Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B

Miesbach, W et al, 2018, Blood

Link to abstract


Gene therapy for hemophilia B is an area of active investigation. The first trial using an adeno-associated virus (AAV) - 8 vector demonstrated durable Factor IX (F9) expression, with reduction in bleeding rates and usage of factor replacement products. However, T-cell activation in response to the viral vector led to loss of transgene, which was temporally associated with transaminitis. The AAV-5 vector has a preferential immune profile, with lower prevalence of neutralizing antibodies and an apparent lack of cellular immune response. As such, it may be a better vector for F9 gene therapy.


10 adults with Hemophilia B either on prophylactic therapy or bleeding manifestations were given a single IV infusion of AMT-060 - a codon-optimized wild-type F9 within an AAV-5 vector. Safety outcome measures included neutralizing antibodies, F9 antibodies, and treatment-related adverse events. Efficacy outcomes included use of F9 concentrates, F9 plasma levels, bleed data, and joint health scores.

Results Summary

6 participants experienced a total of 14 adverse events, most of which were mild, and three had mild elevations of liver transaminases. No patients developed any neutralizing antibodies to AAV-5 or F9. F9 activity rose in all participants and remained stable - patients in the lower-dose cohort achieved mean levels of > 2 U/dL and those in the higher-dose cohort achieved levels of >5 U/dL. Eight of the 9 patients on prophylaxis were able to stop, with a total reduction in F9 use of 79% across all participants.


This is a small cohort with a limited duration of follow up. Long term durability of the transgene remains to be determined.

Bottom Line

Utilization of the AAV-5 vector for F9 gene transfer was not associated with vector specific T-cell responses or loss of F9 activity, suggesting it may be a preferable gene delivery system.

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