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Published on: September 30, 2021
Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A
Lindsey A George1, Paul E Monahan1, M Elaine Eyster1
1From the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania (L.A.G., B.J.S.-J.), the Division of Hematology and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia (L.A.G., B.J.S.-J.), and Spark Therapeutics (P.E.M., A.M., K.J., R.N., M.C., K.K., F.M., T.C., K.Z.R., X.M.A., K.A.H.), Philadelphia, the Department of Medicine, Division of Hematology and Oncology, Penn State Health Milton S. Hershey Medical Center, Hershey (M.E.E.), and the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.) - all in Pennsylvania; the Department of Pediatrics, Division of Hematology, Mississippi Center for Advanced Medicine, Madison (S.K.S.); the Department of Pediatrics, Harvard Medical School, and the Division of Hematology and Oncology, Boston Children's Hospital - both in Boston (S.E.C.); the Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, and the Gene and Stem Cell Therapy Program, Centenary Institute, Faculty of Medicine and Health, University of Sydney - both in Camperdown, NSW, Australia (J.E.J.R.); the Hemophilia Center, Oregon Health and Science University, Portland (M.R.); and the American Thrombosis and Hemostasis Network, Rochester, NY (M.R.).
Gene therapy using SPK-8011 in hemophilia A patients demonstrated sustained Factor VIII expression in most participants, significantly reducing bleeding episodes. This offers a promising new treatment avenue with manageable safety profiles.
Area of Science:
- * Gene Therapy
- * Hematology
- * Virology
Background:
- * Hemophilia A gene therapy aims for long-term, stable Factor VIII expression to reduce bleeding.
- * Adeno-associated viral (AAV) vectors are investigated for delivering therapeutic genes.
- * Achieving therapeutic Factor VIII levels with minimal vector dose is a key objective.
Purpose of the Study:
- * To evaluate the safety and preliminary efficacy of SPK-8011 gene therapy in hemophilia A patients.
- * To assess the expression and durability of Factor VIII following AAV vector infusion.
- * To determine the optimal vector dose for sustained therapeutic benefit.
Main Methods:
- * Phase 1-2 trial involving 18 men with hemophilia A receiving SPK-8011 AAV vector.
- * Four dose cohorts ranging from 5x10^11 to 2x10^12 vector genomes per kilogram.
- * Monitoring of Factor VIII expression, bleeding rates, and adverse events, with some participants receiving glucocorticoids.
Main Results:
- * Sustained Factor VIII expression was maintained in 16 of 18 participants over a median follow-up of 36.6 months.
- * A significant 91.5% reduction in annualized bleeding rate was observed post-treatment.
- * Two participants experienced loss of Factor VIII expression due to an anti-AAV immune response.
Conclusions:
- * SPK-8011 gene therapy led to sustained Factor VIII expression and reduced bleeding in most hemophilia A patients.
- * Treatment allowed for discontinuation of prophylaxis and demonstrated a favorable safety profile.
- * This study highlights the potential of AAV-mediated gene therapy for hemophilia A management.
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