Trojan horse gene therapy of inclusion body disease

包涵体病的特洛伊木马基因治疗

• 批准号: 8090430
• 负责人: EAIN M CORNFORD
• 金额: $ 26.7万
• 依托单位: BRENTWOOD BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090430
• 关键词: Adult; Animal Model; Antibodies; Base of the Brain; Blood - brain barrier anatomy; Blood capillaries; Body Burden; Brain; Cell Death; Cessation of life; Characteristics; Child; Chromosomes; Chronic; Clinical; Deterioration; Disease; Dose; Early treatment; Enzymes; Equus caballus; Extravasation; Fabry Disease; Female; Gene Expression; Gene Mutation; Genes; Heterozygote; Immunoglobulin G; Immunoliposome; Inclusion Bodies; Infant; Injection of therapeutic agent; Knockout Mice; Laboratory Research; Lafora Disease; Life; Liposomes; Luc Gene; Luciferases; Lysosomal Storage Diseases; Measures; Mediating; Methods; Molecular; Mono-S; Mus; Mutant Strains Mice; Mutate; Neurologic; Newborn Infant; Niemann-Pick Diseases; Pathology; Perception; Placenta; Plasma Proteins; Plasmids; Polyethylene Glycols; Prevention; Protein Tyrosine Phosphatase; Regimen; Relative (related person); Research Personnel; Single-Gene Defect; Specificity; System; Tay-Sachs Disease; Therapeutic; Tight Junctions; Tissues; Transferrin Receptor; Transgenic Mice; Treatment Protocols; Ursidae Family; Viral Vector; age related; base; capillary; enzyme deficiency; fetal; gene therapy; in utero; in vivo; intravenous administration; intravenous injection; molecular trojan horse; mouse model; mutant; nervous system disorder; neuron loss; peptidomimetics; pregnant; prevent; programs; protein expression; receptor; restoration; transcytosis

DESCRIPTION (provided by applicant): In addition to Lafora's Disease, there are numerous single-gene defect storage diseases that have devastating effects on the children of adult carriers (e.g. Niemann-Pick disease, Tay-Sachs disease, Fabry disease, and many other Lysosomal Storage disorders). A common feature of these disorders is that an enzyme deficiency (and the intracellular accumulation of undigested metabolites) leads to progressive neurologic deterioration and early death. In all cases, the mutated gene and enzyme deficiency is known. But copies of the potentially life-saving genes sit dormant in research laboratories because of problems in delivery and expressing an exogenous gene throughout the brain. Large molecule therapeutics alone do not cross the brain capillaries, leading to the perception that the blood-brain barrier (BBB) may be an insoluble problem. Complications seen with viral vector-delivery of gene therapies further suggest that new methods need to be devised for the delivery of large-molecule genes across the BBB. We propose to use recently developed immunoliposome BBB delivery systems to successfully deliver a normal gene therapeutically through the BBB of knock-out mice with Lafora's Disease, via intravenous administration. If this non-viral delivery system can treat the disease in animal models, an immunoliposome-based cure for this fatal inclusion body disorder could be developed for clinical use. The aims are: (1) To prepare pegylated immunoliposomes (PIL) and establish BBB delivery of a) an exogenous gene and b) delivery of the normal EPM2a/laforin gene, in mice bearing a significant inclusion body burden. (2) To demonstrate transplacental and fetal brain delivery of an exogenous gene after i.v. administration to the dam. (3) To confirm uniform delivery of the laforin gene to the brain of knock-out mice after a single intravenous injection, and determine how Lafora-body burdens change. And (4) to develop an optimal therapeutic regimen of multiple i.v. injections which suppresses Lafora body burdens for 6-12 months in knock-out mice. Examinations of BBB integrity and capillary tight-junctions will show the absence of microvascular pathology, even after chronic PIL treatments

描述（由申请人提供）：除了拉福拉氏病外，还有许多单基因缺陷贮积病对成年携带者的子女具有毁灭性影响（例如尼曼-皮克病、泰-萨克斯病、法布里病和许多其他溶酶体贮积病）。这些疾病的一个共同特征是酶缺乏（以及未消化的代谢物在细胞内积累）导致进行性神经功能恶化和过早死亡。在所有情况下，突变基因和酶缺陷都是已知的。但由于在整个大脑中传递和表达外源基因的问题，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。单独的大分子疗法不能穿过脑毛细血管，导致人们认为血脑屏障（BBB）可能是一个无法解决的问题。病毒载体递送基因疗法的并发症进一步表明，需要设计新方法来跨血脑屏障递送大分子基因。我们建议使用最近开发的免疫脂质体 BBB 传递系统，通过静脉注射成功地通过患有拉福拉氏病的基因敲除小鼠的 BBB 传递正常基因。如果这种非病毒传递系统可以在动物模型中治疗这种疾病，那么就可以开发出一种基于免疫脂质体的疗法来治疗这种致命的包涵体疾病，并用于临床。目的是：(1) 制备聚乙二醇化免疫脂质体 (PIL)，并在具有显着包涵体负担的小鼠中建立 a) 外源基因和 b) 正常 EPM2a/laforin 基因的 BBB 递送。 (2) 证明静脉注射后外源基因的经胎盘和胎儿大脑递送。对大坝的管理。 (3) 确认Laforin基因单次静脉注射后均匀递送至敲除小鼠大脑，并确定Lafora身体负荷如何变化。 (4) 制定多次静脉注射的最佳治疗方案。注射可抑制 Lafora 基因敲除小鼠的身体负担达 6-12 个月。即使在长期 PIL 治疗后，血脑屏障完整性和毛细血管紧密连接的检查也将显示不存在微血管病理学

项目成果

Body weight reduction in rats by oral treatment with zinc plus cyclo-(His-Pro).

通过口服锌加环-(His-Pro) 治疗可减轻大鼠体重。

• DOI: 10.1111/j.1476-5381.2009.00201.x
• 发表时间: 2009
• 期刊: British journal of pharmacology
• 影响因子: 7.3
• 作者: Song,MK;Rosenthal,MJ;Song,AM;Uyemura,K;Yang,H;Ament,ME;Yamaguchi,DT;Cornford,EM
• 通讯作者: Cornford,EM