Preclinical Development of AAV-Galanin for Epilepsy

描述(由申请人提供)：本提案旨在利用腺相关病毒(AAV)载体介导的基因治疗方面的专利技术进步，开发基于AAV的Galanin基因递送用于癫痫的治疗。Asklepios生物制药公司(Askbio)已获得知识产权，将开发一种包含三项关键技术的抗癫痫生物制剂并将其商业化。指导甘丙素分泌的基因盒，2.)使用自我互补的基因组，以及3.)特别进化的嵌合AAV2.5衣壳。将这些技术纳入癫痫的可行替代基因疗法是这项提案的一个新组成部分，这为美国约350-70万抗癫痫药物无效的患者带来了巨大的希望。这项第一阶段提案中详细介绍的可行性实验将确定含有自我互补FIB-Galanin转基因盒的嵌合体AAV2.5的有效剂量范围，以及使用两种不同的小鼠边缘癫痫模型：局灶性电点燃和外周红藻氨酸注射，研究脑内注射dsAAV2.5 FIB-GAL治疗中颞叶癫痫(MTLE)的疗效和安全性。我们完全期待拟议研究的结果将支持推进到第二阶段研究，包括在啮齿动物和大型动物模型上的明确的临床前研究，以及支持IND提交的关键的安全性和毒理学研究。拟议的初步临床研究将在MTLE患者中进行，他们已经是手术切除的候选对象，并将采用一项研究设计，涉及在预定切除致痫/dsAAV2.5 FIB-GAL注入组织之前进行基因传递。与公共卫生相关：Asklepios生物制药公司正在开发一种治疗中颞叶癫痫(MTLE)的药物。目前的治疗策略仅限于抗癫痫药物，其中大多数已有几十年的历史。对于350-70万名药物治疗未能解决癫痫发作的患者，手术切除提供了一个潜在的解决方案。拟议的治疗方法是AAV介导的Galanin递送，旨在提供一种替代疗法来满足这一长期的医疗需求。

DESCRIPTION (provided by applicant): This proposal seeks to leverage proprietary technical advances in Adeno-Associated Virus (AAV) vector mediated gene therapy to develop an AAV based Galanin gene delivery for the treatment of epilepsy. Asklepios Biopharmaceutical, Inc. (Askbio) has obtained intellectual property rights to develop and commercialize an anti-epileptic biologic containing three key technologies: 1.) a gene cassette directing secretion of galanin, 2.) use of a self complementary genome, and 3.) the specifically evolved chimeric AAV2.5 capsid. The incorporation of these technologies into a viable alternative gene therapy for epilepsy is a novel component of this proposal, and on that offers a great deal of hope to the estimated 350-700K patients in the U.S. for whom anti-epileptic drugs fail. The feasibility experiments detailed in this Phase I proposal will determine an efficacious dose range for the chimeric AAV2.5 containing a self-complementary FIB-Galanin transgene cassette (dsAAV2.5 FIB-GAL), as well as examine the efficacy and safety of intracranial administration of dsAAV2.5 FIB-GAL to treat Mesiotemporal lobe epilepsy (MTLE) using two different mouse models of limbic seizure, focal electrical kindling and peripheral kainic acid administration. We fully expect the results of the proposed studies to support advancing to a Phase II study consisting of definitive preclinical studies, in both rodent and large animal models, as well as pivotal safety and toxicology studies in support of an IND submission. The proposed initial clinical study will be undertaken in subjects with MTLE, who are already candidates for surgical resection, and will employ a study design involving gene delivery prior to scheduled resection of epileptogenic/dsAAV2.5 FIB-GAL infused tissue. PUBLIC HEALTH RELEVANCE: Asklepios Biopharmaceutical, Inc. is developing a therapeutic to treat people with Mesiotemporal lobe epilepsy (MTLE). Current treatment strategies are limited to anti-epileptogenic drugs, most of which are several decades old. For the 350-700K patients in whom drug therapies fail to resolve seizures, surgical resection offers a potential resolution. The proposed therapeutic, an AAV-mediated delivery of Galanin, is designed to provide an alternative therapy to meet this longstanding medical need.