title: Gene Editing of Human Hematopoietic Stem and Progenitor Cells: Promise and Potential Hurdles.
abstract: Hematopoietic stem and progenitor cells (HSPCs) have great therapeutic potential because of their ability to both self-renew and differentiate. It has been proposed that, given their unique properties, a small number of genetically modified HSPCs could accomplish lifelong, corrective reconstitution of the entire hematopoietic system in patients with various hematologic disorders. Scientists have demonstrated that gene addition therapies-targeted to HSPCs and using integrating retroviral vectors-possess clear clinical benefits in multiple diseases, among them immunodeficiencies, storage disorders, and hemoglobinopathies. Scientists attempting to develop clinically relevant gene therapy protocols have, however, encountered a number of unexpected hurdles because of their incomplete knowledge of target cells, genomic control, and gene transfer technologies. Targeted gene-editing technologies using engineered nucleases such as ZFN, TALEN, and/or CRISPR/Cas9 RGEN show great clinical promise, allowing for the site-specific correction of disease-causing mutations-a process with important applications in autosomal dominant or dominant-negative genetic disorders. The relative simplicity of the CRISPR/Cas9 system, in particular, has sparked an exponential increase in the scientific community's interest in and use of these gene-editing technologies. In this minireview, we discuss the specific applications of gene-editing technologies in human HSPCs, as informed by prior experience with gene addition strategies. HSPCs are desirable but challenging targets; the specific mechanisms these cells evolved to protect themselves from DNA damage render them potentially more susceptible to oncogenesis, especially given their ability to self-renew and their long-term proliferative potential. We further review scientists' experience with gene-editing technologies to date, focusing on strategies to move these techniques toward implementation in safe and effective clinical trials.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Kyung-Rok
authors.initials: KR
authors.lastname: Yu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Hannah
authors.initials: H
authors.lastname: Natanson
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health , Bethesda, Maryland.
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
mesh_terms: D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D000072669:Gene Editing / Q000379:methods*; D015316:Genetic Therapy; D005822:Genetic Vectors; D015894:Genome, Human; D006402:Hematologic Diseases / Q000235:genetics / Q000628:therapy*; D006412:Hematopoietic Stem Cells; D006801:Humans; D033581:Stem Cell Transplantation; D013234:Stem Cells