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

基本信息

  • 批准号:
    7937917
  • 负责人:
  • 金额:
    $ 40.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Frances E Jensen其他文献

Developmental regulation of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor subunit expression in forebrain and relationship to regional susceptibility to hypoxic/ischemic injury. II. Human cerebral white matter and cortex
前脑α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸受体亚基表达的发育调节及其与缺氧/缺血性损伤的区域易感性的关系II。
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Delia M Talos;Pamela L. Follett;R. Folkerth;Rachel Fishman;F. Trachtenberg;J. Volpe;Frances E Jensen
  • 通讯作者:
    Frances E Jensen

Frances E Jensen的其他文献

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{{ truncateString('Frances E Jensen', 18)}}的其他基金

Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease
癫痫发作诱导的突触信号增强调节阿尔茨海默病中 tau 蛋白的传递性
  • 批准号:
    10611518
  • 财政年份:
    2022
  • 资助金额:
    $ 40.47万
  • 项目类别:
Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease
癫痫发作诱导的突触信号增强调节阿尔茨海默病中 tau 蛋白的传递性
  • 批准号:
    10455852
  • 财政年份:
    2022
  • 资助金额:
    $ 40.47万
  • 项目类别:
The NKCC1 inhibitor bumetanide as a novel therapy in TSC
NKCC1 抑制剂布美他尼作为 TSC 的新型疗法
  • 批准号:
    8457417
  • 财政年份:
    2012
  • 资助金额:
    $ 40.47万
  • 项目类别:
The NKCC1 inhibitor bumetanide as a novel therapy in TSC
NKCC1 抑制剂布美他尼作为 TSC 的新型疗法
  • 批准号:
    8554384
  • 财政年份:
    2012
  • 资助金额:
    $ 40.47万
  • 项目类别:
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
  • 财政年份:
    2009
  • 资助金额:
    $ 40.47万
  • 项目类别:
Understanding the Cognitive Impact of Early Life Epilepsy
了解早期癫痫对认知的影响
  • 批准号:
    7341202
  • 财政年份:
    2007
  • 资助金额:
    $ 40.47万
  • 项目类别:
Understanding the Cognitive Impact of Early Life Epilepsy
了解早期癫痫对认知的影响
  • 批准号:
    8650480
  • 财政年份:
    2007
  • 资助金额:
    $ 40.47万
  • 项目类别:
Understanding the Cognitive Impact of Early Life Epilepsy
了解早期癫痫对认知的影响
  • 批准号:
    8119615
  • 财政年份:
    2007
  • 资助金额:
    $ 40.47万
  • 项目类别:
Understanding the Cognitive Impact of Early Life Epilepsy
了解早期癫痫对认知的影响
  • 批准号:
    7914219
  • 财政年份:
    2007
  • 资助金额:
    $ 40.47万
  • 项目类别:
Understanding the Cognitive Impact of Early Life Epilepsy
了解早期癫痫对认知的影响
  • 批准号:
    7681264
  • 财政年份:
    2007
  • 资助金额:
    $ 40.47万
  • 项目类别:

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