Host Barriers to In Vivo HSC Gene Therapy with Helper-Dependent Adenovirus Vectors

Abstract

Ex vivo hematopoietic stem cell (HSC) gene therapy strategies have proved effective for the treatment of various diseases, with recent advances leading to the clinical approval of several cell products. To overcome issues associated with the cost and technical complexity of ex vivo strategies, we turn towards in vivo strategies that will allow us to avoid myeloablative transplantation and broaden access. Advances in the engineering of adenoviruses have made them a promising platform for the targeted in vivo delivery of gene therapy vectors to HSCs. This narrative review highlights host barriers to in vivo HSC gene therapy using helper-dependent adenovirus vectors including innate and adaptive immune responses in the blood, virus uptake and sequestration by non-target cells and tissues, difficulty accessing the bone marrow niche, and the inefficient targeting of quiescent HSCs. We present recent advances aimed at overcoming these barriers including immune modulation and vector engineering strategies, improved predictive models, novel HSC targeting strategies, and enrichment of modified HSCs. This forward-looking review highlights a path towards achieving the clinical translation of predictable, safe and accessible in vivo adenovirus-mediated HSC gene therapies.