title: Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates.
abstract: Farber disease is a rare lysosomal storage disorder (LSD) that manifests due to acid ceramidase (AC) deficiencies and ceramide accumulation. We present a preclinical gene therapy study for Farber disease employing a lentiviral vector (LV-huAC/huCD25) in three enzymatically normal nonhuman primates. Autologous, mobilized peripheral blood (PB) cells were transduced and infused into fully myelo-ablated recipients with tracking for at least 1 year. Outcomes were assessed by measuring the AC specific activity, ceramide levels, vector persistence/integration, and safety parameters. We observed no hematological, biochemical, radiological, or pathological abnormalities. Hematological recovery occurred by approximately 3 weeks. Vector persistence was observed in PB and bone marrow (BM) cells by qualitative and quantitative PCR. We did not observe any clonal proliferation of PB and BM cells. Importantly, AC-specific activity was detected above normal levels in PB and BM cells analyzed post-transplantation and in spleens and livers at the endpoint of the study. Decreases of ceramide in PB cells as well as in spleen and liver tissues were seen. We expect that this study will provide a roadmap for implementation of clinical gene therapy protocols targeting hematopoietic cells for Farber disease and other LSDs.
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, M5G 2M1, Canada.
authors.forename: Jagdeep S
authors.initials: JS
authors.lastname: Walia
authors.forename: Anton
authors.initials: A
authors.lastname: Neschadim
authors.forename: Orlay
authors.initials: O
authors.lastname: Lopez-Perez
authors.forename: Abdulfatah
authors.initials: A
authors.lastname: Alayoubi
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.forename: Stéphane
authors.initials: S
authors.lastname: Carpentier
authors.forename: Melissa
authors.initials: M
authors.lastname: Madden
authors.forename: Chyan-Jang
authors.initials: CJ
authors.lastname: Lee
authors.forename: Fred
authors.initials: F
authors.lastname: Cheung
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.forename: J Andrea
authors.initials: JA
authors.lastname: McCart
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D055573:Acid Ceramidase / Q000235:genetics*; D000818:Animals; D055577:Farber Lipogranulomatosis / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D016086:Lentivirus; D008253:Macaca mulatta; D008297:Male; D014161:Transduction, Genetic; D014182:Transplantation, Autologous
chemical_list: D055573:Acid Ceramidase