title: Muscle Gene Therapy for Hemophilia.
abstract: Muscle-directed gene therapy for hemophilia is an attractive strategy for expression of therapeutic levels of clotting factor as evident from preclinical studies and an early phase clinical trial. Notably, local FIX expression by AAV-mediated direct intramuscular injection to skeletal muscle persists for years. Development of intravascular delivery of AAV vector approaches to skeletal muscle resulted in vector in widespread areas of the limb and increased expression of FIX in hemophilia B dogs. The use of FIX variants with improved biological activity may provide the opportunity to increase the efficacy of these approaches. Studies for hemophilia A are less developed at this point, but utilizing transgenes that improve hemostasis independent of FIX and FVIII has potential therapeutic application for both hemophilia A and B. Continuous monitoring of humoral and T cell responses to the transgene and AAV capsid in human trials will be critical for the translation of these promising approaches for muscle gene therapy for hemophilia.
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA ; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Denise E
authors.initials: DE
authors.lastname: Sabatino
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA ; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Valder R
authors.initials: VR
authors.lastname: Arruda
keywords: AAV; Gene therapy; Hemophilia; Immunology; Skeletal muscle