotechnology firm, secured exclusive rights to key intellectual property covering novel recombinant adeno-associated viral vectors discovered at Penn in the Wilson lab. Today, over 75 disease programs across more than 25 companies use the AAV-based platform. AAV9 was the vector used in the Phase I SMA clinical trial at Nationwide Children's Hospital for the approved therapy Zolgensma. REGENXBIO licensed the vector to AveXis in 2014, and AveXis was subsequently acquired by Novartis in 2018.
In published clinical trial results of Zolgensma, all 15 patients who received the therapy were alive and did not need permanent ventilation at 24 months after treatment. Eleven out of 12 participants who received the proposed therapeutic dose could sit unassisted for more than five seconds, a milestone never before achieved in SMA patients. In addition, some children maintained their developmental motor milestones four years after infusion. Toxicities observed included elevated liver enzymes and decreased platelet count.
"This approval is a huge milestone for the rare disease community because the approach can be leveraged across many different diseases," Wilson said.
Families impacted by SMA point to today's news as a fresh turning point for their children, following the 2016 FDA approval of Spinraza, a different, non-gene-therapy treatment for SMA.
For one rare disease to have two FDA drug approvals in a three-year window is unheard of."
Steven Cannady, MD, an associate professor of Clinical Otorhinolaryngology, Head and Neck Surgery at Penn
Cannady and his wife, Gina, have two daughters with SMA -; one with SMA-2 and one with SMA-3 -; who have both participated in earlier clinical trials. "At one point, we decided to simply live in the moment more than think about the future. The SMA drugs and gene therapy now being used are allowing us to dream again," Cannady said.
Zolgensma has another tie to Penn Medicine, the Clinic for Special Children (CSC) in Strasburg, PA, which has a long-standing clinical relationship with Lancaster General Health, was a site for clinical trials for this drug. CSC is an established, private clinic that serves children with rare, genetic disorders in the Amish and Mennonite communities of Lancaster County.