Attenuating the retinal and CNS adverse effects of vigabatrin with NKCC1 inhibito

通过 NKCC1 抑制剂减轻氨己烯酸对视网膜和中枢神经系统的不良影响

• 批准号: 7829070
• 负责人: Frances E Jensen
• 金额: $ 40.88万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7829070
• 关键词: 4-Aminobutyrate aminotransferase; Address; Adjuvant; Adult; Adverse effects; Affect; Animal Model; Animals; Anticonvulsants; Antiepileptic Agents; Area; Attenuated; Brain; Bumetanide; Butyric Acids; Calcium; Cell Death; Cell model; Cells; Cerebrum; Charge; Chloride Ion; Chlorides; Clinical Trials; Cognitive; Comorbidity; Data; Diuretics; Edema; Epilepsy; Equilibrium; Eye Banks; FDA approved; Free Radicals; GABA Receptor; Grant; Human; Incidence; Infantile spasms; Injury; Lead; Life; Literature; Live Birth; Magnetic Resonance Imaging; Mediating; Membrane; Mental Retardation; Modeling; National Institute of Neurological Disorders and Stroke; Neurotransmitters; Oligodendroglia; Patients; Pharmaceutical Preparations; Photoreceptors; Population; Prevention; Rattus; Recovery; Recurrence; Refractory; Registries; Relative (related person); Research; Retina; Retinal; Retinal Photoreceptors; Rodent; Rodent Model; Safety; Sampling; Screening procedure; Seizures; Severities; Subgroup; Syndrome; Testing; Tissues; Toxic effect; Translational Research; Translations; Vigabatrin; Visual Fields; Work; alternative treatment; cell injury; cell type; gamma-Aminobutyric Acid; improved; infancy; inhibitor/antagonist; nervous system disorder; neuronal excitability; novel; novel therapeutic intervention; overexpression; patient population; pre-clinical; preclinical study; prevent; programs; protective effect; public health relevance; therapeutic development; white matter; white matter injury

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Areas (15) Translational Science, and Specific Challenge Topic 15-NS-103 Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease "Entry into the NINDS translational research program requires evidence that a new therapeutic approach is efficacious in an animal or cell model of a neurological disease. The NINDS seeks grants to conduct research that establishes proof-of-concept sufficient to initiate a preclinical therapeutic development effort". The Challenges and Potential Impact Epilepsy (recurrent seizures often with cognitive comorbidities) affects over 1% of the population, and has higher incidences in early life and infancy. Over 30% of patients with epilepsy suffer refractory seizures, and do not reach seizure suppression with conventional anticonvulsants. Infantile spasms is a subgroup of epilepsy and has an incidence of approximately 1 per 2000 live births, with seizures being refractory and if untreated leads to greater than a 50% incidence in mental retardation. These compelling numbers have lead to a recent increase in newer antiepileptic drugs (AEDs) being approved by the FDA. One of the most recent drugs for refractory seizures to be approved is vigabatrin. It was approved for use in 1/09 for the treatment of a devastating syndrome termed infantile spasms, and also for treatment of refractory seizures in adults. Vigabatrin has a unique profile of efficacy in these two populations, however while the drug has been available for human use for over 20 years, a major roadblock to its approval had been its adverse effects: retinal toxicity causing progressive irreversible visual field deficits and a potential injury to cerebral white matter regions. Despite vigabatrin now being the only FDA approved agent for infantile spasms, when it was finally approved in 1/09, its use for both indications was conditional upon rigorous screening and a registry for retinal toxicity, as the incidence of this side effect is over 30% of treated patients. While further progression can be avoided by discontinuation of vigabatrin, there is no recovery of loss already induced. The fact that the FDA approved a drug with such limiting side effects is testimony to the need for vigabatrin in a population of patients where there are little to no alternative treatment options. The present proposal is a preclinical study to test the novel use of bumetanide, an NKCC1 chloride transporter inhibitor and FDA approved diuretic, as an adjuvant administered with vigabatrin, to prevent its high incidence and use-limiting side effect of retinal toxicity with visual field deficits. To date, the mechanism of these adverse effects is unknown, and no specific curative or preventative treatment exists. Vigabatrin also appears to induce injury to white matter tracts (intramyelinic edema) in animal models and MRI white matter abnormalities in human patients. There are well established described rat models of the retinal toxicity and intramyelinic edema, making it feasible to test "proof-of-concept" in animal models. The proposal hinges on a central hypothesis that vigabatrin, a 3-amino butyric acid (GABA) transaminase inhibitor that increases tissue levels of the endogenous inhibitory and anticonvulsant neurotransmitter GABA, causes damage to retinal cells and white matter oligodendrocytes via paradoxical toxic effects of GABA. GABA in most instances inhibits neuronal excitability by hyperpolarizing the membrane via being a channel for influx of negatively charged ion chloride (Cl--). This is the likely mechanism for its effective anticonvulsant use. Cl- levels are maintained by balancing actions of a membrane Cl- importer NKCC1 and the exporter KCC2. Importantly, when NKCC1 is overexpressed relative to KCC2, Cl- will be high intracellularly and thus when GABA receptors are activated. Cl- will flow out of the cell, causing depolarization and excitation. This excitation could trigger activation of excitotoxic cell death cascades mediated by calcium and free radical accumulation. A major focus of my research has been on mechanisms of seizures and modulation of neurotransmitter function. There is substantial evidence in experimental literature to suggest that there is elevated NKCC1 expression in retinal photoreceptors and white matter oligodendrocytes, which are precisely the affected cell types in vigabatrin toxicity. This proposal will test the effects of the NKCC1 inhibitor bumetanide, a well tolerated FDA-approved diuretic, in models of vigabatrin-induced retinal toxicity and white matter injury. In addition, we will evaluate human retinal samples to explore the cell specific expression of NKCC1 to determine whether this is a valid target for treatment in humans. Hence this proposal is both a "proof-of-concept" research plan as well as providing data regarding the human expression of the target that might facilitate further translation to clinical trials if these data show efficacy. Amelioration and/or prevention of the severity of this use limiting side effect would enable more widespread use of vigabatrin, which is now the only FDA approved agent for infantile spasms, and also a very important alternative treatment option for the 30% of patients with epilepsy that is refractory to other antiepileptic drugs (AEDs). Hence this proposal also addresses an important unmet need. PUBLIC HEALTH RELEVANCE: Epilepsy affects over 1% of the US population, and up to 30% of people suffering from epilepsy do not respond to conventional antiepileptic drugs (AEDs). The newly FDA-approved AED vigabatrin has improved efficacy in this population yet its use has been limited by a 30% incidence of severe irreversible retinal and brain toxicity. The present proposal addresses the mechanism of this toxicity and proposes to attenuate this with a novel agent bumetanide, which has a good safety profile in humans in its use for unrelated indications. No current treatment for the irreversible side effects of vigabatrin exists, and successful demonstration of efficacy of bumetanide in animal models of vigabatrin toxicity proposed here will facilitate clinical trials in patients receiving vigabatrin for refractory epilepsy.

描述（由申请人提供）：本申请涉及广泛的挑战领域 (15) 转化科学和具体挑战主题 15-NS-103 展示神经系统疾病新治疗方法的“概念验证”“进入 NINDS 转化研究计划需要有证据表明新的治疗方法在神经系统疾病的动物或细胞模型中有效。NINDS 寻求拨款来开展建立概念验证的研究足以 启动临床前治疗开发工作”。挑战和潜在影响 癫痫（反复发作通常伴有认知合并症）影响超过 1% 的人口，并且在生命早期和婴儿期发病率较高。超过30%的癫痫患者患有难治性癫痫发作，并且常规抗惊厥药物无法抑制癫痫发作。婴儿痉挛症是癫痫的一个亚组，发病率约为每 2000 名活产婴儿中就有 1 人罹患，癫痫发作是难治性的，如果不治疗，会导致智力低下的发生率超过 50%。这些引人注目的数字导致最近 FDA 批准的新型抗癫痫药物 (AED) 有所增加。最近获得批准的治疗难治性癫痫发作的药物之一是氨己烯酸。它于 1/09 被批准用于治疗一种称为婴儿痉挛症的破坏性综合征，也用于治疗成人难治性癫痫发作。氨己烯酸对这两个人群具有独特的功效，然而，虽然该药物已用于人类超过 20 年，但其批准的主要障碍是其副作用：视网膜毒性导致进行性不可逆的视野缺损，并对大脑白质区域造成潜在损伤。尽管氨己烯酸目前是 FDA 唯一批准的治疗婴儿痉挛症的药物，但当它最终于 1 月 9 日获得批准时，它对这两种适应症的使用都取决于严格的筛查和视网膜毒性登记，因为这种副作用的发生率超过治疗患者的 30%。虽然通过停用氨己烯酸可以避免进一步的进展，但已经引起的损失无法恢复。 FDA 批准了一种具有如此有限副作用的药物这一事实证明，在几乎没有替代治疗选择的患者群体中需要氨己烯酸。本提案是一项临床前研究，旨在测试布美他尼（一种 NKCC1 氯转运蛋白抑制剂和 FDA 批准的利尿剂）作为与氨己烯酸一起服用的佐剂的新用途，以防止其高发生率和限制使用的视网膜毒性副作用（伴有视野缺陷）。迄今为止，这些不良反应的机制尚不清楚，也没有具体的治疗或预防方法。氨己烯酸似乎还会引起动物模型白质束损伤（髓鞘内水肿）和人类患者的 MRI 白质异常。已经建立了完善的视网膜毒性和髓鞘内水肿大鼠模型，使得在动物模型中测试“概念验证”成为可能。该提案基于一个中心假设，即氨己烯酸是一种 3-氨基丁酸 (GABA) 转氨酶抑制剂，可增加内源性抑制和抗惊厥神经递质 GABA 的组织水平，通过 GABA 的矛盾毒性作用对视网膜细胞和白质少突胶质细胞造成损害。在大多数情况下，GABA 通过成为带负电荷的氯化物 (Cl-) 流入通道而使膜超极化来抑制神经元兴奋性。这可能是其有效抗惊厥用途的机制。 Cl- 水平是通过膜 Cl- 输入器 NKCC1 和输出器 KCC2 的平衡作用来维持的。重要的是，当 NKCC1 相对于 KCC2 过度表达时，细胞内的 Cl- 会很高，因此当 GABA 受体被激活时。 Cl-会流出细胞，引起去极化和激发。这种兴奋可能触发由钙和自由基积累介导的兴奋毒性细胞死亡级联的激活。我研究的一个主要重点是癫痫发作的机制和神经递质功能的调节。实验文献中有大量证据表明，视网膜光感受器和白质少突胶质细胞中 NKCC1 表达升高，而这正是氨己烯酸毒性中受影响的细胞类型。该提案将测试 NKCC1 抑制剂布美他尼（一种 FDA 批准的耐受性良好的利尿剂）在氨己烯酸诱导的视网膜毒性和白质损伤模型中的效果。此外，我们将评估人类视网膜样本，探索 NKCC1 的细胞特异性表达，以确定这是否是人类治疗的有效靶点。因此，该提案既是一个“概念验证”研究计划，又提供了有关目标的人类表达的数据，如果这些数据显示出功效，则可能有助于进一步转化为临床试验。改善和/或预防这种使用限制性副作用的严重性将使氨己烯酸得到更广泛的使用，氨己烯酸目前是 FDA 批准的唯一治疗婴儿痉挛症的药物，对于 30% 的其他抗癫痫药物 (AED) 无效的癫痫患者来说，也是一种非常重要的替代治疗选择。因此，该提案还解决了一个重要的未满足需求。 公共卫生相关性：癫痫影响超过 1% 的美国人口，高达 30% 的癫痫患者对传统抗癫痫药物 (AED) 没有反应。 FDA 新批准的 AED 氨己烯酸 (vigabatrin) 改善了该人群的疗效，但其使用受到 30% 的严重不可逆视网膜和脑毒性发生率的限制。本提案解决了这种毒性的机制，并建议用一种新药布美他尼来减轻这种毒性，布美他尼在用于不相关的适应症时对人类具有良好的安全性。目前尚无针对氨己烯酸不可逆副作用的治疗方法，本文提出的氨己烯酸毒性动物模型中成功证明布美他尼的功效将有助于接受氨己烯酸治疗难治性癫痫的患者进行临床试验。