Preclinical Evaluation of Foamy Virus Vector-Mediated Gene Addition in Human Hematopoietic Stem/Progenitor Cells for Correction of Leukocyte Adhesion Deficiency Type 1

Hum Gene Ther. 2022 Dec;33(23-24):1293-1304. doi: 10.1089/hum.2022.065. Epub 2022 Nov 1.

Abstract

Ex vivo gene therapy procedures targeting hematopoietic stem and progenitor cells (HSPCs) predominantly utilize lentivirus-based vectors for gene transfer. We provide the first pre-clinical evidence of the therapeutic utility of a foamy virus vector (FVV) for the genetic correction of human leukocyte adhesion deficiency type 1 (LAD-1), an inherited primary immunodeficiency resulting from mutation of the β2 integrin common chain, CD18. CD34+ HSPCs isolated from a severely affected LAD-1 patient were transduced under a current good manufacturing practice-compatible protocol with FVV harboring a therapeutic CD18 transgene. LAD-1-associated cellular chemotactic defects were ameliorated in transgene-positive, myeloid-differentiated LAD-1 cells assayed in response to a strong neutrophil chemoattractant in vitro. Xenotransplantation of vector-transduced LAD-1 HSPCs in immunodeficient (NSG) mice resulted in long-term (∼5 months) human cell engraftment within murine bone marrow. Moreover, engrafted LAD-1 myeloid cells displayed in vivo levels of transgene marking previously reported to ameliorate the LAD-1 phenotype in a large animal model of the disease. Vector insertion site analysis revealed a favorable vector integration profile with no overt evidence of genotoxicity. These results coupled with the unique biological features of wild-type foamy virus support the development of FVVs for ex vivo gene therapy of LAD-1.

Keywords: foamy virus; hematopoietic stem and progenitor cells; leukocyte adhesion deficiency type 1; β2 integrin.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD34 / genetics
  • CD18 Antigens / genetics
  • Genetic Vectors / genetics
  • Hematopoietic Stem Cells
  • Humans
  • Leukocyte-Adhesion Deficiency Syndrome* / genetics
  • Leukocyte-Adhesion Deficiency Syndrome* / therapy
  • Mice
  • Spumavirus* / genetics

Substances

  • CD18 Antigens
  • Antigens, CD34

Supplementary concepts

  • Leukocyte adhesion deficiency type 1