Magazine Article | September 3, 2018

Gene Therapy Pioneer's 30 Years Of Problem-Solving

Source: Life Science Leader

By Cathy Yarbrough, Contributing Editor
Follow Me On Twitter @sciencematter

Physician-scientist Katherine High, M.D., cofounder, president, and head of R&D at Spark Therapeutics, has had to solve many technological and clinical problems in her 30-year-long quest to turn genes into medicines for patients with hemophilia and other diseases caused by a single flawed or missing gene. For example, there was the problem that halted the second clinical trial of an experimental gene therapy for hemophilia B. The therapy was designed to deliver a functional copy of the gene for the blood-clotting factor to a patient’s liver cells. The Phase 1 trial, initiated in 2001, was sponsored by the now-defunct biotech company Avigen. Dr. High, who had collaborated with Avigen scientists in the design of the gene therapy’s recombinant adeno-associated viral (AAV) vector, was then head of hematology research at Children’s Hospital of Philadelphia (CHOP).

The trial came to a standstill when laboratory tests detected the vector’s DNA in the semen of a hemophilia B patient. In her lab at CHOP, Dr. High developed a rabbit model of biodistribution that revealed that the vector’s DNA was only a temporary resident of semen. As it had in rabbits, the vector’s DNA “washed out” of the patients treated with the experimental gene therapy. Avigen’s clinical trial protocol was amended to recommend that patients use barrier birth control until laboratory tests no longer detected vector DNA in their semen. Subsequent clinical trial protocols for gene therapy also have included this recommendation.

However, until several years ago, relatively few clinical studies of experimental gene therapies were conducted. After a series of adverse events in clinical studies of gene therapy in 1999 and the early 2000s, many biotech companies went out of business or discontinued or significantly reduced their R&D investment in these treatments. Although abandoned by bio-pharmaceutical companies, gene therapy R&D did not cease. “It returned to academic medical centers, which were the right place for gene therapy R&D to be. In the 1990s, when the first generation of gene therapy companies were active, there were still too many problems that had not yet been identified and solved,” said Dr. High.


To continue her work on gene therapy, Dr. High needed a reliable source of clinical-grade AAV vectors. Since Avigen had terminated its hemophilia B gene therapy program, the company was no longer manufacturing vectors. In 2004, CHOP came to the rescue by funding the Center for Cellular and Molecular Therapeutics (CCMT). For 20 years, Dr. High was founding director of the center, which she staffed with experts in the generation and purification of clinical-grade vectors, clinical research, and regulatory affairs. Some of Avigen’s “highest performers” joined CCMT, she said.

CCMT’s accomplishments in gene therapy helped reinvigorate the life sciences industry’s interest in the field. About 150 gene therapies are now under development at Spark Therapeutics and other second-generation gene therapy companies. An MIT report predicts that about 40 gene therapy products will obtain regulatory approval by the end of 2022.

When Spark Therapeutics was launched in 2013 as a spin-off of CHOP, the biotech company inherited several key CCMT assets, including experimental gene therapies for hemophilia and a rare form of inherited retinal disease (IRD) caused by the RPE65 gene mutation. Dr. High left CCMT to join Spark soon after it opened its doors. (See sidebar.)


In 2017, the FDA approved LUXTURNA (voretigene nepar-vovec-rzyl), the company’s gene therapy for IRD. Development of the gene therapy was not without challenges. For example, the FDA required that Spark’s randomized, controlled Phase 3 clinical trial of the gene therapy document patients’ functional vision before and after treatment. To fulfill this requirement, Spark researchers created a multi-luminance mobility test, the results of which were the primary endpoint of the Phase 3 trial. “We put a lot of effort into developing the test, which is conducted at a series of different light levels,” said Dr. High.

Dr. High has continued to advance the development of a hemophilia B gene therapy that delivers functional copies of the factor IX gene to patients’ cells. The gene encodes the factor IX blood clotting protein, whose abnormally low levels in hemophilia B patients are responsible for the life-threatening spontaneous bleeds that characterize the disease. According to Dr. High, the ideal gene therapy will sustain the expression of the factor IX clotting factor at levels that will prevent the occurrence of spontaneous bleeds while freeing patients of the costly daily infusions of plasma-derived or recombinant factor IX, the current standard of care for hemophilia B patients. Infusions cost patients about $300,000 each year in the U.S.

In their initial hemophilia B studies, Dr. High and research colleagues found that boosting the gene therapy dose resulted in high levels of the clotting factor in the patients’ blood circulation. However, the effect lasted only 12 weeks because the patients’ immune systems attacked the cells in which AAV vectors had transplanted therapeutic genes, also known as transgenes. The immune response was not directed at the transgenes but at the vector capsid, the protein shell that envelops the viral genome.


Because the capsid is gradually degraded and cleared from cells, Dr. High and her team proposed a short-term immunomodulatory therapy to help dampen the patients’ immune response. But the researchers wanted to do more to ensure an ideal gene therapy for hemophilia B. They redesigned the AAV vector to transport the recently-discovered Padua variant of the factor IX gene. The variant’s much higher activity levels result in increased levels of the clotting factor in the patients’ blood. The variant enabled Spark researchers to lower the gene therapy dose to a level that greatly reduces the risk of an immune response to the vector’s capsid.

In 2014, just one year after Spark Therapeutics was established, Pfizer became a partner in the development of the biotech company’s hemophilia B gene therapy. “When the decision to work with Pfizer was made, Spark Therapeutics was a new company. We knew that hemophilia B would be a big market, but we did not yet have experience in commercializing a therapy,” said Dr. High. Pfizer’s resources and long record in hemophilia therapy impressed her and other company leaders. Pfizer’s products include a recombinant factor IX infusion for patients with hemophilia B.

"Gene therapy remains a class of therapeutics that requires a great deal of focused effort and attention to realize its full promise."

Katherine High, M.D.
Cofounder, president, & head of R&D, Spark Therapeutics


In May 2018, Spark and Pfizer reported that routine factor IX infusions no longer were needed by the 15 patients with severe or moderately severe hemophilia B who were participating in the Phase I/II clinical trial of the gene therapy. None of the patients experienced serious adverse events. In July 2018, Pfizer initiated the first stage of the critical Phase 3 trial of the hemophilia B therapy (fidanacogene elaparvovec ). The trial began with an open-label, multi-center, lead-in study to evaluate current factor IX prophylaxis replacement therapy in the usual care setting. The data obtained in the lead-in study will serve as the within-subject control group for those patients who enroll in the next part of the Phase 3 trial that will evaluate fidanacogene elaparvovec. In addition to conducting the Phase 3 trial, Pfizer will be responsible for regulatory submissions, and if the therapy is approved by the FDA and the European Medicines Agency, the global commercialization of the product.

In January 2018, Spark Therapeutics struck a partnership with another Big Pharma partner, Novartis, which obtained the rights to commercialize Luxturna outside the U.S. For its experimental hemophilia A gene therapy, Spark intends to “go it alone and manage without a partner,” said Dr. High. In August 2018, Spark announced that it will sponsor a Phase 3 clinical trial of the hemophilia A gene therapy that will begin with a run-in study later in the year. Spark’s clinical pipeline also includes an experimental gene therapy for choroideremia, a hereditary disease characterized by progressive vision loss.


If Dr. High had a motto for gene therapy R&D, it would be: “Don’t let the perfect be the enemy of the good.” For example, scientists sometimes spend a great deal of time and effort in the lab to improve a very good vector so that it will be a perfect vector. “But they would save time if they stopped to evaluate their very good vector,” she said. Investigating the very good vector in a small-scale clinical study often reveals problems that were not yet known and that should be corrected before additional resources are spent to create the perfect vector.

Early small-scale clinical studies also can reveal potential problems that laboratory animal studies failed to detect. In Dr. High’s research to develop a safe, effective gene therapy for hemophilia B, lab animal studies did not predict that patients’ immune systems would attack AAV vector capsids. “With these complex biologics, only a certain amount can be learned from animal models,” she said. “Gene therapy remains a class of therapeutics that requires a great deal of focused effort and attention to realize its full promise.”

Looking to the future, she predicted that clinical development timelines for the next generation of AAV-based gene therapies will not be as long as the 10 years required for Luxturna. The Phase 1 trial of Luxturna began in October 2007. The FDA approved the landmark gene therapy in December 2017. “We can assume that development timelines will be shorter going forward, since at least for Spark, much of the work required to get to commercial manufacturing standards has now been done,” Dr. High said.

Over the next three to five years, Dr. High said, safe and effective gene therapies for single gene disorders such as spinal muscular atrophy, sickle cell anemia, and beta thalassemia likely will be produced. “Then I hope that the scope of gene therapy will widen to include genetic strategies for complex acquired disorders ranging from age-related macular degeneration to congestive heart failure and perhaps even Alzheimer’s,” she said.


“I’ve spent my whole career working on gene therapies for genetic diseases, and I wanted to be darn sure they made it over the finish line,” said Katherine High, M.D., cofounder, president and head of R&D at Spark Therapeutics. When Spark Therapeutics was launched in 2013, Dr. High could have continued to work on gene therapy at Children’s Hospital of Philadelphia (CHOP)’s Center for Cellular and Molecular Therapeutics (CCMT), which she founded in 2003. “My feeling was that if there ever was a time when gene therapies could be developed to help patients, this was the time,” she said. Thus, Dr. High took the leap into industry after several decades in academia. At Spark Therapeutics, she spends her time much as she did at CCMT in laboratory research and high-profile clinical trials.

Dr. High’s keen interest in developing gene therapies for hemophilia and other single- gene diseases began during her postdoctoral fellowship in hematology in the early 1980s at Yale University School of Medicine. When the genes for factor VIII and IX clotting factors were cloned in 1982 and 1984 respectively, she began thinking about gene therapy as a potential treatment for hemophilia.

Subsequently, as a faculty member at the University of North Carolina (UNC) at Chapel Hill, Dr. High led the team that in 1989 isolated the gene for the canine version of factor IX in dogs with naturally occurring hemophilia B. She showed that a single dose of gene therapy could achieve over 10 years of therapeutic levels of clotting factor expression in dogs.

Dr. High’s next step was CHOP, where her clinical research on gene therapy for hemophilia and other single-gene diseases began.