Gene Transfer for Prevention of Diabetic Neuropathy

描述（由申请人提供）：我们已经开发了重组的、复制能力不足的、基于基因组的单纯疱疹病毒（HSV）载体，用于基因转移到神经系统。在之前的资助中，我们已经证明HSV介导的神经营养因子-3 （NT-3）、血管内皮生长因子（VEGF）或红细胞生成素（EPO）在体内背根神经节（DRG）中的表达可以阻止链脲佐菌素（STZ）诱导的糖尿病小鼠神经病变的进展。在这一竞争更新中，我们将继续利用HSV载体对DRG周围感觉神经元的天然倾向，进一步验证通过HSV载体将神经保护因子基因转移到DRG的假设，可以用来预防糖尿病神经病变的进展，最终目的是开发一种有效治疗人类神经病变的疗法。描述了四个具体目标。(1)确定hsv介导的神经保护因子表达是否能阻止1型糖尿病链脲佐菌素模型中DRG神经元的丢失；(2)探讨hsv介导的神经保护因子在db/db 2型糖尿病小鼠模型中治疗糖尿病神经病变的作用；(3)构建具有可调节开关的载体，安全控制转基因表达；(4)检测间歇性调节保护因子表达对stz - diabetes和db/db小鼠糖尿病神经病变进展的影响。公共卫生相关性：神经病变是1型和2型糖尿病的重要且常致残的并发症，目前尚无有效的治疗方法可预防并发症的进展。这些研究旨在开发可用于有效治疗该疾病的新型药物。

DESCRIPTION (provided by applicant): We have developed recombinant, replication-incompetent, genomic herpes simplex virus (HSV)-based vectors for gene transfer to the nervous system. In the previous period of funding we have demonstrated that HSV- mediated expression of neurotrophin-3 (NT-3), vascular endothelial growth factor (VEGF), or erythropoietin (EPO) in dorsal root ganglion (DRG) in vivo prevents the progression of neuropathy in mice with streptozotocin (STZ)-induced diabetes. In this competing renewal, we will continue to exploit the natural tropism of HSV vectors for peripheral sensory neurons of the (DRG) to further test the hypothesis that gene transfer of neuroprotective factors to the DRG by means of an HSV-based vector can be used to prevent the progression of diabetic neuropathy, with the ultimate aim of developing a therapy that will be effective for the treatment of human neuropathy. Four specific aims are described. (1) to determine whether HSV-mediated neuroprotective factor expression prevents the loss of DRG neurons in the streptozocin model of type 1 diabetes; (2) to examine the effect of HSV-mediated delivery of neuroprotective factors in the treatment of diabetic neuropathy in the db/db mouse model of type 2 diabetes; (3) to construct a vector with a regulatable switch to control transgene expression safely; and, (4) to test the effect of intermittent regulated protective factor expression on the progression of diabetic neuropathy in the STZ-diabetic and db/db mouse. PUBLIC HEALTH RELEVANCE: Neuropathy is an important and often disabling complication of both type 1 and type 2 diabetes mellitus, and there are no currently available treatments that are effective in preventing the progression of the complication. These studies are designed to develop novel agents that could be used to treat the disease effectively.