Clinical hematopoietic stem cell-based gene therapy

Hematopoietic stem cell (HSC)-based gene therapies have seen extraordinary progress since their initial conception, now fundamentally transforming the treatment paradigms for various inherited hematologic, immunologic, and metabolic conditions-with additional use cases under exploration. Decades worth of work with advances in viral vector technologies and cell manufacturing have paved the way for HSC gene therapy with marked improvement in the safety and efficiency of gene delivery into HSCs. These have been augmented by the recent rise of innovative genome-editing techniques, particularly using clustered regularly interspaced short palindromic repeats CRISPR-associated proteins (CRISPR-Cas)-based technologies, which have enabled more precise and reproducible genome alterations in HSCs and fostered opportunities for targeted gene modification or gene correction. These breakthroughs have led to the development of many active clinical trials and culminated in the recent federal regulatory-agency approvals of multiple clinical HSC gene therapies for various indications that are now becoming available across different geographies. These treatments aim to offer significant, long-lasting benefits to patients worldwide without the toxicities of alternative treatment approaches. This review explores the history and advancements in HSC gene therapies and provides a comprehensive overview of the latest clinical innovations and cell-therapy products. Further, it concludes with a discussion of the persistent challenges that have limited adoption and potential future opportunities that aspire to enable curative treatment of many different patients through such personalized medicines.