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Plaque Presentation for Gene Therapy
By Rebecca Salowe and Emma Wells

Scheie Vision Summer 2018

Children born with Leber’s Congenital Amaurosis (LCA) are not defined by blindness, but will face obstacles unimaginable to most sighted individuals. With low vision from an early age, these children may be sidelined from regular activities such as sports, bike riding, and trick-or-treating. They may be unable to see the chalkboard in the classroom and be highly sensitive to distracting noises, making it difficult to learn. They will need to memorize fire escape routes, be escorted across the street, explain their condition countless times to teachers and peers, and rely on others to describe surroundings. Children with LCA tend to overcome these challenges with outstanding resilience. Their visual impairment makes them no less intelligent, creative, or talented. What distinguishes a child with LCA from his/her peers is a rare genetic mutation, a microscopic error in the biological blueprint. 

Over the past 25 years, a team of scientists has worked to prove that DNA is not as fixed as previously believed—that defects caused by a mutated gene can be overcome by delivery of a normal copy of the gene. Jean Bennett, MD, PhD and Al Maguire, MD have dedicated their careers to the belief that a single genetic mutation should not determine a child’s fate. On December 19th, 2017, the world saw the beginning of a new era as this vision was realized. The FDA had officially approved their gene therapy regimen for a form of LCA caused by an RPE65 mutation. Luxturna, the brand name for this treatment, had just become the first gene therapy for an inherited disease ever approved in the United States.


It All Began in Anatomy Lab

Just two decades earlier, gene therapy was a field with few promising results. The idea that normal genes could be used to correct mutations causing genetic disorders was an exciting one, but difficult to implement—and often dangerous.

These setbacks did not deter Dr. Bennett. After completing her PhD in zoology and post-doc in molecular biology, she attended Harvard Medical School to gain expertise in diseases that could potentially be treated in the future with gene therapy. There, she met her now-husband, Dr. Maguire, working over a cadaver in anatomy lab. A partnership that extended beyond marriage and into the world of research was formed.

Dr. Bennett carefully followed the progress of gene therapy during medical school and subsequent fellowships. Meanwhile, Dr. Maguire completed his training to become a retinal surgeon.

Then, in 1990, Dr. William French Anderson conducted the first gene therapy on a human: a four-year-old girl named Ashanti DeSilva, who had adenosine deaminase (ADA) deficiency, a genetic disease leaving her defenseless against infections. The therapy involved treatment of Ashanti’s cells in a dish and then return of these treated cells into Ashanti’s bloodstream. This “ex vivo” treatment was successful, and led to a partial improvement in Ashanti’s condition.

The breakthrough ignited an idea in Dr. Maguire. He asked his wife, “Do you think we could ever develop a gene therapy to cure inherited forms of blindness?” She immediately answered: “Yes, of course.”

Early Failures in Gene Therapy

Ever the optimist, Dr. Bennett did not initially mention to Dr. Maguire the long list of ingredients that would be required to design successful gene therapy for retinal degeneration. For example, the genes involved in inherited blindness had not yet been identified. Extrapolation of the approach used in Ashanti’s case to treatment of the retina was unlikely to be effective. Viruses were being considered for gene delivery to retinal cells, but none had been shown to do so safely. There were no genetically characterized animal models of retinal disease. The surgical techniques to deliver genes to the retina had not yet been developed. Finally, even if these hurdles were overcome, there were no metrics to evaluate the effect of gene therapy on vision. However, these obstacles did not discourage Drs. Bennett and Maguire.

By the 1990s, Drs. Bennett and Maguire, now married, had been recruited to the Scheie Eye Institute at the University of Pennsylvania (UPenn). Their initial gene therapy experiments yielded frustrating results, though they eventually demonstrated a proof-of-concept of gene therapy in a mouse model of retinitis pigmentosa. Meanwhile, faith in gene therapy was crumbling around them. In 1999, an 18-year-old boy named Jesse Gelsinger died in a gene therapy trial (in which they were not involved) at UPenn. All gene therapy trials across the nation were immediately halted. 

“There had been a general sense that this was a therapy that was not ready for primetime, that there were too many things we didn’t understand,” said Katherine High, MD, the then-director of the Center for Molecular Therapeutics at Children’s Hospital of Philadelphia (CHOP), in the PBS documentary Genes as Medicine. “All the companies that had been involved in gene therapy were either turning away from it or they were failing.

Again, despite the seemingly insurmountable barriers in this field, Drs. Bennett and Maguire persevered. “With the belief that our approaches for treating retinal disease would be safe and effective, we continued to move forward cautiously with our bench research despite the unpopularity of gene therapy,” said Dr. Bennett. By 2000, they were ready to test a gene therapy procedure in dogs that were blind from Leber’s Congenital Amaurosis (LCA), an inherited retinal degeneration characterized by severe vision loss at birth. The treatment delivered a healthy copy of the RPE65 gene into the retina of dogs using an adeno-associated virus.

Soon after treatment, the dogs were placed in an obstacle course, which they had previously blundered through blindly. Now, the dogs ran through the course safely and quickly. They turned in circles, looking around at the world with the treated eye for the first time. Electroretinograms, carried out by their colleagues at Scheie, confirmed that the photoreceptor response of the dogs was restored.

The story of blind dogs regaining sight was featured in numerous media outlets, including Good Morning America, and was presented at the U.S. Congress. “The obvious next thought was, wouldn’t it be great to use this approach so that blind children could see?” said Dr. Bennett.

Seeing the Sun for the First Time

In 2005, Dr. Katherine High, a gene therapy expert, approached Dr. Bennett with a proposal. “She walked into my office, and I looked up and she said, ‘Jean, how would you like to run a clinical trial?’ And I was just totally floored,” said Dr. Bennett in Genes as Medicine. Dr. Bennett agreed without hesitation. “That was the beginning of a whole infusion of energy and enthusiasm and support.

Over the next several years, Dr. Bennett and her team worked relentlessly to prepare for the clinical trial. They created a clinical viral vector, generated a full set of safety and efficacy data, bred animals, designed protocols, defined outcome measures, and purchased equipment. After less than two and a half years of preparation, they enrolled the first subject.

The safety bar for human gene therapy protocols had been heightened following the death of Jesse Gelsinger—and this matter was further complicated by the inclusion of children in the trial, which necessitated a special review by the US Recombinant DNA Advisory Committee. However, when the time came for the first injection, Drs. Bennett and Maguire were fully confident in the safety of the treatment.

“It was a bold step embarking on the first injection,” Dr. Bennett recalled. “Although Albert’s and my criteria for moving forward were far more stringent than any of the institutional or federal criteria. That was, if our child was affected with this condition, would we allow him/her to participate? Our definitive answer was yes.”

The Phase I clinical trial at CHOP, which was conducted simultaneously with two other trials at University College London and University of Florida, enrolled 12 subjects with RPE65-related LCA. The subjects received an injection of the viral vector containing the RPE65 gene into their worse-performing eye, while the other eye acted as a control.

When the bandages over their eyes were removed, patients reported seeing the brightness of the sun for the first time. They commented on the colors of the world. They passed the obstacle course test with ease–a radical change from their difficulty navigating just days earlier. Further testing showed that all subjects had safe and stable improvement in retinal and visual function in the treated eye. Most subjects showed improvement in light sensitivity, navigational ability, activation in the visual cortex, and structure and function of the visual pathways. As predicted, the outcomes in the younger subjects provided them vision most similar to that in normal-sighted individuals.

Overjoyed. They deeply care for their patients, often referring to them as family. Before and after treatment, Dr. Bennett often visited the patients’ homes or watched the kids give music recitals. She and Dr. Maguire waived all financial gain if the therapy proved successful, in order to ensure their ethical standards remained high.

Will it Last?

The next step was readministration of the therapy to the contralateral eye. “The concern was that the initial injection of the virus would serve as a vaccination,” explained Dr. Bennett. “Then, when the second eye was treated, an immune response might not only prevent benefit in the second eye, but might also cause damage to the initially injected eye through immune sequelae.”

The team returned to the lab, performing readministration in six dogs with LCA-RPE65 who had previously received the treatment in one eye, as well as in four normal-sighted monkeys. The bilateral injection was found safe and effective, producing no inflammatory response.

The team cautiously continued with readministration studies in the human clinical trial subjects. The trial was a resounding success: no adverse effects resulted from the vector, and repeat administration led to durable improvements in retinal and visual function. This trial represented the first successful readministration of gene therapy in humans.

Interestingly, the results also shed light on the tremendous plasticity of the human visual system. It was previously thought that the brain lost its malleability after about three years of age. However, Manzar Ashtari, MD, the Director of CNS Imaging at UPenn’s CAROT, explored an additional potential outcome measure to the clinical trial, proving that patients can experience brain restructuring after the critical period of vision development. Before gene therapy, patients’ visual pathways were impaired structurally, potentially due to atrophy after long-term visual deprivation. However, after gene therapy, the visual pathways in the treated retina were similar to those of control subjects, suggesting that visual experience can lead to structural changes in the brain.

Scaling Up the Therapy

In the following years, Dr. Bennett, Dr. Maguire, and colleagues continued follow-up studies on LCA patients, as well as exploring gene therapy options for other degenerative eye diseases. In 2013, a new gene therapy startup company, Spark Therapeutics, was founded specifically to serve the RPE65 project. Dr. High became the president of the company. Dr. Bennett and her team worked with Spark to further test the intervention.

The treatment was soon tested in a Phase III clinical trial. This trial enrolled 31 individuals whose RPE65-mediated retinal degenerations would otherwise progress to total blindness. (Among these patients was Christian Guardino, whose story is featured in this issue.) Patients in the intervention group underwent injection of the viral vector in both eyes. Additional patients were designated as controls and did not receive the reagent for the first year, but were treated in both eyes in the second year. Again, the treatment was a success, leading to stable and durable improvements in retinal and visual function. There were no serious adverse events or immune responses related to the product.

Meanwhile, the idea for a center at UPenn where scientists could continue researching and treating blinding conditions was born. The Center for Advanced Retinal and Ocular Therapeutics (CAROT) was established in 2014, with Drs. Bennett and Maguire as Co-Directors and immunologist Junwei Sun, MS, MBA, as Chief Administrator. Tomas Aleman, MD was recruited as an expert in retinal degenerative conditions and to run clinical trials. The mission of CAROT is to develop novel therapies for retinal and ocular disorders and to restore sight in visually impaired or blind individuals.

The Final Hurdle

Following the success of the Phase III trial, the final step to making the therapy available to the public was approval from the US Food and Drug Administration (FDA). In October 2017, physicians, researchers, patients, and their parents converged in Silver Spring, Maryland to testify to an FDA advisory panel during a daylong hearing. The panel would then make a recommendation to the FDA for or against approval.

The day saw emotional testimonies from patients and their families whose lives were transformed by the treatment.

“I just want you to know that this was significant to me, significant in the way that I can plan and live my life,” said Caitlin Corey, who received the treatment a few days before her 21st birthday in 2013. “I can finally live my life the way I want to.”

"What I saw in the clinic was remarkable," said Dr. Maguire to the panel. "Most patients became sure of themselves and pushed aside their guides. Rarely did I see a cane after treatment."

The vote for approval came in at a unanimous 16-0. Then all there was to do was wait for the final decision from the FDA.

On December 19, 2017, Drs. Bennett and Maguire got the call that Luxturna had been approved.


A Brighter Future

Luxturna marks many firsts. It is the first FDA-approved gene therapy for an inherited disease, the first pharmacological treatment for an inherited retinal degeneration, and the first gene therapy to use an adeno-associated virus vector. But, the most important first for this therapy is undoubtedly the opportunity it presents individuals with RPE65-related LCA. For the very first time, the one to two thousand people with this disease have a promising treatment option that will likely greatly improve their sight.

As of now, the therapy is available at only designated treatment facilities throughout the country, in order to ensure safe administration. On March 20, 2018, groups at three different institutions: Bascom Palmer, Children’s Hospital Los Angeles, and Massachusetts Eye and Ear simultaneously performed the first injections of Luxturna since the approval.

Not only will this technique help to restore sight in patients blind from LCA, but it will also guide the development of similar products for other blinding diseases. To date, 265 genes have been identified to cause inherited retinal degeneration—a sharp contrast to the zero genes identified when Dr. Bennett began her research. Today, there are close to three dozen ocular gene therapy trials in progress or follow-up, with even more targets being considered by various groups. A dozen additional ocular gene therapy targets are in the pipeline for clinical trials at Scheie and CAROT.

“I believe that the success of the Luxturna clinical development program will pave the way for the development of other gene therapies, that may help the millions of patients with genetic diseases who currently have limited or no treatment options,” said Dr. Bennett, in a Spark press release.

The FDA agrees. “I believe gene therapy will become a mainstay in treating, and maybe curing, many of our most devastating and intractable diseases,” said FDA commissioner Dr. Scott Gottlieb. “This milestone reinforces the potential of this breakthrough approach in treating a wide range of challenging diseases.”

“It now sets a path for others to follow going forward, where there was none before,” said Dr. Bennett, in an interview with Penn Medicine Magazine. “This is looking way down the road, but maybe not as far as you think.”

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