Gene therapy vectors for pediatric brain disease

描述（应用摘要）：由于小脑的发展超过了一个 在相当长的一段时间内，它容易受到广泛的遗传， 环境和药物干扰物。人们也越来越清楚， 小脑参与运动和认知学习; 因此，小脑缺陷可以成为或参与广泛的 发育性脑障碍，包括胎儿酒精综合征、 大脑畸形，遗传性小脑退化，婴儿自闭症， 共济失调毛细血管扩张症可能还有阅读障碍由于延长 在发育和可塑性时间段内，治疗这种疾病也是可行的。 通过促进婴儿期和幼儿期的细胞生长来治疗疾病。 然而，更多的知识，这两个细胞因素，影响小脑 发展，以及改变这些的最佳方法将是必需的， 该项目的长期目标是建立操纵 小脑基因这将需要两个层次的知识， 基因表达，以及传递和控制基因疗法的能力。 在这个提议中的实验将包括两个潜在的发展 神经生物学和载体技术来操纵基因。初始实验 将测试猫慢病毒作为转移载体，在这种情况下， 成功的量化参数是可用的。小鼠突变体staggerer (sg)将被用作一个模型系统，因为它显示了一个良好的特点， 有缺陷的小脑发育，该基因已被克隆，其许多 形态学、遗传学和生物化学效应是已知的。系统 然后可用于优化细胞特异性启动子和载体靶向 战略布局一旦该测定系统对于一种载体就位，它也可以是 用于检测载体特异性和表达的修饰，以及 另外的载体如AAV复合物。

DESCRIPTION (application abstract): Since the cerebellum develops over a considerable period of time, it is vulnerable to a wide range of genetic, environmental and pharmaceutical perturbants. It is also increasingly clear that the cerebellum participates in both motor and cognitive learning; therefore cerebellar defects can underlie or participate in a wide range of developmental brain disorders including fetal alcohol syndrome, seizures due to brain malformations, hereditary cerebellar degenerations, infantile autism, ataxia telangiactasia, and possibly dyslexia. Because of the extended developmental and plastic time-period, it may also be feasible to treat such disorders by enhancing cell outgrowth during infancy and early childhood. However, more knowledge of both the cellular factors that influence cerebellar development, and optimal methods for altering these will be required, The long-term goal of this project is to establish methods to manipulate the cerebellum genetically. This will require both knowledge of the hierarchy of gene expression, and a capacity to deliver and control gene therapies. Experiments in this proposal will encompass both the underlying developmental neurobiology and vector technology to manipulate the genes. initial experiments will test a feline lentivirus as a transfer vector, under circumstances where quantitative parameters of success are available. The mouse mutant staggerer (sg) will be used as a model system, since it shows a well-characterized defective cerebellar development, the gene has been cloned, and many of its morphological, genetic and biochemical effects are already known. The system can then be used to optimize cellspecific promoters and vector targeting strategies. Once this assay system is in place for one vector, it can also be used to test modifications of vector specificity and expression, as well as additional vectors such as AAV complexes.