Past, present and future of haemophilia gene therapy: From vectors and transgenes to known and unknown outcomes

Since the 1960s, the pace of innovation in haemophilia treatment has been fast and furious and occasionally with unintended consequences. As newer technologies are harnessed to better treat, and potentially cure, haemophilias A and B, an understanding of their underlying scientific principles and their benefits and risks are essential for all stakeholders. This review summarizes the starts and stops of introducing FVIII and FIX transgenes clinically, beginning 20 years ago. Lessons from earlier nonclinical and clinical experiments have been utilized to improve vector selection, vector design, promoter/enhancer cis control regions and codon-optimized transgenes to trigger in vivo clinical FVIII and FIX levels in the near-normal to normal ranges. Many known and unknown questions remain, and some, based upon benefit and risk, should be answered during larger phase 3 clinical trials. Prior clinical outcomes in haemophilia trials have not been standardized, making between-trial comparisons difficult. Going forward, haemophilia gene therapy clinical trials should utilize a standard set of core outcomes, to facilitate comparisons to other gene- and protein-based therapies. These outcomes will be more important as the field moves beyond the first-generation gene therapies into more complex vectors that may address the shortcomings of first-generation vectors and offer greater benefits to the patient.