preparation-gene-modification-nonhuman-primate-hematopoietic-stem

Preparation and Gene Modification of Nonhuman Primate Hematopoietic Stem and Progenitor Cells

Hematopoietic stem and progenitor cell (HSPC) transplantation has been a cornerstone therapy for leukemia and other cancers for nearly half a century, ...

Fred Hutchinson Cancer Research Center

Sorting Out the Best: Enriching Hematopoietic Stem Cells for Gene Therapy and Editing.

Preclinical feasibility, safety, and efficacy testing of hematopoietic stem cell (HSC)-mediated gene therapy approaches is commonly performed in large-animal models such as nonhuman primates (NHPs). Here, we wished to determine whether mouse models would allow engraftment of NHP HSPCs, which would enable more facile and less costly evaluation of promising strategies. In this study, we comprehensively tested two mouse strains for the engraftment of NHP CD34 hematopoietic stem and progenitor cells (HSPCs). No engraftment of NHP HSPCs was observed in NSG mice, whereas the gene-humanized MISTRG model did demonstrate dose-dependent multilineage engraftment of NHP cells in the peripheral blood, bone marrow, spleen, and thymus. Most importantly, and closely mimicking the hematopoietic recovery of autologous stem cell transplantations in the NHP, only HSC-enriched CD34CD90CD45RA cell fractions engrafted and reconstituted the bone marrow stem cell niche in MISTRG mice. In summary, we here report the first "monkeynized" mouse xenograft model that closely recapitulates the autologous hematopoietic reconstitution in the NHP stem and progenitor cell transplantation and gene therapy model. The availability of this model has the potential to pre-evaluate novel HSC-mediated gene therapy approaches, inform studies in the NHP, and improve the overall outcome of large-animal experiments.

Article	Year
Sorting Out the Best: Enriching Hematopoietic Stem Cells for Gene Therapy and Editing. Molecular therapy : the journal of the American Society of Gene Therapy\| PubMed ID: 30220614	2018
MISTRG mice support engraftment and assessment of nonhuman primate hematopoietic stem and progenitor cells. Experimental hematology\| PubMed ID: 30590092	2019
Human hematopoietic stem cell maintenance and myeloid cell development in next-generation humanized mouse models. Blood advances\| PubMed ID: 30696625	2019

Stefan Radtke

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