Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A
| Autor: | Sean M. Armour, Mallory Willet, Marti A. DiPietro, Marco Crosariol, Stephanie Kutza, Raffaella Toso, Chuansong Wang, Katherine A. High, Robert J. Davidson, Jennifer Frick, Xavier M. Anguela, Liron Elkouby, Yuhuan Wang, Giang N. Nguyen, Denise E. Sabatino, Joseph Silverberg |
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| Rok vydání: | 2022 |
| Předmět: |
optimized vectors
viruses Genetic enhancement Transgene QH426-470 codon optimization Immune system Genetics Potency Medicine Vector (molecular biology) Molecular Biology Gene QH573-671 business.industry AAV Orders of magnitude (mass) low AAV dose Capsid Immunology Molecular Medicine Original Article hemophilia A Cytology business preclinical development |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 24, Iss, Pp 20-29 (2022) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| DOI: | 10.1016/j.omtm.2021.11.005 |
| Popis: | 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 × 1012 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. Graphical Abstract The studies presented here represent the proof-of-concept work that generated the investigational agent SPK-8011, currently being evaluated in a phase 1/2 study (NCT03003533) for treatment of hemophilia A. Through a multi-pronged optimization approach, an adeno-associated viral vector capable of expressing therapeutic levels of hFVIII at the lowest possible vector dose was generated. |
| Databáze: | OpenAIRE |
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