Gene therapy for Haemophilia A; version 1
Research type
Research Study
Full title
GO-8: Gene therapy for haemophilia A using a novel serotype 8 capsid pseudotyped adeno-associated viral vector encoding Factor VIII-V3
IRAS ID
207751
Contact name
Pratima Chowdary
Contact email
Sponsor organisation
University College London (UCL)
Eudract number
2016-000925-38
Duration of Study in the UK
16 years, 11 months, 30 days
Research summary
This application focuses on assessing safety and efficacy of gene therapy for patients with severe haemophilia A, an x-linked, life threatening bleeding disorder arising from defects in the coagulation factor VIII (FVIII) gene. Current treatment for haemophilia A, the commonest inherited bleeding disorder (prevalence of 1 in 5000 individuals) consists of life-long, 2-3X/week, intravenous injection of clotting factor concentrates, which is demanding, exceedingly expensive not widely available nor curative. In contrast, gene therapy offers the potential of a cure for haemophilia A as illustrated by our first unequivocal success in a related condition, haemophilia B. In that study we showed that a single intravenous administration of a serotype 8 based adeno-associated virus, (AAV8) vector encoding the factor IX (FIX) gene resulted in stable (>6 years) therapeutic expression of FIX without long-lasting toxicity. We plan to use the same AAV8 platform to evaluate a novel FVIII expression cassette, AAV2/8-HLP-FVIII-V3, in patient with haemophilia A. Extensive preclinical studies demonstrate that AAV2/8-HLP-FVIII-V3 leads to long-term, endogenous expression of FVIII in mouse and non-human primate models without toxicity even when fifty-fold higher doses than the proposed starting clinical trial dose were used. Therefore, an open label, Phase I/II dose escalation study entailing a single systemic administration of AAV2/8-HLP-FVIII-V3 in adults (>18 years of age) with severe haemophilia A who have baseline factor FVIII levels of <1% of normal has been designed to establish safety and efficacy of our approach. Dosing will begin at 6x10^11 vector genome (vg)/kg progressing sequentially to 2x10^12vg/kg and ultimately 6x10^12vg/kg in the absence of toxicity. A minimum of 2 patients will be recruited at each dose with a possibility of expanding the dose cohort to a maximum of 6 patients based on safety and efficacy. The study duration for each patient will be 15 years after vector infusion.
REC name
South Central - Oxford A Research Ethics Committee
REC reference
16/SC/0537
Date of REC Opinion
4 Jan 2017
REC opinion
Further Information Favourable Opinion