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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.
AuthorsJagdeep S Walia, Anton Neschadim, Orlay Lopez-Perez, Abdulfatah Alayoubi, Xin Fan, Stéphane Carpentier, Melissa Madden, Chyan-Jang Lee, Fred Cheung, David A Jaffray, Thierry Levade, J Andrea McCart, Jeffrey A Medin
JournalHuman gene therapy (Hum Gene Ther) Vol. 22 Issue 6 Pg. 679-87 (Jun 2011) ISSN: 1557-7422 [Electronic] United States
PMID21280983 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Acid Ceramidase
Topics
  • Acid Ceramidase (genetics)
  • Animals
  • Farber Lipogranulomatosis (therapy)
  • Genetic Therapy (methods)
  • Genetic Vectors
  • Hematopoietic Stem Cell Transplantation (methods)
  • Hematopoietic Stem Cells (physiology)
  • Lentivirus
  • Macaca mulatta
  • Male
  • Transduction, Genetic
  • Transplantation, Autologous

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