Muczynski, Vincent; Christophe, Olivier D; Tanner, Lewis; Vayssiere, Charlotte; Guérin, Alice; Casari, Caterina; McIntosh, Jenny Hazel; ... Nathwani, Amit C; + view all Muczynski, Vincent; Christophe, Olivier D; Tanner, Lewis; Vayssiere, Charlotte; Guérin, Alice; Casari, Caterina; McIntosh, Jenny Hazel; Lee, Doyoung; Ling, Gavin; Gohil, Satyen Harish; Lenting, Peter J; Tuddenham, Edward G; Nathwani, Amit C; - view fewer (2025) Alternative AAV gene therapy for hemophilia A using expression of Bi8, a novel single-chain FVIII-mimetic antibody. Blood , Article blood.2024027709. 10.1182/blood.2024027709.

Text 1-s2.0-S0006497125023031-main.pdf - Accepted Version Access restricted to UCL open access staff until 23 September 2026. Download (5MB)

Abstract

The recent approval of adeno-associated virus (AAV)-based gene therapies for haemophilia A (HA) represents a major advancement in the management of this X-linked bleeding disorder, offering multi-year bleed protection and improved quality of life over factor VIII (FVIII) replacement. However, challenges remain-including concerns over long-term durability of expression and the difficulty of packaging the oversized FVIII transgene into AAV vectors. To address these limitations, we developed AAV8-Bi8, a liver-directed gene therapy encoding Bi8, a novel 54.5 kDa FVIII mimetic antibody. Bi8 is expressed as a compact, single-chain tandem scFv and is delivered via a 4.4 kb expression cassette packaged within AAV8 capsids-well within the vector packaging capacity. In vitro, Bi8 demonstrated FVIII mimetic activity and effectively corrected FVIII-deficient human plasma to levels comparable with emicizumab, the current market standard. In vivo, a single administration of AAV8-Bi8 in FVIII-deficient mice resulted in dose-dependent, durable expression of Bi8, complete phenotypic correction of bleeding, and therapeutic equivalence to both emicizumab-treated and wild-type animals. Importantly, no toxicity or anti-drug antibody responses were observed. This approach, based on delivering FVIII mimetic antibodies through AAV rather than truncated FVIII transgenes, could provide a more flexible and efficient platform for gene therapy in haemophilia A. AAV8-Bi8 has the potential to offer sustained, life-long haemostatic control, including in patients who have developed inhibitors to FVIII.

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