Due to donor-derived cells’ capacity to deliver enzymes to enzyme-deficient tissues and organs for the rest of one’s life, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become widely used as a therapeutic approach for many inborn errors of metabolism (IEM) over the past 30 years. However, patients who have IEM were the only ones who could clinically benefit from allo-HSCT, patients still had a large burden from their residual illness, and allo-HSCT was still linked to severe short- and long-term toxicities as well as transplant-related death.

In the 1990s, hematopoietic stem/progenitor cell gene therapy (HSPC-GT) was developed for the treatment of a few monogenic primary immunodeficiencies, and in recent years, its use has expanded to include a number of IEM. Gene-corrected hematopoietic progenitors could provide supra-physiological enzyme levels to hard-to-reach regions, such as the brain and skeleton, with a possible improved therapeutic effect. This made HSPC-GT particularly appealing in neurodegenerative IEM.

Furthermore, HSPC-GT had lower rates of morbidity and death than allo-HSCT, albeit it must be weighed against the chance of insertional mutagenesis. Clinical trials in the IEM sector were multiplying quickly, and certain HSPC-GT items had just lately been given the go-ahead. In contrast to tried-and-true treatment approaches like allo-HSCT, the review discussed the development of ex vivo HSPC-GT in a variety of IEM with an emphasis on current findings from GT clinical trials and risks vs. benefits considerations.

Reference: onlinelibrary.wiley.com/doi/10.1111/bjh.18179