New gene therapy for hemophilia has led to

image: Lindsey A. George, MD, lead study author and attending hematologist at Children’s Hospital of Philadelphia
seen Following

Credit: Children’s Hospital of Philadelphia

Philadelphia, November 18, 2021—According to a new study by researchers at Children’s Hospital of Philadelphia (CHOP). The results of the phase 1/2 trial, which were published today in the New England Journal of Medicine, are the first to demonstrate the stability of coagulation factor VIII in patients with hemophilia A after gene therapy.

“The results of this study provide convincing data to support the current approach to transfer of hemophilia A genes which may indeed confer stable expression of factor VIII over several years for an enhancing effect close to disease, ”said lead study author Lindsey A. George, MD, clinical director of In Vivo Gene Therapy and attending physician in the hematology division of the Children’s Hospital of Philadelphia, as well as researcher principal of the phase 1/2 study sponsored by Spark Therapeutics. “These data build on the history of decades of hemophilia gene therapy research at Children’s Hospital of Philadelphia, which has sought to provide curative therapies to these patients.”

Hemophilia A is the most common inherited hemorrhagic disease, affecting 1 in 5,000 men worldwide. The disease is the result of a missing clotting factor known as factor VIII (FVIII), which leads to uncontrolled bleeding episodes, crippling joint disease and an increased risk of death. The current standard of care involves regular infusions of the FVIII protein to replace the missing clotting factor, which involves significant coordination of daily activities and does not improve the risk of joint disease or death for patients and families.

Previous trials have shown initial success using adeno-associated viral vector (AAV) gene therapy to enable patients with hemophilia A to express FVIII, with the goal of a single therapy to modify sickness. However, trial participants experienced an unexpected and marked decline in FVIII expression after one year, and FVIII levels continued to decline in follow-up studies, raising the possibility that gene therapy might not. is unable to provide sustained expression of FVIII.

Despite these results from other trials, researchers at CHOP and their colleagues at other institutions, including Harvard Medical School, University of Sydney in Australia, University of Pittsburgh, Penn State Hershey Medical Center, Oregon Health and Science University and Spark Therapeutics hypothesized that gene therapy induced expression of FVIII in the liver can produce safe and long-lasting levels of clotting factor sufficient to treat hemophilia A prophylactically.

In an international multicenter trial, researchers infused SPK-8011, a novel recombinant AAV vector designed to produce FVIII in host liver cells, in 18 men with hemophilia A (aged 18 to 52), dividing the group into four Dose and subsequent cohorts up to four years for expression, safety and preliminary efficacy. Most of the participants received steroids in conjunction with experimental gene therapy, as previous research has shown that many patients develop an immune response to the outer protective envelope of the AAV vector, causing the vector to be cleared by the immune system. and, in turn, the expression of FVIII.

Of the 18 participants, there were no major safety concerns. Sixteen participants maintained FVIII expression throughout their participation in the trial. Twelve of these participants were followed for more than two years and found no apparent decrease in FVIII activity over time. Overall, the men in the trial demonstrated a 91.5% reduction in bleeding episodes. However, two of the 18 participants lost their expression within a year of administration of the vector due to a suspected immune response to the AAV vector, showing that steroids do not universally prevent loss of expression.

“These data support our hypothesis that liver-directed AAV gene therapy is a viable approach for the long-term treatment of hemophilia A,” said Dr. George. “Future research will aim to further improve this work to safely achieve sustained, stable and predictable levels of FVIII in all patients with hemophilia A.”

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 created 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. “Multiannual expression of factor VIII after transfer of the AAV gene for hemophilia A”, New England Journal of Medicine, November 18, 2021, DOI: 10.1056 / NEJMoa2104205


About Philadelphia Children’s Hospital: The Children’s Hospital of Philadelphia was founded in 1855 as the country’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric health professionals, and initiating major research initiatives, the Children’s Hospital has fostered many discoveries that have benefited children around the world. whole. Its pediatric research program is one of the largest in the country. In addition, its unique family-centered care and public service programs have earned the 595-bed hospital a reputation as a leading advocate for children and youth. For more information visit

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