Following FDA approval of a gene therapy for muscular dystrophy that he helped develop, neurologist Jerry Mendell treats his first patient, Gideon Griffiths (watched by his mother Erin).Credit: Nationwide Children's Hospital
Evelyn Villarreal was only eight weeks old when her parents, Milan and Elena, enrolled her in the first gene therapy trial for spinal muscular atrophy (SMA), a rare inherited disease, of which her 15-month-old sister, Josephine, had already died. SMA gradually robs children of muscle strength, leaving those with the most severe form, type 1, unable to move, swallow, speak and, ultimately, breathe. At that time, lack of effective treatments meant that nearly all children with SMA1 died before the age of two, reports neurologist Jerry Mendell, who led Evelyn’s trial in 2015 at Nationwide Children’s Hospital in Columbus, Ohio.
The pioneering trial included 15 babies with SMA1 who each received a one-time dose of an investigational gene therapy. The treatment replaced the gene that is mutated or missing in SMA1, which encodes survival motor neuron protein. As its name suggests, this protein is essential for motor neurons — nerve cells that control muscle movement — to remain alive and functional.
The trial was successful1: all 15 infants survived until at least 20 months. Historical observational studies, which acted as the control cohort, had a comparable 20-month survival rate of 8%. What’s more, most trial participants gained the ability to lift their heads, roll over, and sit unaided — milestones no patient in the historical cohorts ever achieved. Eleven of the treated children were able to talk, and two — including Evelyn — could also walk independently. The therapy worked so well that the readers of Science voted it as the Breakthrough of 2017.
The technology was licensed to Avexis, which was acquired by Novartis who further developed the treatment as Zolgensma and obtained FDA approval in 2019, making it the first systemic gene therapy for SMA. “The FDA’s decision validated decades of work to change the course of this relentless, fatal disorder,” says Mendell, principal investigator at Nationwide Children’s Hospital’s Center for Gene Therapy.
The SMA story is not a one-off: Mendell and his team of physician-scientists have published more than 300 studies evaluating pioneering gene therapies for children born with devastating neuromuscular diseases. Just recently, they had another FDA approval for a treatment for Duchenne muscular dystrophy (DMD). Research at Nationwide Children’s covers not just gene therapies but the full spectrum of discovery science, translational, outcomes, and population health research. Nationwide Children’s, one of the top ten children’s hospitals in the United States, is supporting more than 250 investigators and more than 2,500 clinical research projects.
A discovery engine
In 2009, a team led by gene therapy pioneer and former Nationwide Children’s principal investigator Brian Kaspar demonstrated that an AAV subtype called AAV9 can cross the blood–brain barrier and carry DNA directly to neurons2.
The AAV9 discovery lets physician-scientists use a simple IV infusion to send replacement genes to the brain and spinal fluid, sparing children from neurosurgery. This research underpins several gene therapies developed at Nationwide Children’s.
Thanks to that foundational research, Nationwide Children’s has spawned several gene therapy startups that continue to develop its pioneering work. One of the newest, launched in 2020, is Andelyn Biosciences. Its mission: to support biotech companies to develop and manufacture novel gene therapies.
Named after two children treated in pivotal clinical trials at Nationwide Children’s, Andrew Kilbarger and Evelyn Villarreal, the company offers a state-of-the-art manufacturing facility for gene therapy products, as well as access to regulatory experts and Nationwide Children’s renowned physician-scientists for help with tricky research challenges.
To date, Andelyn has helped develop and manufacture products for more than 100 global clinical trials of investigational drugs for childhood diseases most people have never heard of, says Andelyn’s CEO Wade Macedone. “Our physician-scientists have a saying that no genetic disease is too rare for us to help,” he says. “SMA is a perfect example: it occurs in only one in 10,000 newborns worldwide.” Furthermore, each discovery made could go on to help children with even rarer inherited conditions, he adds.
Duchenne muscular dystrophy
Nationwide Children's Hospital in Columbus, Ohio, is one of the top 10 paediatric hospitals in the United StatesCredit: Nationwide Children's Hospital
Co-invented by Mendell and molecular biologist Louise Rodino-Klapac, the new treatment was decades in the making. One of the most daunting challenges was how to fit the dystrophin gene into an AAV vector. “The gene we’re trying to replace is the largest in the human body — more than triple the size of the AAV needed to deliver it,” says Rodino-Klapac, now chief scientific officer at Sarepta Therapeutics, a Cambridge, Massachusetts-based biotech specializing in genetic medicines for rare diseases.
The solution the team came up with known as SRP-9001, was inspired by the work of Scott Harper and Jeff Chamberlain, then at the University of Michigan (Harper is now a faculty member at Nationwide Children’s). Their research developed a miniature version of the dystrophin gene known as micro-dystrophin, which was smaller yet still functional. SRP-9001 (marketed as Elevidys by Sarepta) packaged a modified version of micro-dystrophin into an AAV vector.
Results from Mendell and Rodino-Klapac’s latest clinical trial (part 2 of the pivotal study evaluated by the FDA) indicate that the new genetic medicine was able to preserve motor function in children with DMD for 96 weeks after treatment, compared with a functional decline in a control group of untreated children the same age3.
“It’s always been Doctor Mendell’s dream to develop a therapy for these boys,” says Rodino-Klapac. “During the 18 years we worked together to fulfill it, I’ve come to share his passion.” She adds that the stories of young children living with DMD, who after treatment can take part in the same energetic activities as their friends, are profoundly inspiring. “If I was one of their caregivers, I’d want researchers like us fighting every day to give their children a better life — and brighter future.”