Gene Therapy of AIDS Dementia

艾滋病痴呆症的基因治疗

基本信息

批准号：
6547098
负责人：
ROGER J POMERANTZ
金额：
$ 29.83万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-25 至 2005-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Human immunodeficiency virus type- I (HIV-1) infection can lead to a series of devastating clinical conditions in the central nervous system (CNS) of certain HIV-1-infected individuals. AIDS dementia complex (ADC) is a collective term to describe AIDS-related cognitive dysfunction, motor difficulties, coordination abnormalities and other neurological signs and symptoms. Blood-brain barrier mainly constituted of micro vascular endothelial cells (MVECs) a protective sheath is a potential obstacle for conventional antiretroviral penetration into the brain. Gene therapy is one the most promising avenues for treatment of neurodegenerative disorders in general and AIDS dementia in particular. Our laboratories in recent past have utilized retroviral vectors for gene delivery in CNS based cells both in vitro and in vivo. Cell-type-specific gene delivery into distinct cells of the central nervous system will be one of the major prerequisites for successful human gene therapy of neurological disorders. In the past decade, Dr. Dornburg's laboratory has gained extensive experience in the construction of cell-type-specific retroviral vectors, derived from the avian reticuloendotheliosis viruses REV-A and spleen necrosis virus, SNV, which display single chain antibodies (scAs) or other targeting ligands on the viral surface. Moreover, pseudotyping REV-derived vectors with the envelope protein of a neurotropic rabies virus strain enabled cell-type-specific gene delivery into neurons in vitro and in vivo. The main goals of this research project are the further development of retroviral vectors, which enable cell-type-specific gene delivery into neurons and brain MVECs. A series of novel retroviral vectors will be developed which transduce therapeutic genes useful for gene therapy of AIDS dementia. The vector design will enable expression of the therapeutic gene from cell-type-specific or inducible promoters. These vectors will be tested in vitro and in vivo. In vitro testing include long-term studies of the efficiency of the therapeutic gene, microarray assays to determine changes of normal gene expression in neurons or brain MVECs, and the testing of the vectors in vitro blood brain barrier systems. Dr. Mukhtar has extensive experience in this area. In vivo experiments will be performed in mice to test long-term gene expression and to determine whether macroscopic or microscopic changes occur in the brains of animals which express the therapeutic genes. The development of cell-type-specific vector specific for neurons and brain MVECs will not only be useful for possible future application of gene therapy of AIDS dementia, but also for numerous other disorders of the CNS.

描述（由申请人提供）：人类免疫缺陷病毒I型（HIV-1）感染可导致某些HIV-1感染个体的中枢神经系统（CNS）的一系列破坏性临床状况。艾滋病痴呆症复合体（ADC）是一个集体术语，用于描述与艾滋病相关的认知功能障碍，运动困难，协调异常以及其他神经系统征兆和症状。血脑屏障主要由微血管内皮细胞（MVEC）组成，保护性护套是常规抗逆转录病毒渗透到大脑中的潜在障碍。基因疗法是治疗神经退行性疾病的最有希望的途径，尤其是AIDS痴呆症。最近，我们的实验室在体外和体内利用了逆转录病毒载体用于基于中枢神经系统的细胞的基因递送。细胞型特异性基因递送到中枢神经系统的不同细胞中将是成功的人类神经系统疾病基因疗法的主要先决条件之一。在过去的十年中，Dornburg博士的实验室在构建细胞型特异性逆转录病毒载体方面具有丰富的经验，这些载体源自鸟类网状网状上升病毒病毒Rev-A和Spleen坏死病毒，SNV，SNV，SNV，该病毒在单链抗体（SCAS）或其他靶向Ligants上显示了病毒表面。此外，与神经性狂犬病病毒菌株的包膜蛋白进行假性转化的载体，使细胞型特异性基因在体外和体内递送到神经元中。该研究项目的主要目标是逆转录病毒载体的进一步发展，该载体能够将细胞类型的基因递送到神经元和脑MVEC中。将开发一系列新型的逆转录病毒载体，这些逆转录病毒载体转导可用于艾滋病痴呆基因治疗的治疗基因。矢量设计将使细胞类型特异性或诱导启动子的治疗基因表达。这些载体将在体外和体内进行测试。体外测试包括对治疗基因效率的长期研究，微阵列测定法，以确定神经元或脑MVEC中正常基因表达的变化以及在体外血脑屏障系统中对载体的测试。 Mukhtar博士在这方面拥有丰富的经验。体内实验将在小鼠中进行测试长期基因表达，并确定在表达治疗基因的动物的大脑中是否发生了宏观或微观变化。针对神经元和脑MVEC的细胞类型特异性载体的开发不仅可用于将来可能应用艾滋病痴呆的基因治疗，而且对于中枢神经系统的许多其他疾病。