Gene Therapy and Seizures

描述（由申请人提供）：约1%的人口患有癫痫，但其中近30%的人被证明具有耐药性，手术切除是最后的治疗选择（Hauser和Hesdoffer， 1990）。最近，Haberman等人（2003）建立了一种新的基因治疗平台，其中神经活性肽的表达和组成性分泌。这些AAV载体在体内表达和分泌足够的丙氨酸，以显著减弱局灶性和全局性边缘癫痫发作活动。此外，McCown（2006）最近表明，表达和分泌甘丙氨酸的AAV载体可以显著减弱甚至阻断边缘癫痫发作活动。然而，在任何临床考虑之前，必须解决两个重要问题。在人类中，任何基因治疗都不可避免地会遇到癫痫诱导的病理组织和对AAV血清2型的预先免疫。目前的建议将首先确定慢性癫痫发作活动模型中最有效的AAV载体配置，重点关注AAV血清型5，自互补AAV和人类突触蛋白启动子。其次，正如Peden等人（2004）所发现的那样，研究将证实AAV血清5型载体能够逃避对AAV血清2型的免疫，并特别关注抗癫痫的功效。为了进一步优化抗癫痫效果，研究将确定是否包含furin切割位点支持单个AAV载体中两个或多个基因产物的表达和分泌，从而增加AAV载体对中枢神经系统疾病的潜在治疗应用。总之，这些研究将为设计最有效的AAV载体抗癫痫基因治疗提供关键信息，并建立新的技术进步，这将极大地有利于整个基因治疗界。

DESCRIPTION (provided by applicant): Epilepsy afflicts approximately 1% of the population, yet close to 30% of this population proves drug resistant, leaving surgical resection as the last treatment option (Hauser and Hesdoffer, 1990). Recently, Haberman et al. (2003) established a novel gene therapy platform where neuroactive peptides are expressed and constitutively secreted. These AAV vectors expressed and secreted enough galanin in vivo to significantly attenuate both focal and generalized limbic seizure activity. Furthermore, McCown (2006) recently showed that AAV vectors that expressed and secreted galanin could significantly attenuate, or even block, limbic seizure activity. However, two important issues must be addressed prior to any clinical consideration. In humans, any gene therapy will inevitably encounter both seizure-induced pathological tissue and pre-existing immunity to AAV serotype 2. The present proposal will first determine the most efficacious AAV vector configuration in a model of chronic seizure activity, focusing upon AAV serotype 5, self-complementary AAV and a human synapsin promoter. Secondly, as found by Peden et al. (2004), studies will confirm the ability of AAV serotype 5 vectors to evade immunity to AAV serotype 2 with a particular focus on anti-seizure efficacy. To further optimize the anti-seizure efficacy, studies will determine if the inclusion of a furin cleavage site supports the expression and secretion of two or more gene products from a single AAV vector, thus increasing the potential therapeutic applications of AAV vectors to CNS disorders. All together, these studies will provide information crucial for devising the most effective AAV vector antiepileptic gene therapy, as well as establish novel technological advances that will greatly benefit the entire gene therapy community. Epilepsy afflicts approximately 1% of the population, yet close to 30% of this population prove drug resistant, leaving surgical resection as the last treatment option. The present proposed studies will define the most efficacious adeno-associated virus vector which will provide a viable gene therapy treatment for intractable epilepsy.