新颖的治疗方法-猫眼课题宝

新颖的治疗方法

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

项目状态：

已结题

起止时间：

2008-12-01 至 2015-11-30

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

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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.

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