Current and emerging gene therapies for haemophilia A and B

Abstract

IntroductionAfter decades of stumbling clinical development, the first gene therapies for haemophilia A and B have been commercialized and have normalized factor (F)VIII and factor (F)IX levels in some individuals in the long term. Several other clinical programs testing adeno‐associated viral (AAV) vector gene therapy are at various stages of clinical testing.DiscussionMultiyear follow‐up in phase 1/2 and 3 studies showed long‐term and sometimes curative but widely variable and unpredictable efficacy. Liver toxicities, mostly low‐grade, occur in the 1st year in at least some individuals in all haemophilia A and B trials and are poorly understood. Wide variability and unpredictability of outcome and slow decline of FVIII levels are a major disadvantage because immune responses to AAV vectors preclude repeat dosing, which otherwise could improve suboptimal or restore declining expression, while overexpression may predispose to thrombosis. Long‐term safety outcomes will need lifelong monitoring because AAV vectors infused at high doses integrate into chromosomes at rates that raise questions about potential oncogenicity and necessitate vigilance. Alternative gene transfer systems employing gene editing and/or non‐viral vectors are under development and promise to overcome some limitations of the current state of the art for both haemophilia A and B.ConclusionsAAV gene therapies for haemophilia have now become new treatment options but not universal cures. AAV is a powerful but imperfect gene transfer platform. Biobetter FVIII transgenes may help solve some problems plaguing gene therapy for haemophilia A. Addressing variability and unpredictability of efficacy, and delivery of gene therapy to ineligible patient subgroups may require different gene transfer systems, most of which are not ready for clinical translation yet but bring innovations needed to overcome the current limitations of gene therapy.

Advancing Liver Gene Therapy: Enhanced Transduction with GalNAc-Bioconjugated rAAV Capsids

“…[3] Moreover, the sophisticated secretory apparatus of the liver provides an opportunity to express and release proteins not typically synthesized in this organ. This capability extends to the treatment of diseases or deficiencies such as hemophilia, [4] Wilson's disease, [5] alpha-1 antitrypsin deficiency, [6] or hemochromatosis. [7] Among current treatments, viral vector-based gene therapy can be mentioned.…”