The future of hematopoietic stem cell and stem cell gene therapy for metabolic diseases

Over the past four decades, significant advances in stem cell transplantation (SCT) have expanded its use in metabolic diseases. The therapeutic efficacy of SCT relies on the capacity of hematopoietic stem and progenitor cells (HSPCs) and their committed progeny to engraft, migrate, and differentiate within target tissues including the liver, spleen, bone, and hematopoietic system, thereby serving as a continuous source of functional enzyme for cross-correction of enzyme-deficient cells. Within the central nervous system, donor-derived cells can differentiate into microglia, enabling partial correction of neurological pathology. Long-term outcomes of SCT in metabolic diseases vary according to the underlying disorder and the extent to which transplantation can arrest or modify disease progression, with differential responses observed across organ systems. Despite its benefits, SCT is limited by transplant-related morbidity and mortality, as well as restricted access to suitable HLA-matched donors. Recent technological advances have led to the emergence of autologous hematopoietic stem cell gene therapy (HSC-GT) as a promising alternative therapeutic strategy for several metabolic diseases, with encouraging early clinical outcomes. In this narrative review, we evaluate the present landscape of SCT and the evolving role of autologous HSC-GT in the treatment of metabolic diseases, and highlight the key challenges that must be addressed to advance future applications.