A novel technology for protein delivery to the CNS

一种将蛋白质输送至中枢神经系统的新技术

• 批准号: 6788633
• 负责人: MANI RAMASWAMI
• 金额: $ 12.66万
• 依托单位: Q THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-20 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788633
• 关键词: biotechnology; central nervous system disorders; enzyme deficiency; gene delivery system; gene targeting; gene therapy; glia; green fluorescent proteins; laboratory mouse; nerve stem cell; nervous system transplantation; neuronal ceroid lipofuscinosis; secretion; stem cell transplantation; technology /technique development

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a cell-based system for delivering therapeutic gene products to brain and spinal cord. Several candidate protein pharmaceuticals exist whose use for treatment of genetic or other CNS disorders is severely hampered by the absence of a convenient delivery mechanism. A stable cell-based delivery system for such therapeutics could bypass the almost prohibitive clinical requirement for multiple intracranial injections of molecules that may often be expensive to obtain at the required levels of purity. A successful cell-based delivery system requires two problems to be solved. First, a population of cells must be identified that, when transplanted into the adult CNS, will migrate, integrate efficiently, and survive in diseased tissue. Based on preliminary rodent studies, it appears that Q Therapeutics' patented glial precursor cells, conveniently obtained from adult or embryonic tissue, overcome this problem. Second, an expression technology must be devised that bypasses problems associated with currently available forms of gene therapy including toxicity, side effects associated with inappropriate integration sites, and transgene silencing. This Phase 1 SBIR proposes to establish such a technology. Homologous recombination based integration of transgenes downstream of strong promoters, if successful in glial progenitor cells, will allow targeted transgene integration without additional vector sequences that are likely to be the source of several problems with current gene therapy vectors. Research proposed here will establish the feasibility of homologous recombination in glial progenitor cells and expression of integrated transgenes after transplanation into rodent hosts. The first anticipated target of this therapeutic strategy is Battens disease, a heritable lysosomal storage disease that results in strong neurological phenotype in infants. If successful, this will establish the feasibility of a novel therapeutic strategy to combat several highly prevalent neurological diseases.

描述（由申请人提供）：这项研究的长期目标是开发基于细胞的系统，用于将治疗基因产物传递给脑和脊髓。存在几种候选蛋白药物，其用于治疗遗传或其他中枢神经系统疾病的使用受到方便的递送机制严重阻碍。用于此类治疗剂的稳定基于细胞的递送系统可以绕过几乎颅内注射分子的几乎急需的临床要求，这些分子通常通常在所需的纯度水平上获得昂贵的分子。成功的基于细胞的输送系统需要解决两个问题。首先，必须确定一群细胞群，当移植到成年中心时，将迁移，有效地整合并在患病组织中生存。根据初步的啮齿动物研究，看来从成人或胚胎组织方便地获得的Q Therapeutics专利的神经胶质前体细胞克服了这一问题。其次，必须设计一种表达技术，该技术绕过与当前可用的基因治疗形式相关的问题，包括毒性，与不当集成位点相关的副作用以及转基因沉默。这一阶段1 SBIR提议建立这样的技术。 如果在神经胶质祖细胞中成功，基于强启动子下游的转基因的基于同源重组的整合将允许有针对性的转基因整合，而无需其他矢量序列，而其他载体序列可能是当前基因治疗载体的几个问题的来源。此处提出的研究将确定在神经胶质祖细胞中同源重组的可行性，并在移植到啮齿动物宿主中的综合转基因的表达。这种治疗策略的第一个预期靶标是TATES疾病，这是一种可遗传的溶酶体储存疾病，可导致婴儿中强烈的神经表型。如果成功，这将确定一种新型治疗策略的可行性，以打击几种高度普遍的神经系统疾病。