An Open Label Dose-escalation, Multi-site, Gene Therapy Trial of a Novel Serotype 8 Capsid Pseudotyped Adeno-associated Viral Vector Encoding Factor VIII-V3 in Subjects with Haemophilia A

HUMAN CLINICAL TRIAL Primary Objective: To assess the safety of systemic administration of our novel single-stranded AAV2/8-HLP-FVIII-V3 vector in adults with severe haemophilia A over three dose levels: 6x1011, 2x1012, and 6x1012vg/kg. Secondary Objective: (1) Determine efficacy, defined as expression of hFVIII at level of > 5% (>5IU/dl) at a minimum as this is sufficient to change the bleeding phenotype from severe to mild. Our ultimate aim is to achieve stable expression of hFVIII at levels that approach normal values which range from 40-150% of physiological values. (2) Determine kinetics of hFVIII expression, (3) Describe the immune responses to the hFVIII transgene product and AAV capsid proteins following systemic administration of AAV2/8-HLP-FVIII-V3, (4) Assess changes in annualised bleed rates, (5) Assess reduction in FVIII protein concentrate usage after gene transfer (6) Describe clearance of vector from secretions/excretions. Exploratory: To investigate the impact of endogenous production of FVIII following a single administration of vector on quality of life in severe haemophilia A