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

• 批准号: 9918905
• 负责人: K Michael GIBSON
• 金额: $ 39.55万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918905
• 关键词: 4-Aminobutyrate aminotransferase; Address; Adjuvant Therapy; Analysis of Variance; Antiepileptic Agents; Aspartate Transaminase; Autophagocytosis; Cells; Cerebral cortex; Cerebrospinal Fluid; Chronic; Clinical; Clinical Research; Clinical Trials; Coupled; Development; Disease; Down Syndrome; Drug toxicity; Electron Microscopy; Epilepsy; Eye; Eye Development; FDA approved; FRAP1 gene; Functional disorder; Genes; Genetic; Hereditary Disease; Heritability; Immunohistochemistry; In Vitro; Infantile spasms; Intervention; Laboratories; 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; Role; 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; autism spectrum disorder; clinical development; clinically relevant; clinically significant; combinatorial; dosage; gamma-Aminobutyric Acid; inhibitor/antagonist; insight; mTOR Inhibitor; medication safety; mouse model; mutation screening; neurobehavioral; neurophysiology; novel; oxidative damage; pre-clinical; preclinical efficacy; preclinical study; research clinical testing

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.

超生理 GABA 是主要的抑制性神经递质，可以破坏自噬，导致自噬增加 线粒体数量和氧化应激，雷帕同种药物（雷帕霉素，Torin 1）可减轻这种影响 与自噬调节因子 mTOR（雷帕霉素的机制靶标）的相互作用。 GABA 相关病理学是 表现在遗传和药物诱导状态，包括遗传性琥珀酸半醛脱氢酶 缺乏症（SSADHD），以及抗癫痫药物（AED）氨己烯酸（VGB）的干预，其不可逆转 GABA 转氨酶 (GABA-T) 失活在机制上在 AED 中是独一无二的。长期VGB 然而，由于以下原因，干预措施（FDA 批准的唯一治疗婴儿痉挛症的方法）受到限制： 视网膜毒性的发展。假设 1 认为自噬途径涉及 GABA、mTOR 和 线粒体功能可以通过 rapalogs 来减轻，这将为患有遗传性、 或药物引起的 (VGB) GABA-T 和 SSADH 功能障碍。假设2假设rapalogs适用 局部（眼睛）与 VGB 结合，将改善视网膜毒性并扩展该 AED 的效用。目标1 以临床相关剂量向野生型小鼠长期施用 VGB，然后表征 全身/眼部影响以及雷帕霉素类似物减轻病理的潜力。目标 1a 将采用视觉诱发 视觉大脑皮层中的电位（VEP）以评估 VGB 眼部（视网膜）毒性，同时系统地瞄准 1b 使用光学/电子显微镜和免疫组织化学检查 VGB 治疗小鼠的视网膜以查明 细胞层与 VGB 诱导的毒性相关。目标 2 评估临床前 rapalog 的功效 在SSADHD小鼠模型中进行给药。目标 2a 询问神经行为和神经生理学 rapalog 干预对 aldh5a1-/- 小鼠的影响，而 Target 2b 检查 rapalog 在逆转细胞中的功效 信号传导-自噬-mTOR 异常，结合药物安全性和初步体外评估 毒性。我们将采用方差分析来了解 rapalog 干预对表型的影响及其 交互作用，然后进行调整后的 t 检验。 rapalogs 在患有以下疾病的患者中正在进行的临床评估 遗传性结节性硬化症为将我们的临床前结果转化为临床提供了先例。 消除VGB视网膜毒性的药物将在癫痫治疗中具有巨大的临床价值 疗法。此类药物还对SSADHD具有治疗相关性，同时可能导致新的治疗方法 其他疾病（自闭症、成瘾、唐氏综合症）的治疗范例，其中 GABA 升高很可能 具有病理生理学作用，进一步强调了我们的建议的广泛临床影响。

项目成果

Preferential accumulation of the active S-(+) isomer in murine retina highlights novel mechanisms of vigabatrin-associated retinal toxicity.

• DOI: 10.1016/j.eplepsyres.2020.106536
• 发表时间: 2021-03
• 期刊: Epilepsy research
• 影响因子: 2.2
• 作者: Walters DC;Jansen EEW;Salomons GS;Arning E;Ashcraft P;Bottiglieri T;Roullet JB;Gibson KM
• 通讯作者: Gibson KM