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Novel Treatment & Screening Strategies in Gamma-Hydroxybutyric Aciduria

新颖的治疗方法

基本信息

批准号：
8390456
负责人：
K Michael GIBSON
金额：
$ 25.94万
依托单位：
WASHINGTON STATE 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 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8390456
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 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 screening 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）：人琥珀半醛脱氢酶（SSADH；乙醛脱氢酶 5a1 (Aldh5a1)）缺陷是一种影响 GABA 神经递质系统的罕见神经遗传性疾病。 Aldh5a1-/- 小鼠表现出早期失神性癫痫发作，并演变成致命的全身性惊厥性癫痫，类似于在人类疾病中观察到的癫痫表型。研究人员的长期目标是为患者制定有效的治疗策略，并为扩大新生儿 SSADH 缺乏症筛查奠定基础。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，对 Aldh5a1-/- 小鼠长期应用 SGS-742（一种口服活性 GABAB 受体 (GABABR) 拮抗剂）将防止早期致死并使神经药理学异常正常化。具体目标 1 将表征经 SGS-742 治疗的 Aldh5a1-/- 小鼠的拟人化、神经药理学、癫痫阈值和 GABABR 结构。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恢复因长期暴露于超生理 GABA 水平而下调的 GABABR 功能。具体目标 2 将是在六名成年 SSADH 缺陷患者中进行 SGS-742 的试点试验，使用神经精神评估和经颅磁刺激（TMS；估计 GABABR 功能）作为结果测量。假设 3 是胍基丁酸 (GB)，一种 GABA 类似物，在 SSADH 缺乏的生理液中升高，是识别新生儿血斑中 SSADH 缺乏的可靠生物标志物。具体目标 3 对新生儿 SSADH 缺乏症筛查进行试点评估，建立规范范围和敏感性/特异性相关性。该设计是队列对照，目标 2 除外，其中每个患者将作为自己的对照。尽管在这种疾病中使用非侵入性 TMS 是新颖的，但整个过程中都应用了公认的方法（神经药理学、串联质谱法、神经心理学电池）。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Placental stem cell correction of murine intermediate maple syrup urine disease.

DOI：
10.1002/hep.26150
发表时间：
2013-03
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Skvorak, Kristen J.;Dorko, Kenneth;Marongiu, Fabio;Tahan, Veysel;Hansel, Marc C.;Gramignoli, Roberto;Gibson, K. Michael;Strom, Stephen C.
通讯作者：
Strom, Stephen C.

Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease.

DOI：
10.1186/1750-1172-9-73
发表时间：
2014-05-08
期刊：
Orphanet journal of rare diseases
影响因子：
3.7
作者：
Vogel KR;Arning E;Wasek BL;McPherson S;Bottiglieri T;Gibson KM
通讯作者：
Gibson KM

Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAHENU2 mice.

DOI：
10.1007/s10545-012-9524-8
发表时间：
2013-05
期刊：
JOURNAL OF INHERITED METABOLIC DISEASE
影响因子：
4.2
作者：
Vogel, Kara R.;Arning, Erland;Wasek, Brandi L.;Bottiglieri, Teodoro;Gibson, K. Michael
通讯作者：
Gibson, K. Michael

Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood-brain phenylalanine transport in Pah enu2 mice: preliminary findings.

2-(甲基氨基)链烷酸限制 Pah enu2 小鼠血脑苯丙氨酸转运能力的表征：初步发现。