Rapalog Therapy in Heritable and Vigabatrin-Induced GABA Metabolic Disorders

Rapalog 疗法治疗遗传性和氨己烯酸诱导的 GABA 代谢紊乱

基本信息

批准号：
9555110
负责人：
K Michael GIBSON
金额：
$ 8.65万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9555110
关键词：
4-Aminobutyrate aminotransferase Address Adjuvant Therapy Analysis of Variance Antiepileptic Agents Aspartate Transaminase Autistic Disorder Autophagocytosis Cells Cerebral cortex Cerebrospinal Fluid Chronic Clinical Clinical Research Clinical Trials Coupled Development Disease Down Syndrome Electron Microscopy Epilepsy Eye Eye Development FDA approved FRAP1 gene Functional disorder Genes Genetic Heritability Immunohistochemistry In Vitro Infantile spasms Intervention Laboratories Light Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Target Mus Neurotransmitters Orphan Outcome Oxidative Stress Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Pilot Projects Retina Retinal Role Safety Scotoma Signal Transduction Sirolimus Succinate-semialdehyde dehydrogenase deficiency Testing Therapeutic Toxic effect Translating Tuberous Sclerosis Vigabatrin Visual Visual evoked cortical potential Wild Type Mouse Yeasts addiction adverse outcome aldehyde dehydrogenases clinical development clinically relevant clinically significant combinatorial dosage gamma-Aminobutyric Acid inhibitor/antagonist insight mTOR Inhibitor mouse model mutation screening neurobehavioral neurophysiology novel oxidative damage pre-clinical preclinical efficacy preclinical study research clinical testing

项目摘要

Supraphysiological GABA, the primary inhibitory neurotransmitter, can disrupt autophagy resulting in increased mitochondrial number and oxidative stress, an effect mitigated by rapalog drugs (rapamycin, Torin 1) via interaction with the autophagy regulator, mTOR (mechanistic target of rapamycin). GABA-related pathology is manifest in genetic and drug-induced states, including heritable succinate semialdehyde dehydrogenase deficiency (SSADHD), and intervention with the antiepileptic drug (AED) vigabatrin (VGB), whose irreversible inactivation of GABA-transaminase (GABA-T) is mechanistically unique among AEDs. Long-term VGB intervention (the sole FDA-approved treatment for infantile spasms), however, is curtailed due to the development of retinal toxicity. Hypothesis 1 posits that autophagic pathways involving GABA, mTOR and mitochondrial function can be mitigated with rapalogs that will provide clinical benefit in patients with heritable, or medication-induced (VGB), dysfunction of GABA-T and SSADH. Hypothesis 2 posits that rapalogs applied locally (eye), in combination with VGB, will ameliorate retinal toxicity and extend the utility of this AED. Aim 1 chronically administers VGB to wild type mice in clinically relevant dosages, followed by characterization of systemic/ocular effects and the potential of rapalogs to mitigate pathology. Aim 1a will employ visual evoked potentials (VEPs) in the visual cerebral cortex to assess VGB ocular (retinal) toxicity, while aim 1b systematically examines the retina of VGB-treated mice using light/electron microscopy and immunohistochemistry to pinpoint cell layers associated with VGB-induced toxicity. Aim 2 evaluates the efficacy of preclinical rapalog administration in a murine model of SSADHD. Aim 2a interrogates the neurobehavioral and neurophysiological effects of rapalog intervention in aldh5a1-/- mice, while aim 2b examines the efficacy of rapalogs in reversing cell signaling-autophagy-mTOR abnormalities, coupled to a preliminary in vitro assessment of drug safety and toxicity. We will employ ANOVA to understand the impact of rapalog intervention on phenotype, and their interactions, followed by adjusted post hoc t-tests. Ongoing clinical evaluation of rapalogs in patients with heritable tuberous sclerosis provides the precedent for translating our preclinical outcomes to the bedside. Pharmaceutical agents that eliminate the retinal toxicity of VGB will have enormous clinical value in epilepsy therapeutics. Such agents will also have therapeutic relevance to SSADHD, while potentially leading to novel treatment paradigms for other disorders (autism, addiction, Down syndrome) in which elevated GABA may well have pathophysiological roles, further highlighting the broad clinical impact of our proposal.

主抑制性神经递质Supraphyologology GABA可能会破坏自噬，从而增加线粒体数和氧化应激，通过Rapalog药物（雷帕霉素，Torin 1）通过与自噬调节剂MTOR（雷帕霉素的机械靶标）相互作用。与GABA相关的病理是在遗传和药物诱导的状态中表现出来，包括可遗传的琥珀酸酯半二醛脱氢酶缺乏症（SSADHD）和抗癫痫药（AED）Vigabatrin（VGB）的干预在AED中，GABA - Tansaminase（GABA-T）的失活在机械上是独一无二的。长期VGB 但是，干预（唯一的FDA批准治疗婴儿痉挛）由于视网膜毒性的发展。假设1认为涉及GABA，MTOR和的自噬途径线粒体功能可以通过RAPALOG来减轻，这些旋转将为具有遗传性，可遗传的患者提供临床益处或药物诱导的（VGB），GABA-T和SSADH的功能障碍。假设2假设蓝胶应用局部（眼）与VGB结合使用，可以改善视网膜毒性并扩展该AED的效用。目标1 长期以临床相关剂量为野生型小鼠的VGB，然后表征全身/眼效应以及甲壳虫减轻病理学的潜力。 AIM 1A将使用视觉唤起视觉大脑皮层中的电势（VEP）评估VGB眼（视网膜）毒性，而AIM 1B系统地。使用光/电子显微镜和免疫组织化学来查明经VGB处理的小鼠的视网膜以查明与VGB诱导的毒性相关的细胞层。 AIM 2评估临床前蓝胶的功效在SSADHD的鼠模型中给药。 AIM 2A询问神经行为和神经生理学 Rapalog干预对AldH5A1 - / - 小鼠的影响，而AIM 2B检查了Rapalogs在逆转细胞中的功效信号 - 自助噬菌异常，结合药物安全的体外评估和毒性。我们将采用ANOVA了解Rapalog干预对表型的影响及其相互作用，然后进行调整后的事后t检验。正在进行的临床评估对患者的Rapalogs 可遗传的结节硬化症为将我们的临床前结果转化为床边提供了先例。消除VGB视网膜毒性的药物将具有癫痫的巨大临床价值疗法。此类药物也将与SSADHD具有治疗性相关，同时有可能导致新颖其他疾病的治疗范例（自闭症，成瘾，唐氏综合症），其中升高的GABA可能很好具有病理生理作用，进一步强调了我们的提议的广泛临床影响。