Jean Bennett, MD, PhD, and Albert M. Maguire, MD PHILADELPHIA – In a historic move, the U.S. Food and Drug Administration (FDA) today approved a gene therapy initially developed by researchers at the University of Pennsylvania and Children’s Hospital of Philadelphia (CHOP) for the treatment of a rare, inherited form of retinal blindness. The decision marks the nation’s first gene therapy approved for the treatment of a genetic disease, and the first in which a new, corrective gene is injected directly into a patient.

The therapy, known as LUXTURNA™ (voretigene neparvovec-ryzl), significantly improves eyesight in patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Patients with RPE65 mutations suffer from severe visual impairment at infancy or early childhood, and by mid-life become totally blind. They previously had no pharmacologic treatment options.

Spark Therapeutics, a Philadelphia biotechnology company created in 2013 by CHOP in an effort to accelerate the timeline for bringing new gene therapies to market, led the late-stage clinical development of LUXTURNA and built in West Philadelphia the first licensed manufacturing facility in the U.S. for a gene therapy treating an inherited disease. Spark was built on the foundational research conducted over a ten-year period by CHOP’s Center for Cellular and Molecular Therapeutics (CCMT). Those efforts were led by Jean Bennett, MD, PhD, the F.M. Kirby professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Scheie Eye Institute, and Katherine A. High, MD, who directed the CCMT and now serves as Spark’s president and head of research and development. Albert M. Maguire, MD, a professor of Ophthalmology at the Perelman School of Medicine and an attending physician at CHOP, served as the principal investigator of the clinical trials which led to today’s FDA approval.

The approval is a culmination of more than 25 years of studies on congenital blindness by married-couple team Bennett and Maguire at Penn and CHOP, starting with pioneering work in mice and dogs.

“I’ve witnessed the dramatic changes in the vision of patients who would have otherwise lost their sight, and feel exhilarated that this therapy will now make a difference in the lives of more children and adults,” Bennett said. “I’m hopeful that the path we’ve made with this research, with the help of our collaborators near and far, will be useful to other groups, so that other gene therapies can be developed faster and help more people with other diseases.”

Today’s news marks the second FDA approval for a University of Pennsylvania/CHOP-developed therapy within six months. In August, the personalized cellular therapy known as Kymriah™ was approved for the treatment of advanced acute lymphoblastic leukemia in children and young adults.

There are an estimated 1,000 to 2,000 patients in the United States with RPE65 mutations. The newly approved therapy will be available at select treatment centers across the nation.

The one-time therapy corrects the deficits resulting from mutations in the gene RPE65, which is responsible for producing proteins that make light receptors work in the retina and vision possible. To restore production of those proteins, corrected versions of the RPE65 gene are delivered in a single injection, using a genetically engineered, benign adeno-associated virus to carry the genes to the retina. Within weeks, a patient’s vision can begin to improve. The FDA recommends the use of the therapy for patients ages 12 months and older.

“Today’s landmark approval is a great moment for science and the many individuals and families who live with genetic disease,” High said. “One of the hopes of the Human Genome Project had been that it would be possible to develop gene therapy to expand therapeutic options for people with genetic disease. Now that hope is a reality. We offer our sincere gratitude to the patients and their families as well as the expert investigators who continue to participate in this and other clinical development programs."

The Penn gene therapy work tightly links animal and human health, having begun in affected mice and dogs during the 1990s. In 2001, Bennett and Maguire and Penn colleagues Greg Acland, Tomas Aleman, Samuel Jacobson, and Artur Cideciyan reported they had successfully restored the sight of three blind dogs with a canine form of LCA, in collaboration with Cornell University’s Gus Aguirre (now a professor of Medical Genetics and Ophthalmology at the University of Pennsylvania School of Veterinary Medicine) and the University of Florida’s Bill Hauswirth. After the therapy, the dogs freely navigated through a dimly lit obstacle course, whereas before they would bump into objects.

The first Penn/CHOP-led Phase 1/2 clinical studies began in late 2007, with a total of 12 patients ranging from eight to 46 years old, most of whom experienced vision improvements within weeks of receiving the therapy. Half of the patients improved enough to no longer be classified as legally blind. Those initial clinical trials brought together patients and scientists from Penn and the Second University of Naples in Italy and Ghent University Hospital in Belgium. The first three patients to receive the therapy in 2007 are all now in their 20s and 30s, and continue to enjoy their improved vision.

Results presented in 2015 from a pivotal phase III trial of 29 patients aged 4 to 44, some of whom were treated at the University of Iowa, showed the therapy had significantly improved their ability to navigate an obstacle course designed to mimic daily activities in low light. The therapy dramatically restored most patients’ ability to see, increased their sensitivity to light, and improved their side vision, the researchers reported.

In the trials, the gene therapy safety profile was consistent with vitrectomy and subretinal injection procedures. Side effects included cataracts, changes in intraocular pressure, changes in macular structure (macular thinning, macular pucker, macular hole), intraocular infection in one patient, and a reduction in visual acuity in one patient.

To date, a total of 41 patients have been treated with the therapy at CHOP and Iowa.

Many of them are now reading the chalkboard, grocery shopping, taking driver’s license tests, having more job opportunities, and recognizing people’s faces, among other activities that seemed impossible before. “It has been amazing watching them grow up,” Bennett said. “It’s like they are an extended part of our family.” Bennett and Maguire have also adopted two dogs, Mercury and Venus, that were part of early trials of the new approach.

“The approval of the gene therapy approach for LCA opens up the door to develop therapies that target other mutations behind hereditary blindness and retinal diseases, and emphasizes the importance of genetic testing so that people living with inherited diseases can potentially benefit from gene treatments as they emerge,” Maguire said. “It also serves as a stepping stone to more prevalent diseases.”

A gene therapy clinical trial that delivers a corrected gene in patients with wet macular degeneration, for instance, is already underway at centers including the Scheie Eye Institute. Today, patients with this disorder must receive injections of a much-needed protein once a month. Using gene therapy could bring that down to just a single injection. Similar types of therapy may also help treat other diseases, such as hearing-related problems and muscular dystrophy, for example.

Additional contributors to the research include Jeannette Bennicelli, J. Fraser Wright, Shangzhen Zhou, Jennifer Wellman, Federico Mingozzi, Manzar Ashtari, Junwei Sun, Kathleen Marshall, Nadine Dejneka, Vibha Anand, Arkady Lyubarsky, Valder Arruda, Ken Shindler, Dan Chung, Sarah McCague, Dominique Cross, Julie DiStefano-Pappas, T. Michael Redmond, Kristina Narfstrom, Defne Amado, Julia Haller, Alberto Auricchio, Enrico Surace, Tim Hopkins, Tonia Rex, Eric Pierce, Michael Ward, Ali Zaidi, Jason Ruggiero, Dina Gewaily, Edwin Stone, Francesca Simonelli, Bart LeRoy, and Stephen Russell­.

Editor’s Note: The University of Pennsylvania has licensed certain patent rights to Spark Therapeutics, including intellectual property that covers Luxturna, which may provide financial benefits to Penn in the future.