Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates.
Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates.
复制标题
非人灵长类动物中慢载体/酸性神经酰胺酶转导的造血细胞的自体移植。
DOI：
10.1089/hum.2010.195
复制
发表时间：
2011
影响因子：
4.2
通讯作者：
Medin,JeffreyA
中科院分区：
文献类型：
--
作者：
Walia,JagdeepS;Neschadim,Anton;Lopez-Perez,Orlay;Alayoubi,Abdulfatah;Fan,Xin;Carpentier,Stephane;Madden,Melissa;Lee,Chyan-Jang;Cheung,Fred;Jaffray,DavidA;Levade,Thierry;McCart,JAndrea;Medin,JeffreyA
法伯病是一种罕见的溶酶体贮积症（LSD），表现为酸性神经酰胺酶（AC）缺乏和神经酰胺积累。我们提出了一个法伯病的临床前基因治疗研究采用慢病毒载体（LV-huAC/huCD 25）在三个酶正常的非人灵长类动物。自体动员的外周血（PB）细胞被转导并输注到完全骨髓消融的受体中，并跟踪至少1年。通过测量AC比活性、神经酰胺水平、载体持久性/整合和安全性参数来评估结局。我们未观察到血液学、生化学、放射学或病理学异常。大约3周后血液学恢复。通过定性和定量PCR在PB和骨髓（BM）细胞中观察到载体持久性。我们没有观察到PB和BM细胞的任何克隆性增殖。重要的是，在移植后分析的PB和BM细胞以及研究终点时的脾脏和肝脏中检测到AC特异性活性高于正常水平。PB细胞以及脾和肝组织中的神经酰胺减少。我们希望这项研究将为实施针对法伯病和其他LSD的造血细胞的临床基因治疗方案提供路线图。
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.
登录
查看更多内容
源自转导骨髓细胞的循环 α-半乳糖苷酶 A：与法布里病校正基因转移的相关性。
影响因子：
4.2
作者：
T. Takenaka;G. Qin;R. Brady;J. Medin
通讯作者：
J. Medin
影响因子：
1.5
作者：
G. Haraoka;M. Muraoka;N. Yoshioka;S. Wakami;I. Hayashi
通讯作者：
I. Hayashi
影响因子：
12.4
作者：
Sato, Takeya;Neschadim, Anton;Medin, Jeffrey A.
通讯作者：
Medin, Jeffrey A.
DOI：
10.1016/j.jpeds.2003.09.051
发表时间：
2004
期刊：
The Journal of pediatrics
影响因子：
--
作者：
J. Vormoor;K. Ehlert;A. Groll;H. Koch;M. Frosch;J. Roth
通讯作者：
J. Roth
不累及中枢神经系统的法伯氏病：骨髓移植提供了一种有前途的新方法
影响因子：
27.4
作者：
K. Ehlert;J. Roth;M. Frosch;N. Fehse;N. Zander;J. Vormoor
通讯作者：
J. Vormoor