Characterizing an AMPA Receptor Splice Modulator in Preventing Epileptogenesis

表征 AMPA 受体剪接调节剂预防癫痫发生的作用

• 批准号: 8323886
• 负责人: MELANIE K TALLENT
• 金额: $ 16.09万
• 依托单位: LIFESPLICE PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323886
• 关键词: AMPA Receptors; Adult; Alternative Splicing; Animal Disease Models; Animal Model; Antisense Oligonucleotides; Bilateral; Brain; Chemistry; Chronic; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Comorbidity; Development; Disease; Dose; Epilepsy; Epileptogenesis; Gene Targeting; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Hour; Human; Infant; Injection of therapeutic agent; Kinetics; Marketing; Mediating; Modeling; Monitor; Motor; Mus; Muscular Dystrophies; Neonatal; Oligonucleotides; Pharmaceutical Preparations; Pilocarpine; Predisposition; Property; Protein Isoforms; RNA Splicing; Reporting; Research; Seizures; Small Interfering RNA; Specificity; Spinal Muscular Atrophy; Status Epilepticus; Synapses; Technology; Testing; Therapeutic; Time; Tissues; Transcript; Traumatic Brain Injury; Variant; Vulnerable Populations; behavior test; brain tissue; chronic pain; cognitive function; design; excitotoxicity; hippocampal pyramidal neuron; in vivo; kainate; mouse model; neonate; nervous system disorder; neurotransmission; novel; novel strategies; novel therapeutics; prevent; protective effect; receptor expression

DESCRIPTION (provided by applicant): AMPA glutamate receptors mediate the majority of fast excitatory neurotransmission in the brain. Four AMPA receptor subunits exist, GluR1-GluR4, with functional channels containing various combinations of these four subunits. In hippocampal and cortical pyramidal neurons, AMPA receptors are comprised largely of GluR1/GluR2 and GluR2/GluR3 heteromeric tetramers. Dysregulation of AMPA receptor expression has been reported in many neurological disorders, including epilepsy. AMPA receptors are alternatively spliced, with the best-characterized splice variants being the flip and flop isoforms. AMPA receptors containing flip vs. flop cassettes have distinct channel properties. GluR1 flip and flop variants have similar kinetics, but the flip isoform shows greater sensitivity to glutamate, increasing synaptic gain. Expression of flip channels is associated with greater vulnerability to excitotoxicity and hyperexcitability. Increases in GluR1 flip to flop ratio in hippocampus and cortex are found in epileptic tissue in humans and animal models and may contribute to development of epilepsy (epileptogenesis) and seizure susceptibility. Thus normalizing aberrant splicing represents a novel therapeutic strategy for preventing epileptogenesis. Splice modulating oligonucleotides (SMOs) have unique chemistries and distinct advantages over classic antisense oligonucleotides and siRNA, and are in clinical trials for treating muscular dystrophy and spinal muscular atrophy. We have developed an SMO that specifically and potently reduces GluR1 flip in vivo. We have also shown that knockdown of GluR1 flip with its selective SMO protects against seizures in a neonatal epilepsy model and can prevent post-seizure hyperexcitability associated with epileptogenesis. The goals of this application are to continue to test our novel SMO in mouse models of epileptogenesis in both neonates and adults, to determine if it protects against development of chronic seizures and their deleterious cognitive comorbidities. Our studies are the first to target modulation of alternative splicing as a therapeutic approach for preventing the development of epilepsy, a critical unmet need. Further, our approach represents a new platform technology in epilepsy therapeutics that is applicable to many additional gene targets.

描述（由申请人提供）： AMPA谷氨酸受体介导大脑中大部分快速兴奋性神经传递。存在四种AMPA受体亚基，GluR 1-GluR 4，具有含有这四种亚基的各种组合的功能通道。在海马和皮质锥体神经元中，AMPA受体主要由GluR 1/GluR 2和GluR 2/GluR 3异聚四聚体组成。AMPA受体表达失调已在许多神经系统疾病中报道，包括癫痫。AMPA受体是可变剪接的，最具特征的剪接变体是翻转异构体。含有翻转盒的AMPA受体具有不同的通道特性。GluR 1翻转和翻转变体具有相似的动力学，但翻转异构体对谷氨酸表现出更大的敏感性，增加突触增益。翻转通道的表达与兴奋性毒性和过度兴奋性的更大脆弱性相关。在人类和动物模型的癫痫组织中发现海马和皮质中GluR 1翻转比增加，可能有助于癫痫（癫痫发生）和癫痫发作易感性的发展。因此，正常化异常剪接代表了一种新的治疗策略，以防止癫痫发生。剪接调节寡核苷酸（SMOs）具有独特的化学性质和优于经典反义寡核苷酸和siRNA的独特优势，并且正在临床试验中用于治疗肌营养不良和脊髓性肌萎缩。我们已经开发了一种SMO，可以特异性地有效降低体内GluR 1翻转。我们还表明，敲低GluR 1翻转及其选择性SMO可在新生儿癫痫模型中防止癫痫发作，并可预防与癫痫发生相关的癫痫发作后过度兴奋。本申请的目的是继续在新生儿和成人癫痫发生的小鼠模型中测试我们的新型SMO，以确定它是否可以防止慢性癫痫发作及其有害的认知共病的发展。我们的研究是第一个靶向调节选择性剪接作为预防癫痫发展的治疗方法，这是一个关键的未满足的需求。此外，我们的方法代表了癫痫治疗的新平台技术，适用于许多其他基因靶点。