PharmacologyTier 2Medical Sciences concept

Gene therapy in haemophilia (Factor IX Padua, AAV vectors)

Core concept

AAV (adeno-associated virus) vector delivers a functional clotting factor gene to hepatocytes - a single infusion aims for sustained endogenous factor production
Haemophilia B: uses Factor IX Padua (R338L) - a hyperactive natural variant with ~5-8x normal specific activity, achieving therapeutic levels at a lower vector dose
Haemophilia A: delivers a B-domain-deleted factor VIII gene (full-length factor VIII is too large for AAV packaging capacity)

The vector remains episomal (does not integrate into the genome) in hepatocytes - durable in non-dividing cells, but expression could theoretically decline over years/decades
Pre-existing anti-AAV antibodies (from natural viral exposure) exclude a substantial proportion of patients from eligibility - screened for before treatment
Transient transaminitis is common post-infusion, managed with corticosteroids; if severe/prolonged it can blunt transgene expression

Approved gene therapies exist for haemophilia A (valoctocogene roxaparvovec) and haemophilia B (etranacogene dezaparvovec) - one-time treatment, though durability is still being characterised long-term
Not currently suitable for inhibitor-positive patients or those with significant pre-existing liver disease
Reframes management from lifelong prophylactic infusions toward a single definitive intervention

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