Adenosine kinase antisense gene therapy for temporal lobe epilepsy.

腺苷激酶反义基因治疗颞叶癫痫。

• 批准号: 9011551
• 负责人: Detlev Boison
• 金额: $ 41.25万
• 依托单位: LEGACY EMANUEL HOSPITAL AND HEALTH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011551
• 关键词: Adenosine; Adenosine Kinase; Adverse effects; Affect; Anticonvulsants; Antiepileptic Agents; Antisense Technology; Area; Astrocytes; Benchmarking; Biochemistry; Brain; Caffeine; Candidate Disease Gene; Cells; Clinical; Cognitive; Comorbidity; Data; Defect; Dependovirus; Development; Disease model; Dose; Down-Regulation; Effectiveness; Enzymes; Epilepsy; Excision; Gene Transduction Agent; Goals; Grant; Health; Hippocampus (Brain); Histology; Histopathology; Homeostasis; Human; Immune response; Impaired cognition; Injection of therapeutic agent; Intervention; Laboratories; Measures; Metabolic; Modeling; Mus; National Institute of Neurological Disorders and Stroke; Neurologic; Operative Surgical Procedures; Outcome; Pathology; Patients; Purinergic P1 Receptors; RNA; RNA Interference; Rattus; Refractory; Research; Research Proposals; Rodent; Rodent Model; Safety; Seizures; Serotyping; Signal Transduction; Specificity; Syndrome; System; Technology; Temporal Lobe Epilepsy; Therapeutic; Work; base; cell type; clinically relevant; design; gene therapy; knock-down; meetings; mind control; mouse model; neurobehavioral; nonhuman primate; novel strategies; novel therapeutics; overexpression; patient population; preclinical efficacy; preclinical safety; prevent; primary outcome; promoter; safety study; safety testing; standard of care; targeted treatment; therapeutic target; therapy development; vector

 DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) presents as an incapacitating neurological syndrome comprised of seizures and associated comorbidities. Seizures in up to 35% of patients with TLE are refractory to common forms of treatment, which are likewise largely ineffective to control comorbid conditions. In line with the NINDS Epilepsy Re- search Benchmarks this exploratory research proposal aims to develop an antisense gene therapy vector as a new approach for the targeted treatment of seizures and associated comorbidities in mesial TLE (mTLE). Our proposal is based on the rationale that deficiency of the endogenous anticonvulsant and seizure terminator adenosine (ADO) is a pathological hallmark of the epileptic brain. ADO-levels in the brain are controlled by metabolic clearance through the astrocyte-based enzyme adenosine kinase (ADK), which is pathologically overexpressed in the epileptic brain. Research from our and other laboratories has convincingly shown that therapeutic ADO augmentation or pharmacological ADK inhibition effectively prevent seizures in at least three different rodent models of mTLE, including seizures that are refractory to common antiepileptic drugs. Despite the proven effectiveness of ADO in seizure control, critical gaps for therapy development remain local specificity to avoid side effects of systemic ADO augmentation, and long-term effectiveness. The overarching goal of our application is (i) to develop, optimize, and characterize a final clinical gene therapy candidate to reduce (not suppress) ADK expression in the epileptic brain through antisense technology and thereby to reinstate near to normal ADO function, and (ii) to provide rigorous efficacy data in two clinically relevant rodent models of mTLE. Availability of a final clinical candidate and proof of effectiveness in relevant disease models are pre-requisites to initiate a pre-pre-IND interaction with the FDA, which is the final expected deliverable of this application. Our approach is supported by preliminary data showing effectiveness of ADO augmentation in a mouse model of pharmacoresistant mTLE and the availability of antisense constructs to reduce ADK expression in astrocytes. TLE patients with pharmacoresistant seizures and who are candidates for resection surgery are ideal subjects for a mechanism-based gene therapy aimed at down-regulating ADK within the epileptogenic hippocampus for several reasons: (i) identification of ADK as a rational and effective therapeutic target; (ii) defined focal area of epileptogenicity to e targeted by local gene therapy; (iii) confinement of endogenous ADK expression largely to astrocytes minimizes off-target effects of astrocyte-selective therapy; (iv) adverse ADO effects, though un- expected, could be treated with the ADO receptor antagonist caffeine; (v) reversibility (i.e. surgical resection) of gene therapy, if needed. Our Specific Aims are: (1) Develop a clinical candidate gene therapy product to effectively reduce ADK expression in astrocytes. (2) Perform preclinical efficacy and safety tests in two clinically relevant rodent models of mTLE. (3) Prepare regulatory documents for discussion at a pre-pre-IND meeting with the FDA.

 描述（由申请人提供）：颞叶癫痫（TLE）表现为一种失能性神经系统综合征，包括癫痫发作和相关合并症。高达35%的TLE患者的癫痫发作对常见的治疗形式是难治性的，这些治疗形式同样在很大程度上对控制合并症无效。根据NINDS癫痫研究基准，该探索性研究提案旨在开发反义基因治疗载体，作为靶向治疗近中TLE（mTLE）癫痫发作和相关合并症的新方法。我们的建议是基于这样的基本原理，即内源性抗惊厥药和癫痫发作终止剂腺苷（ADO）的缺乏是癫痫脑的病理标志。脑中的ADO水平由通过基于星形胶质细胞的酶腺苷激酶（ADK）的代谢清除控制，ADK在癫痫脑中病理性地过表达。我们和其他实验室的研究令人信服地表明，治疗性ADO增强或药理学ADK抑制可有效预防至少三种不同mTLE啮齿动物模型中的癫痫发作，包括常见抗癫痫药物难治性癫痫发作。尽管ADO在癫痫控制中的有效性已得到证实，但治疗开发的关键差距仍然是避免全身ADO增强的副作用的局部特异性和长期有效性。我们申请的首要目标是（i）开发、优化和表征最终的临床基因治疗候选物，以通过反义技术减少（而不是抑制）癫痫脑中的ADK表达，从而恢复接近正常的ADO功能，以及（ii）在两个临床试验中提供严格的功效数据。 mTLE的相关啮齿动物模型。最终临床候选药物的可用性和相关疾病模型的有效性证明是启动与FDA的pre-pre-IND交互的先决条件，这是本申请的最终预期交付成果。我们的方法得到了初步数据的支持，这些数据显示了ADO增强在耐药性mTLE小鼠模型中的有效性以及反义构建体减少星形胶质细胞中ADK表达的可用性。具有药物抗性癫痫发作并且是切除手术的候选者的TLE患者是旨在下调致癫痫海马内的ADK的基于机制的基因治疗的理想对象，原因如下：（i）ADK被鉴定为合理且有效的治疗靶点;（ii）被局部基因治疗靶向的致癫痫灶性区域被限定;（iii）内源性ADK表达主要局限于星形胶质细胞使星形胶质细胞选择性治疗的脱靶效应最小化;（iv）不良的ADO效应，尽管不是预期的，但可以用ADO受体拮抗剂咖啡因治疗;（V）如果需要，基因治疗的可逆性（即手术切除）。我们的具体目标是：（1）开发临床候选基因治疗产品，以有效降低星形胶质细胞中ADK的表达。(2)在两种临床相关的mTLE啮齿动物模型中进行临床前有效性和安全性试验。(3)准备监管文件，以便在IND前会议上与FDA进行讨论。