Novel Treatment & Screening Strategies in Gamma-Hydroxybutyric Aciduria

新颖的治疗方法

基本信息

批准号：
7938768
负责人：
K Michael GIBSON
金额：
$ 35.6万
依托单位：
MICHIGAN TECHNOLOGICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7938768
关键词：
Absence Epilepsy Adult Adverse effects Affect Affinity Agonist American Amino Acids Animals Arginine Benzodiazepine Receptor Binding Biological Markers Blood Body Fluids Brain Brain region Cerebrospinal Fluid Chronic Clinical Clinical Data Clinical Trials Coupled Data Detection Development Disease Down-Regulation Electroencephalography Ethosuximide Evaluation Exposure to Flumazenil Foundations Generalized convulsive epilepsy Goals Human Human Identifications Intervention Link Liquid substance Mediating Medical Genetics Metabolic Diseases Methodology Methods Mus Nature Neonatal Screening Neuraxis Neurologic Neuropharmacology Neurotransmitters Newborn Infant Outcome Outcome Measure Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase II Clinical Trials Phenotype Phosphinic Acids Physiological Policies Positron-Emission Tomography Research Personnel Resources SGS-742 Safety Screening procedure Secondary to Seizures Sensitivity and Specificity Spottings Structure Succinate-semialdehyde dehydrogenase Succinate-semialdehyde dehydrogenase deficiency Syndrome System Transcranial magnetic stimulation Urine Work aldehyde dehydrogenases analog cohort college cost design effective therapy gamma-Aminobutyric Acid guanidinoacetate human disease improved neurogenetics neuropsychiatry neuropsychological novel pilot trial pre-clinical prevent receptor receptor binding receptor function research clinical testing tandem mass spectrometry treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Human succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1 (Aldh5a1)) deficiency is a rare neurogenetic disorder affecting the GABA neurotransmitter system. Aldh5a1-/- mice manifest early absence seizures which evolve into lethal generalized convulsive epilepsy, similar to seizure phenotypes observed in the human disease. The investigators' long-term goals are to define an effective treatment strategy for patients and springboard that treatment into expanded newborn screening for SSADH deficiency. The investigators will work toward these goals via the following hypotheses and aims: Hypothesis 1 is that chronic application of SGS-742, an orally active GABAB receptor (GABABR) antagonist, to Aldh5a1-/- mice will prevent early lethality and normalize neuropharmacological abnormalities. Specific Aim 1 will characterize anthropormorphics, neuropharmacology, seizure threshold, and GABABR structure in Aldh5a1-/- mice treated with SGS-742. Hypothesis 2 is that SGS-742 intervention in adult SSADH-deficient patients will improve neuropsychological deficits and restore GABABR function downregulated by chronic exposure to supraphysiological GABA levels. Specific Aim 2 will be a pilot trial of SGS-742 in six adult SSADH-deficient patients using neuropsychiatric evaluations and transcranial magnetic stimulation (TMS; estimating GABABR function) as outcome measures. Hypothesis 3 is that guanidinobutyrate (GB), a GABA analogue elevated in SSADH-deficient physiological fluids, represents a reliable biomarker to identify SSADH deficiency in newborn bloodspots. Specific Aim 3 implements a pilot evaluation of newborn screening for SSADH deficiency that will establish normative ranges and sensitivity/specificity correlations. The design is cohort-control except for Aim 2, where each patient will serve as their own control. Accepted methodology is applied throughout (neuropharmacology, tandem mass spectrometry, neuropsychological batteries), although the use of noninvasive TMS in this disorder is novel.

描述（由申请人提供）：人类琥珀酸半甲醛脱氢酶（ssadh;醛脱氢酶5A1（ALDH5A1））缺乏症是一种影响GABA神经递质系统的罕见神经遗传疾病。 Aldh5A1 - / - 小鼠表现出早期脱落的癫痫发作，这些癫痫发作演变成致命的抽搐癫痫，类似于人类疾病中观察到的癫痫发作表型。研究人员的长期目标是为患者定义有效的治疗策略，并将治疗板延长到新生儿筛查中，以减少SSADH缺乏症。研究人员将通过以下假设和目标来实现这些目标：假设1是，SGS-742的长期应用（口服活跃的Gabab受体（GABABR）拮抗剂）在ALDH5A1 - / - 小鼠中会预防早期致死性并正常化肾上腺病理学的人。特定的目标1将表征拟人化，神经药理学，癫痫发作阈值和GABABR结构，以SGS-742处理。假设2是SGS-742对成年SSADH缺陷患者的干预将改善神经心理缺陷，并通过长期暴露于Suphissiology Gaba水平下调的GABABR功能恢复了GABABR功能。具体的目标2将是使用神经精神病学评估和经颅磁刺激（TMS；估计GABABR功能）作为结果指标的六名成年SSADH缺陷患者的SGS-742试验试验。假设3是，在缺乏SSADH缺乏的生理流体中升高的GABA类似物Guanidinobutyrate（GB）代表了一种可靠的生物标志物，可识别新生儿血液中的Ssadh缺乏。特定目标3实施了对SSADH缺乏症的新生儿筛查的试点评估，该筛查将建立规范范围和灵敏度/特异性相关性。该设计是队列控制的，除了AIM 2，每个患者将作为自己的控制。尽管在这种疾病中使用非侵蚀性TMS的使用是新颖的，但在整个过程中都应用了公认的方法学（神经药理学，串联质谱，神经心理学电池）。