Gene Therapy and Seizures

基因治疗和癫痫发作

• 批准号: 7738934
• 负责人: Thomas J. McCown
• 金额: $ 31.37万
• 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/7738934
• 关键词: Address; Aftercare; Antiepileptic Agents; Attention; Attenuated; Central Nervous System Diseases; Chronic; Clinical; Communities; Critiques; Drug resistance; Epilepsy; Evaluation; Excision; Galanin; Gene Transfer; Human; Immunity; Intractable Epilepsy; Kainic Acid; Left; Modeling; Operative Surgical Procedures; Peptides; Population; Proteins; Recurrence; Seizures; Serotyping; Site; Synapsins; Text; Therapeutic; Tissues; adeno-associated viral vector; gene therapy; in vivo; interest; novel; promoter; research study; 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）：大约 1% 的人口患有癫痫症，但该人群中近 30% 的人被证明具有耐药性，因此手术切除是最后的治疗选择（Hauser 和 Hesdoffer，1990）。最近，哈伯曼等人。 (2003)建立了一个新的基因治疗平台，其中神经活性肽被表达和组成型分泌。这些 AAV 载体在体内表达和分泌足够的甘丙肽，以显着减弱局灶性和全身性边缘癫痫活动。此外，McCown (2006) 最近表明，表达和分泌甘丙肽的 AAV 载体可以显着减弱甚至阻断边缘系统癫痫发作活动。然而，在进行任何临床考虑之前必须解决两个重要问题。在人类中，任何基因治疗都将不可避免地遇到癫痫诱发的病理组织和预先存在的对 AAV 血清型 2 的免疫力。本提案将首先确定慢性癫痫活动模型中最有效的 AAV 载体配置，重点关注 AAV 血清型 5 、自我互补的 AAV 和人类突触蛋白启动子。其次，正如 Peden 等人发现的那样。 (2004)，研究将证实 AAV 血清型 5 载体逃避 AAV 血清型 2 免疫的能力，特别关注抗癫痫功效。为了进一步优化抗癫痫功效，研究将确定包含弗林蛋白酶切割位点是否支持单个 AAV 载体表达和分泌两种或多种基因产物，从而增加 AAV 载体在 CNS 疾病中的潜在治疗应用。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，并建立新的技术进步，这将极大地造福整个基因治疗界。 大约 1% 的人口患有癫痫症，但该人群中近 30% 的人被证明具有耐药性，因此手术切除成为最后的治疗选择。目前提出的研究将确定最有效的腺相关病毒载体，该载体将为顽固性癫痫提供可行的基因疗法。