TY - JOUR
T1 - Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates
AU - Walia, Jagdeep S.
AU - Neschadim, Anton
AU - Lopez-Perez, Orlay
AU - Alayoubi, Abdulfatah
AU - Fan, Xin
AU - Carpentier, Stéphane
AU - Madden, Melissa
AU - Lee, Chyan Jang
AU - Cheung, Fred
AU - Jaffray, David A.
AU - Levade, Thierry
AU - McCart, J. Andrea
AU - Medin, Jeffrey A.
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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.
AB - 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.
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U2 - 10.1089/hum.2010.195
DO - 10.1089/hum.2010.195
M3 - Article
C2 - 21280983
AN - SCOPUS:79958209082
SN - 1043-0342
VL - 22
SP - 679
EP - 687
JO - Human gene therapy
JF - Human gene therapy
IS - 6
ER -