UM171 Enhances Lentiviral Gene Transfer and Recovery of Primitive Human Hematopoietic Cells

Mor Ngom; Suzan Imren; Tobias Maetzig; Jennifer E Adair; David J H F Knapp; Jalila Chagraoui; Iman Fares; Marie-Eve Bordeleau; Guy Sauvageau; Philippe Leboulch; Connie Eaves; Richard Keith Humphries

doi:10.1016/j.omtm.2018.06.009

UM171 Enhances Lentiviral Gene Transfer and Recovery of Primitive Human Hematopoietic Cells

Mol Ther Methods Clin Dev. 2018 Jul 5:10:156-164. doi: 10.1016/j.omtm.2018.06.009. eCollection 2018 Sep 21.

Authors

Mor Ngom¹, Suzan Imren¹, Tobias Maetzig¹, Jennifer E Adair², David J H F Knapp¹, Jalila Chagraoui³, Iman Fares³, Marie-Eve Bordeleau³, Guy Sauvageau³, Philippe Leboulch^{4

5}, Connie Eaves^{1

6

7}, Richard Keith Humphries^{1

7}

Affiliations

¹ Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver BC V5Z 1L3, Canada.
² Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
³ Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC H3T 1J4, Canada.
⁴ Atomic and Alternative Energy Commission, Université Paris-Sud, Fontenay-aux-Roses, Paris, France.
⁵ Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Medical Genetics, University of British Columbia, Vancouver BC V6T 1Z4, Canada.
⁷ Department of Medicine, University of British Columbia, Vancouver BC V6T 1Z4, Canada.

Abstract

Enhanced gene transfer efficiencies and higher yields of transplantable transduced human hematopoietic stem cells are continuing goals for improving clinical protocols that use stemcell-based gene therapies. Here, we examined the effect of the HSC agonist UM171 on these endpoints in both in vitro and in vivo systems. Using a 22-hr transduction protocol, we found that UM171 significantly enhances both the lentivirus-mediated transduction and yield of CD34⁺ and CD34⁺CD45RA^- hematopoietic cells from human cord blood to give a 6-fold overall higher recovery of transduced hematopoietic stem cells, including cells with long-term lympho-myeloid repopulating activity in immunodeficient mice. The ability of UM171 to enhance gene transfer to primitive cord blood hematopoietic cells extended to multiple lentiviral pseudotypes, gamma retroviruses, and non-integrating lentiviruses and to adult bone marrow cells. UM171, thus, provides an interesting reagent for improving the ex vivo production of gene-modified cells and for reducing requirements of virus for a broad range of applications.

Keywords: gene transfer; hematopoietic stem cells; lentivirus.