The interdependence between biological and ethical analyses of safety and efficacy in translational gene therapy

Abstract

This research project stems from the successful clinical trials of gene therapy for X-linked severe combined immunodeficiency (SCID-X1). The development of leukaemia in 5 of 20 patients highlighted both the need for safer vectors and the challenge of assessing uncertain risks in translational research. To address these technological and ethical challenges, this project adopted a unique, interdisciplinary approach. The molecular, laboratory-based component of this project examined the impact of vector design on safety and efficacy using a murine model of SCID-X1 gene therapy. A less transcriptionally-active promoter-enhancer was associated with reduced lymphocyte reconstitution, but not with an elevated risk of lymphomagenesis caused by proliferative stress. Additionally, this project explored the feasibility of vector barcoding coupled with next generation sequencing analysis for measuring clonal complexity. Using analyses of defined barcode mixtures, it was possible to resolve true barcodes from sequencing error for samples containing 1 or 10 barcodes, but not 100 barcodes. Therefore, the resolvable degree of library complexity was insufficient to be clinically useful. Finally, the ethical, social sciences-based component of this project investigated how gene therapy researchers assess risks and found that decision-making is influenced by both the severity of disease and the strength of the available preclinical evidence.