Blood-brain barrier gene delivery in knock-out mice.

基因敲除小鼠中的血脑屏障基因传递。

• 批准号: 6878528
• 负责人: EAIN M CORNFORD
• 金额: $ 17.07万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6878528
• 关键词: biotechnology; blood brain barrier; clinical research; disease /disorder model; gene delivery system; gene therapy; genetically modified animals; glucose transporter; human tissue; intravenous administration; laboratory mouse; liposomes; myoclonus epilepsy; nervous system disorder therapy; postmortem; therapy design /development

DESCRIPTION (provided by applicant): In addition to Lafora's Progressive Myoclonic Epilepsy, there are numerous single-gene defect diseases that have devastating effects on the children of adult carriers (e.g. Rett's syndrome, fragile x syndrome, Canavan's disease, and Tay-Sachs disease). For all of these diseases, there are support groups formed by parents and friends of afflicted children. In all cases, the mutated gene is known and cloned. But copies of the potentially life-saving genes sit dormant in research laboratories because of problems in expressing an exogenous gene throughout the brain. Due to the difficulties in delivering large molecule therapeutics across the brain capillaries, there is a perception that the blood-brain barrier (BBB) may be an insoluble problem. Heroic measures, such the transient disruption of the BBB with osmotic shock, have yet to be evaluated for delivery of gene therapeutics in clinical trials. Alternative methods are also not without problems; within the current year the NIH placed a halt on all trials where viral vectors were being used to deliver gene therapies. This action suggests a need to develop and test non-viral alternatives for the delivery of (large-molecule) genes across the BBB. We will test the hypothesis that recently developed immunoliposome BBB delivery systems can be used to successfully promote a gene therapeutic through the BBB of knock-out mice with Lafora's Progressive Myoclonic Epilepsy (PME), after intravenous administration. We propose that if this non-viral delivery system can treat the disease in animal models, an immunoliposome-based cure for this fatal epilepsy can be developed for clinical use. The aims are: (1) To prepare pegylated immunoliposomes (PIL) for delivery of the normal EPM2a/laforin gene; (2) to administer PILs in a knockout mouse model of Lafora's Disease; (3) to confirm uniform delivery of the gene to the brain after intravenous injection, with amelioration of the progressive disease; and (4) to develop an optimal therapeutic regimen which arrests the fatal onset of Lafora's disease in the knock-out mice.

描述（由申请人提供）：除了Lafora进行性肌阵挛性癫痫外，还有许多单基因缺陷疾病对成年携带者的子女具有破坏性影响（例如Rett's综合征，脆性x综合征，Canavan's病和Tay-Sachs病）。对于所有这些疾病，都有由患病儿童的父母和朋友组成的支持小组。在所有情况下，突变基因都是已知和克隆的。但是，由于在整个大脑中表达外源基因的问题，这些可能挽救生命的基因的副本在研究实验室中处于休眠状态。由于通过脑毛细血管输送大分子药物的困难，人们认为血脑屏障（BBB）可能是一个无法解决的问题。英勇的措施，如渗透性休克对血脑屏障的短暂破坏，尚未在临床试验中评估基因治疗的递送。替代方法也不是没有问题；今年，美国国立卫生研究院停止了所有使用病毒载体进行基因治疗的试验。这表明有必要开发和测试非病毒替代方案，以通过血脑屏障传递（大分子）基因。