Haematopoietic stem cell gene therapy in inborn errors of metabolism.

Over the last 30 years, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been adopted as a therapeutic strategy for many inborn errors of metabolism (IEM), due to the ability of donor-derived cells to provide life-long enzyme delivery to deficient tissues and organs. However, (a) the clinical benefit of allo-HSCT is limited to a small number of IEM, (b) patients are left with a substantial residual disease burden and (c) allo-HSCT is still associated with significant short- and long-term toxicities and transplant-related mortality. Haematopoietic stem/progenitor cell gene therapy (HSPC-GT) was established in the 1990s for the treatment of selected monogenic primary immunodeficiencies and over the past few years, its use has been extended to a number of IEM. HSPC-GT is particularly attractive in neurodegenerative IEM, as gene corrected haematopoietic progenitors can deliver supra-physiological enzyme levels to difficult-to-reach areas, such as the brain and the skeleton, with potential increased clinical benefit. Moreover, HSPC-GT is associated with reduced morbidity and mortality compared to allo-HSCT, although this needs to be balanced against the potential risk of insertional mutagenesis. The number of clinical trials in the IEM field is rapidly increasing and some HSPC-GT products recently received market approval. This review describes the development of ex vivo HSPC-GT in a number of IEM, with a focus on recent results from GT clinical trials and risks versus benefits considerations, when compared to established therapeutic strategies, such as allo-HSCT.