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是一种主要的抑制性神经递质，它可以破坏自噬，导致细胞凋亡增加

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