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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）是基因治疗的理想目标。校正的靶细胞是

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