Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

Abstract

Abstract Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life-threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM-funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit. Significance statement Hematopoietic stem cell transplantation (HSCT) is commonly used to treat leukemias and severe disorders of the blood and immune system, but it has not been possible to extend HSCT to many patients in need of transplant, or into various new areas of disease that might benefit. This vast, untapped potential results from inadequate sources of healthy, immune-compatible stem cells for transplant, technological barriers to efficient engraftment, and the significant health risks associated with the HSCT procedure itself. This Perspective elaborates on current limitations of HSCT and describes novel strategies to overcome them, including key innovations developed with support from the California Institute for Regenerative Medicine. Addressing these challenges could greatly expand the feasibility and accessibility of HSCT to all who might benefit, and enable HSCT to serve as a leading paradigm for developing new stem cell-based therapies in the future.