Lentivirus Gene Therapy for Farber Disease in NHPs

慢病毒基因治疗 NHP 法伯病

基本信息

批准号：
7334949
负责人：
JEFFREY A MEDIN
金额：
$ 5.4万
依托单位：
UNIVERSITY HEALTH NETWORK
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-15 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7334949
关键词：
Acer Address Animal Model Animals Area Biological Assay Bone Marrow Bone Marrow Transplantation Brain Calculi Cell Transplants Cell surface Cells Cessation of life Clinical Complement Complementary DNA Complex Cultured Cells Development Disease Engineering Engraftment Enzymes Event Fabry Disease Farber&apos s lipogranulomatosis Gaucher Disease Gene Transfer Gene-Modified Genes Germ Lines Glycoproteins Granuloma Health Heart Human Hydrolase In Vitro Infection Inflammation Kinetics Macaca mulatta Mediating Metabolic Microglia Modeling Neurologic Numbers Outcome Pain Patients Polymerase Chain Reaction Protein Overexpression Protocols documentation Recombinants Reporting Research Research Proposals Retroviridae Site Stem cells Subfamily lentivirinae System Testing Therapeutic Time Toxic effect Training Tropism Universities Vesicular stomatitis Indiana virus cellular engineering cellular transduction clinically relevant early childhood enzyme replacement therapy galactosylgalactosylglucosylceramidase gene therapy implantable device in vivo Model medin nonhuman primate novel programs protocol development research study stem success vector

项目摘要

Lysosomal storage disorders (LSDs) are excellent objectives for gene therapy. Target cells for correction are often are accessible and for many LSDs a phenomenon called 'metabolic cooperativity' occurs. Here cells that overexpress corrective lysosomai enzymes secrete these hydrolases, which can be functionally utilized by unmodified bystander cells. Thus lower efficiencies or directed gene transfer to single sites can still effect systemic correction. Farber disease (FD) is a very severe LSD due to a deficiency in acid ceramidase. FD presents with debilitating manifestations including painful granulomas and pronounced neurological consequences. Death often occurs in early childhood. Current treatment for FD, like for many LSDs, is only palliative. For some LSDs, BMT using unmodified cells has been partially corrective, although little impact on CMS manifestations has been observed. For only the most prevalent LSDs, enzyme replacement therapy is an option. Gene therapy using a variety of delivery systems has also been tested in vitro and in in vivo models of LSDs. A few clinical gene therapy protocols addressing LSDs have also been initiated. No toxicities were reported although clinical improvements have also not been realized. Previously we demonstrated the first conceptual possibility that gene therapy could ameliorate FD. Lately, we have been adapting lentiviruses (LV) for gene augmentation strategies. We have tested successful outcomes using LVs in cell culture and in small animal models for Fabry disease; another LSD. Yet despite this conceptual success, and notwithstanding the growing number of small animal models of LSDs, these experiments are not often predictive of clinical gene therapy outcomes. Thus we have recently initiated gene therapy studies here at the UHN in non-human primates (NHPs) to better predict outcomes in patients and to identify areas wherein more research or protocol development is warranted. This proposed study would thus be the first to fully test LV-mediatedcorrection for an LSD in a more clinically relevant model; that of NHPs.

溶酶体贮积症（LSD）是基因治疗的绝佳目标。校正的目标单元格是通常很容易获得，并且对于许多 LSD 来说，会发生一种称为“代谢协同性”的现象。这里的细胞过度表达纠正性溶酶体酶会分泌这些水解酶，这些水解酶可以被功能性地利用由未经修改的旁观者细胞。因此，较低的效率或定向基因转移到单个位点仍然会产生影响系统性修正。法伯病 (FD) 是一种由于酸性神经酰胺酶缺乏而导致的非常严重的 LSD。 FD 出现使人衰弱的表现，包括疼痛性肉芽肿和明显的神经系统症状结果。死亡常常发生在幼儿期。与许多 LSD 一样，目前对 FD 的治疗仅是姑息治疗。对于某些 LSD，使用未修饰细胞的 BMT 已部分纠正，尽管对已观察到 CMS 表现。仅针对最流行的 LSD，酶替代疗法才有效一个选项。使用多种递送系统的基因治疗也已在体外和体内进行了测试 LSD 模型。一些针对 LSD 的临床基因治疗方案也已启动。不尽管尚未实现临床改善，但已报告了毒性。以前我们证明了基因疗法可以改善 FD 的第一个概念可能性。最近，我们一直在采用慢病毒（LV）进行基因增强策略。我们已经使用 LV 测试了成功的结果用于法布里病的细胞培养和小动物模型；另一种LSD。然而尽管有这个概念尽管 LSD 的小动物模型数量不断增加，但这些实验仍然取得了成功通常不能预测临床基因治疗的结果。因此我们最近启动了基因治疗研究在非人类灵长类动物 (NHP) 的 UHN 中，更好地预测患者的结果并确定领域其中需要更多的研究或方案开发。因此，这项拟议的研究将是第一个在更具临床相关性的模型中全面测试 LV 介导的 LSD 校正； NHP 的。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates.

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
发表时间：
2011
期刊：
Human gene therapy
影响因子：
4.2
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
通讯作者：
Medin,JeffreyA