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Hematopoietic stem cell (HSC) gene therapy has the potential to cure many genetic, malignant, and infectious diseases. We have shown in a nonhuman primate gene therapy and transplantation model that the CD34 + CD90 + cell fraction was exclusively responsible for multilineage engraftment and hematopoietic reconstitution. In this study, we show the translational potential of this HSC-enriched CD34 subset for lentivirus-mediated gene therapy. Alternative HSC enrichment strategies include the purification of CD133 + cells or CD38 low/- subsets of CD34 + cells from human blood products. We directly compared these strategies to the isolation of CD90 + cells using a good manufacturing practice (GMP) grade flow-sorting protocol with clinical applicability. We show that CD90 + cell selection results in about 30-fold fewer target cells in comparison to CD133 + or CD38 low/- CD34 + hematopoietic stem and progenitor cell (HSPC) subsets without compromising the engraftment potential in vivo . Single-cell RNA sequencing confirmed nearly complete depletion of lineage-committed progenitor cells in CD90 + fractions compared to alternative selections. Importantly, lentiviral transduction efficiency in purified CD90 + cells resulted in up to 3-fold higher levels of engrafted gene-modified blood cells. These studies should have important implications for the manufacturing of patient-specific HSC gene therapy and gene-engineered cell products.

Purification of Human CD34+CD90+ HSCs Reduces Target Cell Population and Improves Lentiviral Transduction for Gene Therapy