International Society for Cell & Gene Therapy Stem Cell Engineering Committee report on the current state of hematopoietic stem and progenitor cell-based genomic therapies and the challenges faced.

Genetic manipulation of hematopoietic stem cells (HSCs) is being developed as a therapeutic strategy for several inherited disorders. This field is rapidly evolving with several novel tools and techniques being employed to achieve desired genetic changes. While commercial products are now available for sickle cell disease, transfusion-dependent β-thalassemia, metachromatic leukodystrophy and adrenoleukodystrophy, several challenges remain in patient selection, HSC mobilization and collection, genetic manipulation of stem cells, conditioning, hematologic recovery and post-transplant complications, financial issues, equity of access and institutional and global preparedness. In this report, we explore the current state of development of these therapies and provide a comprehensive assessment of the challenges these therapies face as well as potential solutions.
Competing Interests: Declaration of competing interest Ashish Gupta is a site principal investigator at University of Minnesota for clinical trials in genome editing for sickle cell disease sponsored by Bluebird Bio (NCT04293185) and Beam Therapeutics (NCT05456880). He is also the site principal investigator at University of Minnesota for clinical trials in genome editing for Hurler syndrome (NCT06149403). He has received consultancy fees from Vertex Pharmaceuticals and is on speaker bureau for Emerging Therapies Solutions. He also has research funding from Jazz Pharmaceuticals for an investigator initiated trial. Akshay Sharma has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics and Editas Medicine. He is a medical monitor for an RCI BMT clinical trial for which he receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. Akshay Sharma is also the St. Jude Children's Research Hospital site principal investigator for clinical trials of genome editing for sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907) and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trials, which includes salary support paid to the investigator's institution. Akshay Sharma has no direct financial interest in these therapies. Jaap Jan Boelens has received consultant fees from Sanofi, Sobi, Merck, Immusoft and Smart Immune, is the MSKCC site PI for Novartis Pharmaceuticals (NCT04443907) and received research funding from Sanofi (for investigator-initiated research). Jaap Jan Boelens is also the chair of an independent data safety monitoring board (for bluebird bio gene therapy trials), for which he receives compensation (CRO; Advanced Clinical). Susan Prockop has received support for the conduct of clinical trials from AlloVir, Atara, and Jasper through Boston Children's Hospital. She has received an honorarium from Pierre Fabre and Regeneron and consults for CellEvolve, Smart Immune and Century. She has IP related to the implementation of third-party viral-specific T cells, with all rights assigned to Memorial Sloan Kettering Cancer Center. Chrystal U. Louis has equity in and is an employee of TScan Therapeutics. The other authors have nothing to disclose.
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