Preclinical Development of AAV-Galanin for Epilepsy

AAV-甘丙肽治疗癫痫的临床前开发

• 批准号: 7540498
• 负责人: Scott William John McPhee
• 金额: $ 28.37万
• 依托单位: ASKLEPIOS BIOPHARMACEUTICAL, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540498
• 关键词: Address; Alternative Therapies; Animal Model; Antiepileptic Agents; Antiepileptogenic; Attenuated; Biological Assay; Biological Products; Body Temperature; Capsid; Clinical; Clinical Research; Control Groups; Dependovirus; Development; Dose; Epilepsy; Excision; Feasibility Studies; Focal Seizure; Galanin; Gene Delivery; Generations; Genes; Genome; Image; Infusion procedures; Injection of therapeutic agent; Intellectual Property; Intraventricular; Kainic Acid; Kindling (Neurology); Label; Lobe; Manuscripts; Mediating; Medical; Modeling; Numbers; Operative Surgical Procedures; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase II Clinical Trials; Probability; Public Health; Publishing; Range; Rattus; Reflux; Relative (related person); Research Design; Resistance; Resolution; Rights; Rodent; Safety; Schedule; Seizures; Site; Technology; Temporal Lobe; Testing; Therapeutic; Tissues; Titrations; Toxic effect; Toxicology; Transgenes; Ventricular; Water consumption; adeno-associated viral vector; base; design; food consumption; gene therapy; lateral ventricle; mouse model; novel; novel therapeutics; particle; pre-clinical; preclinical study; research study; response; success; transduction efficiency; vector; ventricular system

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.

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的专有技术进步，开发用于治疗癫痫的基于AAV的甘丙肽基因递送。Asklepios Biopharmaceutical，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.指导甘丙肽分泌的基因盒，2.）使用自身互补基因组，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组成部分，这为美国估计有35万至70万抗癫痫药物无效的患者带来了很大的希望。该I期建议中详述的可行性实验将确定含有自身互补FIB-甘丙肽转基因盒的嵌合AAV 2.5的有效剂量范围（dsAAV2.5 FIB-GAL），以及使用两种不同的边缘癫痫发作小鼠模型检查颅内施用dsAAV2.5 FIB-GAL治疗中颞叶癫痫（MTLE）的功效和安全性，局灶性电点燃和外周红藻氨酸给药。我们完全期望拟议研究的结果支持推进到II期研究，包括啮齿动物和大型动物模型的确定性临床前研究，以及支持IND提交的关键安全性和毒理学研究。所提出的初始临床研究将在患有MTLE的受试者中进行，这些受试者已经是手术切除的候选者，并且将采用涉及在计划切除致癫痫/dsAAV2.5 FIB-GAL输注组织之前进行基因递送的研究设计。公共卫生相关性：Asklepios Biopharmaceutical，Inc.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350- 700 K药物治疗未能解决癫痫发作的患者，手术切除提供了一种潜在的解决方案。所提出的治疗方法，一种AAV介导的甘丙肽递送，旨在提供一种替代疗法，以满足这一长期的医疗需求。