Promises and Challenges in Hematopoietic Stem Cell Gene Therapy

Hematopoietic stem cell-directed gene therapy (HSC-GT) provides an innovative treatment option for hematological disorders. Gene therapy promises to cure the disease "at the root" and is therefore exceptional in its potential, but also formidable in its challenges, as long-term side effects are hard to predict and clinical experience remains limited. Many excellent reviews on the topic by designated experts in the field of HSC-GT have come forth, elucidating the successes and pitfalls in the various clinical studies. This review attempts to discuss what we understand from those studies to represent current state of the art with respect to vectors, stem cell transduction, and pretransplant preparatory regimes, what limitations may remain, and which types of diseases may be more suited for HSC-GT than others (targets). We thus discuss the available vector platforms (tools) and preclinical/clinical and basic research (tricks) that contribute to our current understanding of HSC-GT, as well as some overarching principles we can conclude from these. The field has also learned from previous shortcomings, although some of the major concerns of the past, specifically insertional mutagenesis, may not be of relevance for future trials. This very positive development in HSC-GT, however, has to compete with the improvements in hematopoietic stem cell transplantation or enzyme-replacement therapy, leaving a narrow margin for gene therapy.