Preclinical Development of AAV-Galanin for Epilepsy

描述（由申请人提供）：本申请旨在利用腺相关病毒（AAV）载体介导基因治疗的专有技术进步，开发一种基于AAV的甘丙肽基因递送，用于治疗癫痫。Asklepios biopharmaceuticals, Inc. （Askbio）已获得知识产权，开发并商业化一种抗癫痫生物制剂，其中包含三项关键技术：1.)指导丙氨酸分泌的基因盒，2.)使用自互补基因组，以及3.)特异性进化的嵌合AAV2.5衣壳。将这些技术结合到一种可行的癫痫替代基因疗法中是这项提议的一个新颖组成部分，这为美国估计有35 -70万抗癫痫药物无效的患者带来了很大的希望。该I期方案的可行性实验将确定含有自互补的FIB-Galanin转基因盒（dsAAV2.5 FIB-GAL）的嵌合AAV2.5的有效剂量范围，并采用两种不同的小鼠模型，局部电点燃和外周kainic酸给药，检查颅内给药dsAAV2.5 FIB-GAL治疗中颞叶癫痫（MTLE）的有效性和安全性。我们完全期望拟议研究的结果支持推进到II期研究，包括明确的临床前研究，在啮齿动物和大型动物模型中，以及关键的安全性和毒理学研究，以支持IND提交。拟议的初始临床研究将在MTLE患者中进行，他们已经是手术切除的候选人，并将采用一种研究设计，包括在预定切除致痫性/dsAAV2.5 FIB-GAL灌注组织之前进行基因传递。公共卫生相关性：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，其中大多数是几十年前的。对于药物治疗无法解决癫痫发作的350-700K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介导的丙氨酸递送，旨在提供一种替代疗法，以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.