Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A.

Autor:	Elkouby L; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Colket Translational Research Building, Rm 5020, Philadelphia, PA 19104, USA.; Spark Therapeutics, Inc., Philadelphia, PA, USA., Armour SM; Spark Therapeutics, Inc., Philadelphia, PA, USA., Toso R; Spark Therapeutics, Inc., Philadelphia, PA, USA., DiPietro M; Spark Therapeutics, Inc., Philadelphia, PA, USA., Davidson RJ; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Colket Translational Research Building, Rm 5020, Philadelphia, PA 19104, USA., Nguyen GN; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Colket Translational Research Building, Rm 5020, Philadelphia, PA 19104, USA., Willet M; Spark Therapeutics, Inc., Philadelphia, PA, USA., Kutza S; Spark Therapeutics, Inc., Philadelphia, PA, USA., Silverberg J; Spark Therapeutics, Inc., Philadelphia, PA, USA., Frick J; Spark Therapeutics, Inc., Philadelphia, PA, USA., Crosariol M; Spark Therapeutics, Inc., Philadelphia, PA, USA., Wang Y; Spark Therapeutics, Inc., Philadelphia, PA, USA., Wang C; Spark Therapeutics, Inc., Philadelphia, PA, USA., High KA; Spark Therapeutics, Inc., Philadelphia, PA, USA., Sabatino DE; The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Colket Translational Research Building, Rm 5020, Philadelphia, PA 19104, USA.; Division of Hematology, Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA., Anguela XM; Spark Therapeutics, Inc., Philadelphia, PA, USA.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2021 Nov 24; Vol. 24, pp. 20-29. Date of Electronic Publication: 2021 Nov 24 (Print Publication: 2022).
DOI:	10.1016/j.omtm.2021.11.005
Abstrakt:	Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011 , currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 10 12 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic. Competing Interests: S.M.A., R.T., M.D., M.W., S.K., J.S., J.F., M.C., Y.W., C.W., L.E., K.A.H., and X.M.A. are current or former employees of Spark Therapeutics. K.A.H., X.M.A., L.E., and D.E.S. are inventors on issued and pending patents related to AAV viral vectors for which they have received royalty payments. (© 2021 The Authors.)
Databáze:	MEDLINE
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