Gene therapy and enzyme replacement for Batten disease

描述(由申请人提供)：这项提案的重点是影响D中枢神经系统的溶酶体储存疾病的基因治疗方法。使用晚期婴儿神经元型蜡样脂褐素沉积症(LINCL/Batten病)作为D模型疾病，我建议测试关于将基因传递到小鼠疾病D模型的中枢神经系统的假说。我们实验室的最新数据显示，4型腺相关病毒(AAV4)能有效地引导D溶酶体酶在小鼠脑内的广泛分布，这是一个令人兴奋的发现，因为D LINCL患者表现出广泛的中枢神经系统病理。这里将测试AAV4在LINCL小鼠D模型中直接基因转移的能力。此外，我建议开发一种四环素调节的病毒载体，因为临床应用基因转移可能需要调节表达，以将免疫反应C或其他不良反应降至最低。一个受调控的载体也将使我能够解决D停止酶表达后的益处持续时间。

DESCRIPTION (provided by applicant): This proposal is focused on gene therapy approaches for lysosomal storage diseases affecting the D central nervous system. Using late infantile neuronal ceroid lipofuscinosis (LINCL / Batten Disease) as a D model disease, I propose to test hypotheses regarding delivery of a gene to the CNS of a murine disease D model. Recent data from our lab shows that adeno-associated virus type 4 (AAV4) is effective in directing D widespread distribution of a lysosomal enzyme in the murine brain, which is an exciting finding given that D LINCL patients exhibit widespread CNS pathology. The ability of AAV4 to direct gene transfer in a mouse D model of LINCL will be tested here. In addition, I propose to develop a tetracycline-regulated viral vector as I clinical applications of gene transfer will likely require regulated expression to minimize immune responses C or other adverse effects. A regulated vector will also allow me to address the duration of benefits after D cessation of enzyme expression.