Gene Therapy and Seizures

描述(由申请人提供)：癫痫困扰着大约1%的人口，但近30%的人口被证明具有抗药性，手术切除是最后的治疗选择(Hauser和Hesdoffer，1990)。最近，Haberman et al.(2003)建立了一个新的基因治疗平台，神经活性多肽在其中表达和结构性分泌。这些AAV载体在体内表达和分泌足够的甘丙素，显著减弱局灶性和全身性边缘癫痫发作的活性。此外，McCown(2006)最近发现，表达和分泌甘丙肽的AAV载体可以显著减弱甚至阻断边缘癫痫发作的活动。然而，在临床考虑之前，必须解决两个重要的问题。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预先存在的对AAV 2型的免疫。本方案将首先确定慢性癫痫活动模型中最有效的AAV载体配置，重点是AAV血清型5型、自身互补的AAV和人类突触素启动子。第二，Peden等人的发现。(2004)，研究将证实AAV血清5型载体逃避AAV血清2型免疫的能力，并特别关注抗癫痫效果。为了进一步优化抗癫痫的效果，研究将确定包含Furin裂解位点是否支持从单个AAV载体表达和分泌两个或更多基因产物，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载体抗癫痫基因疗法提供至关重要的信息，并建立将极大地惠及整个基因治疗界的新技术进步。 大约1%的人患有癫痫，但近30%的人被证明具有抗药性，因此手术切除是最后的治疗选择。目前的研究将确定最有效的腺相关病毒载体，它将为难治性癫痫提供可行的基因治疗。

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.