Gene Editing of Human Hematopoietic Stem and Progenitor Cells: Promise and Potential Hurdles

Hum Gene Ther. 2016 Oct;27(10):729-740. doi: 10.1089/hum.2016.107. Epub 2016 Aug 2.


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.

Publication types

  • Review
  • Research Support, N.I.H., Intramural

MeSH terms

  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Gene Editing / methods*
  • Genetic Therapy
  • Genetic Vectors
  • Genome, Human
  • Hematologic Diseases / genetics
  • Hematologic Diseases / therapy*
  • Hematopoietic Stem Cells*
  • Humans
  • Stem Cell Transplantation
  • Stem Cells*