Gene therapy vectors for pediatric brain disease

描述(应用摘要)：由于小脑发育超过 在相当长的一段时间内，它容易受到广泛的遗传、 环境和药物扰动。这一点也越来越清楚 小脑同时参与运动学习和认知学习； 因此，小脑缺陷可导致或参与广泛的 发育性大脑疾病，包括胎儿酒精综合征，癫痫发作 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。因为扩展了 发育和可塑性时期，也可能治疗这种 在婴儿期和儿童早期，通过促进细胞生长而引起的疾病。 然而，对影响小脑的细胞因素有更多的了解 发展，以及改变这些的最佳方法将是必要的， 这个项目的长期目标是建立方法来操纵 从基因上讲是小脑。这将需要了解以下两个层次结构 基因表达，以及提供和控制基因治疗的能力。 这项提案中的实验将包括潜在的开发 神经生物学和载体技术来操纵基因。初步实验 将测试猫慢病毒作为转移媒介，在以下情况下 成功的量化参数是可用的。老鼠突变体摇摇晃晃的 (SG)将被用作模型系统，因为它表现出良好的特性 小脑发育有缺陷的基因已经被克隆，它的许多 形态、遗传和生化效应已为人所知。系统 然后可用于优化细胞特异性启动子和载体靶向 战略。一旦这种检测系统针对一个载体就位，它也可以 用于测试载体特异性和表达的修饰，以及 其他载体，如AAV复合体。

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.