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: 7937917
• 负责人: Frances E Jensen
• 金额: $ 40.47万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7937917
• 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）：该申请涉及广泛的挑战领域（15）转化科学和特定挑战主题15- ns -103神经疾病新治疗方法的“概念验证”演示“进入NINDS转化研究计划需要证据证明新的治疗方法在神经疾病的动物或细胞模型中有效。NINDS寻求拨款进行研究，建立足够的概念证明，以启动临床前治疗开发工作。”癫痫（经常伴有认知合并症的反复发作）影响了超过1%的人口，并且在生命早期和婴儿期的发病率更高。超过30%的癫痫患者出现难治性癫痫发作，常规抗惊厥药不能达到癫痫发作抑制。婴儿痉挛是癫痫的一个亚组，发病率约为每2000例活产1例，癫痫发作难治性，如果不治疗，导致智力迟钝的发生率超过50%。这些令人信服的数字导致最近FDA批准的新型抗癫痫药物（aed）有所增加。最近批准的治疗难治性癫痫发作的药物之一是维加巴林。它于2009年1月被批准用于治疗一种称为婴儿痉挛的破坏性综合征，也可用于治疗成人难治性癫痫发作。Vigabatrin在这两种人群中具有独特的疗效，然而，尽管该药物已经在人类中使用了20多年，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陷和对大脑白质区域的潜在损伤。尽管vigabatrin现在是FDA唯一批准用于婴儿痉挛的药物，但当它最终于2009年1月获得批准时，它用于这两种适应症的条件是严格的筛选和视网膜毒性登记，因为这种副作用的发生率超过30%的治疗患者。虽然可以通过停用维加巴林来避免进一步的进展，但已经引起的损失无法恢复。FDA批准了一种副作用如此有限的药物，这一事实证明，在几乎没有其他治疗选择的患者群体中，vigabatrin是有必要的。目前的建议是一项临床前研究，以测试布美他尼的新用途，一种NKCC1氯化物转运抑制剂和FDA批准的利尿剂，作为维加巴林的辅助用药，以防止其高发病率和使用限制的副作用，视网膜毒性与视野缺陷。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。Vigabatrin在动物模型中似乎也会引起白质束损伤（髓内水肿）和人类患者的MRI白质异常。目前已有成熟的描述视网膜毒性和髓内水肿的大鼠模型，因此在动物模型中进行“概念验证”测试是可行的。该建议基于一个中心假设，即vigabatrin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的矛盾毒性作用导致视网膜细胞和白质少突胶质细胞损伤。在大多数情况下，GABA通过作为带负电荷的氯离子（Cl——）流入的通道，使膜超极化，从而抑制神经元的兴奋性。这可能是其有效使用抗惊厥药的机制。氯离子水平的维持是通过膜氯离子进口NKCC1和出口KCC2的平衡作用。重要的是，当NKCC1相对于KCC2过表达时，当GABA受体被激活时，细胞内Cl-将会高表达。Cl-将流出细胞，引起去极化和兴奋。这种兴奋可以触发由钙和自由基积累介导的兴奋毒性细胞死亡级联反应的激活。我的主要研究重点是癫痫发作的机制和神经递质功能的调节。实验文献有大量证据表明，NKCC1在视网膜光感受器和白质少突胶质细胞中表达升高，而这正是维加巴特林中毒的受影响细胞类型。该提案将测试NKCC1抑制剂bumetanide（一种耐受性良好的fda批准的利尿剂）在维加巴林诱导的视网膜毒性和白质损伤模型中的作用。此外，我们将评估人类视网膜样本，以探索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，这一提议既是一个“概念验证”研究计划，同时也提供了关于目标的人类表达的数据，如果这些数据显示出有效性，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副作用的严重程度将使vigabatrin得到更广泛的使用，vigabatrin是目前FDA批准的唯一用于婴儿痉挛的药物，也是对其他抗癫痫药物（aed）难治性的30%癫痫患者非常重要的替代治疗选择。因此，这项建议也解决了一个重要的未满足的需求。