FRONT PAGE: CHOP-Led Study Shows Novel Gene Therapy For Hemophilia A Leads To Sustained Expression Of Clotting Factor And Reduced Bleeding Events

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Newswise — Philadelphia, November 17, 2021–A novel gene therapy for hemophilia A led to sustained expression of the clotting factor those patients lack, resulting in a reduction – or in some cases complete elimination – of painful and potentially life-threatening bleeding events, according to a new study led by researchers at Children’s Hospital of Philadelphia (CHOP). The phase 1/2 trial’s results were published in the ,New England Journal of Medicine today. They are the first to show stable coagulation factor VIII in hemophilia patients after gene therapy.

“The results of this study offer compelling data to support the current approach to hemophilia A gene transfer can indeed confer stable factor VIII expression over multiple years for near disease ameliorating effect,” said lead study author Lindsey A. George, MD, Director of Clinical In Vivo Gene Therapy and an attending physician in the Division of Hematology at Children’s Hospital of Philadelphia, as well as lead investigator of the phase 1/2 study sponsored by Spark Therapeutics. “These data build on the decades-long history of hemophilia gene therapy research at Children’s Hospital of Philadelphia, which has sought to bring curative therapies to these patients.”

Hemophilia A is the most common inherited bleeding disorder, affecting 1 in 5,000 males worldwide. This condition is caused by a missing factor VIII (FVIII) coagulation factor. It causes uncontrolled bleeding episodes, joint damage, and an increased risk of death. Current care includes regular infusions with FVIII protein to replace missing coagulation factors. This requires significant coordination and does not improve joint disease or reduce mortality risk for patients and their families.

Previous trials have shown initial success using adeno-associated viral (AAV) vector-based gene therapy to enable hemophilia A patients to express FVIII, with the goal of a one-time disease-altering therapy. The trial participants saw a marked decrease in FVIII expression over the following year. FVIII levels continued to drop in follow-up studies. This raises the possibility that gene therapy may not be able sustain FVIII expression. Despite these findings from other trials, CHOP researchers and others at other institutions such as Harvard Medical School in Australia, Penn State Hershey Medical Center in Pennsylvania, Oregon Health and Science University and Spark Therapeutics hypothesized that gene treatment-induced FVIII expression in the liver could produce safe and long-lasting levels of the clotting factors, enough to treat hemophilia B prophylactically.

In a multicenter, international trial, the researchers infused SPK-8011, a novel recombinant AAV vector engineered to produce FVIII in host liver cells, in 18 hemophilia A males (ages 18-52 years), breaking the group into four dose cohorts and following them up to four years for expression, safety, and preliminary efficacy. As previous research has shown, many patients have an immune response to the outer protective shell of the AAV vector, which causes the immune system to destroy the vector, and FVIII expression.

Of the 18 participants there were no major safety concerns. Sixteen participants maintained FVIII expression throughout the trial. Twelve of the participants were monitored for over two years. There was no decrease in FVIII activity. Overall, the men in the trial demonstrated a 91.5% reduction in bleeding episodes. However, two of the 18 participants lost expression within a year following vector administration due to a presumed immune response to the AAV vector, showing that steroids do not universally prevent a loss of expression. These data support our hypothesis of liver-directed AAV genetic therapy as a viable option for long-term hemophilia A treatment,” stated Dr. George. “Future research will aim to further improve on this work to safely achieve sustained, stable, and predictable FVIII levels in all hemophilia A patients.”

The trial was funded by Spark Therapeutics and also received support from the National Institutes of Health (NIH/NHLBI K08 HL 146991 and NIH/NHLBI K08 HL 140078). Spark Therapeutics was originally spun out of CHOP in 2013.

George LA, Monahan PE, Eyster E, Sullivan SK, Ragni MV, Croteau SE, Rask JEJ, Rech M, Samelson-Jones BJ, MacDougall A, Jaworski K, Noble R, Curran M, Kuranda K, Mingozzi F, Chang T, Reape KZ, Anguela XM, High KA. “Multiyear Factor VIII Expression After AAV Gene Transfer for Hemophilia A,” New England Journal of Medicine, November 18, 2021, DOI: 10. 1056/NEJMoa2104205


About Children’s Hospital of Philadelphia: Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Children’s Hospital is a long-standing institution that has been committed to exceptional patient care, training future generations of pediatric healthcare professionals and leading major research initiatives. This has led to many breakthroughs that have benefitted children around the world. It has the nation’s largest pediatric research program. In addition, its unique family-centered care and public service programs have brought the 595-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit

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