Gene Editing of Monogenic Disorders in Human Hematopoietic Stem Cells

Tech ID: 29442 / UC Case 2018-372-0


Researchers at the UCLA Department of Microbiology, Immunology & Molecular Genetics have developed novel methods to achieve efficient, precise gene integration and effective expression of cDNA cassettes to express normal versions of genes in hematopoietic stem cells.


Hematopoietic stem cells (HSCs) have great therapeutic potential because of their ability to both self-renew and differentiate. A small number of genetically modified HSCs could achieve lifelong, corrective reconstitution of the entire hematopoietic system in patients with various hematologic disorders. Many severe primary immune deficiencies (PIDs) are due to defects in lymphoid or hematopoietic cells that can be reconstituted through hematopoietic stem cell transplantation (HSCT). Unlike allogeneic HSCT, gene therapy using autologous HSCs has potential advantages from the absence of graft-versus-host disease and the less intense conditioning and immune suppression needed. Lentiviruses were the most widely used viral vectors to safely and effectively deliver a transgene of interest into HSCs for gene therapy. However, even though lentiviruses have been improved with lower risk of genotoxicity and increased safety compared with gammaretroviruses, lentivirus-based HSC gene therapy can still theoretically result in toxicity due to dysregulated transgene expression or residual genotoxicity.

 HSC-targeted gene editing technologies using engineered nucleases such as CRISPR/Cas9, allow for the site-specific correction of disease-causing mutations and have shown promising clinical benefits in multiple diseases. The ability to correct specific disease-causing mutations, rather than simply deliver a normal gene, extends the potential applications of gene therapy to dominant disorders in addition to those resulting from simple loss-of-function mutations.


Researchers at UCLA have defined optimal design features of homologous donors (cDNA expression cassettes and homology arms) and CRISPR/Cas9 target sites for more efficient, precise gene integration, and effective expression of cDNA cassettes to express normal versions of genes in hematopoietic stem cells. The optimization will help minimize both targeted-re-cutting by nuclease and illegitimate recombination, and allow precise control of transgene expression to the highest level.


  • Gene therapy of hemoglobinopathies (i.e., sickle cell disease, beta-thalassemia) 
  • Gene therapy of immune deficiencies (i.e., different genetic forms of severe combined immunodeficiency, X-linked Hyper IgM Syndrome, X-linked agammaglobulinemia, common variable immune deficiency, chronic granulomatous disease, Wiskott–Aldrich syndrome, hemophagocytic lymphohistiocytosis, leukocyte adhesion deficiency) 
  • Gene therapy of storage and metabolic diseases (i.e., Gaucher, Hurler’s, Hunters, San Filipo, etc.)


  • More efficient and effective gene editing 
  • Better expression of inserted transgenes

State Of Development

The method has been tested in vitro.

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  • Kohn, Donald B.

Other Information


hematopoietic stem cell, gene editing, CRISPR/Cas9, gene therapy

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