Gene Therapy and Seizures

基因治疗和癫痫发作

• 批准号: 7372710
• 负责人: Thomas J. McCown
• 金额: $ 31.69万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372710
• 关键词: Accounting; Address; Antiepileptic Agents; Area; Attenuated; Behavioral; Cell Death; Central Nervous System Diseases; Chronic; Clinical; Communities; Complication; Drug resistance; Effectiveness; Epilepsy; Excision; Exposure to; Focal Seizure; Galanin; Gene Expression; Goals; Human; Immunity; Intractable Epilepsy; Kainic Acid; Kindling (Neurology); Left; Mediating; Modeling; Neurons; Neuropeptides; Numbers; Operative Surgical Procedures; Peptides; Peripheral; Population; Proteins; Rattus; Seizures; Serotyping; Side; Site; Synapsins; Testing; Therapeutic; Tissues; Transduction Gene; Treatment Efficacy; adeno-associated viral vector; clinical application; design; gene therapy; in vivo; novel; piriform cortex; prevent; promoter; therapeutic effectiveness; vector

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.

描述（由申请人提供）：癫痫病大约1％的人口，但近30％的人群证明了耐药性，将手术切除作为最后的治疗选择（Hauser and Hesdoffer，1990年）。最近，Haberman等。 （2003年）建立了一个新型的基因治疗平台，在该平台中，神经活性肽被表达并构成分泌。这些AAV载体在体内表达并分泌了足够的加拉宁，以显着衰减局灶性和广泛的边缘癫痫发作活性。此外，McCown（2006）最近表明，表达和分泌的Galanin的AAV矢量可能会大大减弱甚至阻止边缘癫痫发作活动。但是，必须在任何临床考虑之前解决两个重要问题。在人类中，任何基因疗法都将不可避免地遇到癫痫发作的病理组织和对AAV血清型2的免疫力。目前的提案将首先确定慢性癫痫发作模型中最有效的AAV矢量构型，重点是AAV血清型5，是AAV血清型5，自我掌握的AAV AAV AAV和AAV AAV AAV和AAV AAV AAV和AAV AAV促进剂。其次，如Peden等人所发现的。 （2004年），研究将确认AAV血清型5载体逃避对AAV血清型2免疫的能力，其特定侧重于抗塞氏菌功效。为了进一步优化抗Seizure疗效，研究将确定包含脂蛋白裂解位点是否支持来自单个AAV载体的两个或多个基因产物的表达和分泌，从而增加AAV量对CNS疾病的潜在治疗应用。这些研究总之将为设计最有效的AAV载体抗癫痫基因疗法提供至关重要的信息，并建立新的技术进步，这将极大地使整个基因疗法群落受益。 癫痫遭受了大约1％的人口，但接近该人群的30％证明了耐药性，使手术切除是最后的治疗选择。本提出的研究将定义最有效的腺相关病毒载体，该病毒载体将提供可行的基因治疗治疗，以进行顽固性癫痫。