Penn Medicine, Children's Hospital of Philadelphia team awarded Breakthrough Prize for developing gene therapy for inherited blindness

Today, Jean Bennett, MD, PHD, and Albert Maguire, MD, both emeritus professors of Ophthalmology in the Perelman School of Medicine at the University of Pennsylvania, and Katherine High, MD, an emeritus professor of Pediatrics and the founding director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics at Children's Hospital of Philadelphia (CHOP), received the Breakthrough Prize in Life Sciences for their work in developing the first FDA-approved gene therapy for an inherited condition, which dramatically improves sight in people with a form of blindness called Leber Congenital Amaurosis (LCA).

Their work blazed a trail for the more than 140 gene therapy trials for retinal conditions, including macular degeneration and diabetic retinopathy, diseases that collectively impact about 30 million people in the US. Eighty more trials are currently underway.

"Even 20 years ago, treating people with gene therapy was seen by some as an impossibility," said Jonathan Epstein, MD, dean of the Perelman School of Medicine and executive vice president of the University of Pennsylvania for the Health System. "But this group of incredible physician-scientists persisted and created something that is providing sight to people who would have been completely blind as early as kindergarten. Their belief in the power of life-changing science has led to breathtaking results and richly deserved global recognition."

The Breakthrough Prizes are called the "Oscars of Science" for their high-profile celebration of research and support from celebrities spanning numerous areas of pop culture. Created in 2012 by Sergey Brin, Priscilla Chan and Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki, the prizes are given out in five categories including Life Sciences, Fundamental Physics, and Math, each with an accompanying $3 million award.

This year's accolade now means that nine Penn-affiliated researchers have received the Breakthrough Prize, tied for the most with Harvard University. The prior Penn Medicine award winners are Carl June, PhD (2024), Drew Weissman, MD, PhD, and Katalin Karikó, PhD (2022), and Virginia M.Y. Lee, PhD (2019). Additionally, Penn faculty members Charles Kane, PhD, and Eugene Mele, PhD, won the prize for Physics in 2019. Mathew Madhavacheril, PhD, an assistant professor of Physics and Astronomy in Penn's School of Arts & Sciences, also received recognition at this year's Breakthrough Prize ceremony when he was honored with the New Horizons in Physics award, given to researchers early in their careers.

"Science is rarely a straight path, and those who make the most profound discoveries are resilient and persistent, overcoming obstacles along the way," said J. Larry Jameson, MD, PhD, president of the University of Pennsylvania. "That is exactly what I see in this year's awardees, and it has been true of all our remarkable faculty who have been recognized for scientific breakthroughs. Whether they are discovering what lies beneath Alzheimer's Disease, curing cancer by engineering a patients' own immune cells, or reversing blindness—they have persisted with imagination and rigor. Their steadfastness has pushed the boundaries of what medicine can achieve."

"Developing cell and gene therapies has long been a top priority for our organization," said Madeline Bell, CHOP's CEO. "This breakthrough is the result of decades of investment and collaboration, and reflects our commitment to translating scientific discoveries into therapies that will transform patients' lives. It has paved the way for many more cell and gene therapy innovations and has given hope to families around the world."

"They can see!"

Bennett and Maguire met and married during medical school in the 1980s. It was then that they both became intrigued by the concept of genetic therapy, the practice of replacing a mutated or faulty gene with a functional copy, and started dreaming of treating inherited forms of blindness with the technique, which at that time remained the stuff of science fiction.

It was "like thinking you wanted to go to the moon in 1950," Maguire said many years later.

Both Bennett and Maguire joined Penn's Scheie Eye Institute in the 1990s and began working on their ideas with lab mice. They learned that the University of Pennsylvania School of Veterinary Medicine housed a group of blind dogs who had a condition similar to the human disease: Leber congenital amaurosis (LCA). People born with a mutation on the RPE65 gene have poor vision starting at birth and often progress rapidly to complete blindness, usually by their 20s, but sometimes in early childhood.

The pair developed a therapy that used a virus as a transport, carrying a piece of DNA into cells that would then correct the faulty, blindness-causing proteins formed by the bad gene. The idea: Once the proteins were set right, some sight might return. First, they tested the therapy by injecting it into a single eye in each of three dogs.

It wasn't long until they knew whether it worked. Bennett recalls receiving an excited phone call from a technician at the lab, who exclaimed, "They can see!"

Sure enough, the dogs were twirling around, using their treated eyes to see. Before treatment, the dogs had bumped and tripped through an obstacle course set up to test their sight. After the full treatment, the course was an easy task for the dogs.

A knock on the door

In parallel with Bennett and Maguire's dreams of gene therapy, High was also working to bring the field forward. Like Bennett and Maguire, she had achieved long-term reversal of a serious genetic disease in a dog model: In her case, for hemophilia, a life-threatening bleeding disorder. High had advanced these studies from success in dogs to initial clinical trials in humans, delivering the donated gene into skeletal muscle and the liver.

The work was promising, but the human immune response to the gene delivery vessel—which was derived from a virus in the same way Bennett and Maguire's therapy was—prevented sustained benefits from the therapeutic gene. At the same time, companies and investors, discouraged by high profile negative events, began to turn away from gene therapy. Progress stalled. 

But with support from CHOP, High founded the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (CCMT) in 2004. She recruited experts in all aspects of clinical gene therapy, including specialized knowledge in the manufacturing and release of gene therapy vectors, which are the particles that deliver a healthy copy of a defective gene to patients.

After vector production was set up at CHOP, High went to Bennett's office and knocked on the door with a proposition to start a clinical trial in humans. In 2007, Maguire, who was then a surgeon in Pediatric Ophthalmology at CHOP, administered an injection of the experimental therapy at CHOP into a clinical trial participant – a 26-year-old woman—for the first time. Her twin, with the same condition, received the treatment shortly after.

When the team assessed the treatment of the 37 eligible participants from the original clinical trials, 72 percent reported the maximum possible improvement in a test of low-light conditions, which simulates night vision. Amid these, many reported improved peripheral and central vision, too. One patient, who could only detect changes in light, was suddenly able to navigate walking through Philadelphia at night, unaided, and could make out the clock on City Hall. Another patient was able to see a star for the first time in her life just six days after the procedure.

In 2017, the therapy—by then manufactured by Spark Therapeutics, a spinout from CHOP, and called Luxturna—received approval by the U.S. Food and Drug Administration. It became the first FDA approval of a genetic therapy for an inherited disease. Today, hundreds of people around the world have successfully received the treatment.

A celebration of decades of work

Today's celebration in Los Angeles marks a celebratory milestone in roughly 40 years of work led by Bennett, Maguire, and High that has inspired others in the now vibrant field of gene therapy. In fact, a treatment stemming from High's original work with hemophilia received FDA approval in 2024.

"We always just did what we thought you were supposed to do if you were a doctor: Find treatments for diseases," said Maguire. "Both my father and Jean's worked in science, and it seemed normal to try to push the envelope."

"I think the only surprise for us was that things worked out so well," Bennett said. "For every success, there are usually so many failures. That's just the nature of science. But our team hit on something that has helped so many people and helped progress the field, and we're really grateful for our part in that."

High described the journey between the start of her collaboration with Bennett and Maguire in 2005 and the FDA approval in 2017 as "an arduous one."

"At times, it seemed that the number of obstacles we needed to overcome to reach regulatory approval was never-ending," High said. "Working without the benefit of the guidelines and precedents we now have today, we sought to solve each day's problems so that the program would have a tomorrow. It was a bold and uncertain investment of time, effort, and resources. Few were willing to take on the risks, but it ultimately paid off, and it helped build the foundation of modern gene therapy."

About Penn Medicine:
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service.

The organization consists of the University of Pennsylvania Health System and Penn's Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation's first medical school.

The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with more than $588 million awarded in the 2024 fiscal year. Home to a proud history of "firsts," Penn Medicine teams have pioneered discoveries that have shaped modern medicine, including CAR T cell therapy for cancer and the Nobel Prize-winning mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System cares for patients in facilities and their homes stretching from the Susquehanna River in Pennsylvania to the New Jersey shore. UPHS facilities include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Doylestown Health, Lancaster General Health, Princeton Health, and Pennsylvania Hospital—the nation's first hospital, chartered in 1751. Additional facilities and enterprises include Penn Medicine at Home, GSPP Rehabilitation, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is a $13.7 billion enterprise powered by more than 50,000 talented faculty and staff.

About Children's Hospital of Philadelphia:
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit www.chop.edu. 

Media Contacts:

CHOP PR Contact:
Ashley Moore
[email protected]
267-426-6071

Penn Medicine PR Contact:
Frank Otto
[email protected]
267-693-2999

SOURCE Children's Hospital of Philadelphia