Dietary treatment of Glucose Transporter Type 1 Deficiency (G1D)

1 型葡萄糖转运蛋白缺乏症 (G1D) 的饮食治疗

• 批准号: 9755514
• 负责人: Juan M. Pascual
• 金额: $ 80.94万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755514
• 关键词: Absence Epilepsy; Acetyl Coenzyme A; Acute; Address; Age; American; Anatomy; Ataxia; Attention; Authorization documentation; Biochemical; Blood; Blood Glucose; Brain; Carbohydrates; Carbon; Carbon Dioxide; Cerebrum; Childhood; Citric Acid Cycle; Clinic; Clinical; Clinical Trials; Consumption; Convulsions; Craniocerebral Trauma; Data; Defect; Dementia; Dependence; Development; Diagnosis; Diet; Diet therapy; Dietary Fats; Dimensions; Disease; Dose; Electroencephalography; Encephalopathies; Energy Metabolism; Enrollment; Epilepsy; Ethics; Exhibits; Fatty Acids; Fatty acid glycerol esters; Food; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Future; Genes; Glucose; Glucose Transporter; Health; Hepatic; Hour; Human; Hyperglycemia; Impairment; Inferior; Intervention; Intuition; Investigation; Ketone Bodies; Ketosis; Laboratories; Lead; Lesion; Link; Liver diseases; Longevity; Measures; Medical; Metabolic; Metabolism; Mission; Motivation; Mus; Mutation; Myopathy; Nervous System Physiology; Neurologic; Neurophysiology - biologic function; Neuropsychology; Nutritional; Oils; Organism; Outcome; Outcome Measure; Patients; Performance; Personal Satisfaction; Pharmaceutical Preparations; Physiological; Plasma; Population; Positron-Emission Tomography; Proteins; Public Health; Publishing; Rare Diseases; Reaction; Refractory; Reproducibility; Research; Rodent; Safety; Seizures; Status Epilepticus; Supplementation; Synapses; Syndrome; Testing; Therapeutic; Therapeutic Studies; Tricarboxylic Acids; Triglycerides; United States National Institutes of Health; Water; Work; age group; appropriate dose; beta-Hydroxybutyrate; brain metabolism; clinical investigation; comparative; dietary restriction; disability; expectation; gastrointestinal; glucose metabolism; improved; indexing; innovation; ketogenic diet; ketogentic; medical food; metabolic rate; mouse model; network dysfunction; neuronal excitability; novel; nutrient metabolism; pre-clinical; primary outcome; recruit; restoration; secondary outcome; stem; therapy development

Still considered a rare disease, partial deficiency of the brain glucose transporter type I (G1D) is diagnosed in a broad variety of encephalopathies with increasing frequency. Its most common form – and that with the greatest public health impact – is a childhood-onset epilepsy associated (in all epilepsy cases) with neuropsychological impairment, which is refractory to antiseizure drugs and has consequently remained almost inextricably linked to the ketogenic diet therapy for 25 years. No clinical trials have been conducted for G1D, but the carbohydrate- restricted ketogenic diet (recommended in G1D-associated epilepsy to maximize ketosis and nourish the brain) leads to a physiological - and intuitively counterproductive - decrease in blood glucose available to the brain. Our primary objective is to evaluate whether partial dietary replacement with triheptanoin (C7, a widely available food-grade synthetic triglyceride extensively used in small quantities in human consumption applications) can safely modulate neuropsychological performance (specifically, attention scores) in G1D epilepsy. To support this objective, our published data inform this and other outcome measures chosen here. The scientific motivation is to account for two aspects of brain glucose metabolism: (1) Full degradation of glucose by the tricarboxylic acid (TCA) cycle into CO2 and water; and (2) Stimulation of the TCA cycle (by another glucose fraction amounting to about 20% of all brain glucose) by the refilling of natural TCA precursor loss via carbon-donor reactions collectively termed anaplerosis. In this context, another limitation of ketogenic diets is that their constitutive fatty acids and derivative ketone bodies, are devoid of anaplerotic capacity, and are thus consumed as in (1) without contributing to (2). Results from our and from two other laboratories indicate that C7 metabolites are anaplerotic in rodents, fulfilling both (1) and (2). C7 metabolism also favorably impacts neuronal excitability and convulsions in epileptic mouse models, including G1D. This is the mechanistic framework in which C7 will be examined. Thus, our main hypothesis is that C7 supplementation of a regular diet impacts (and this is key in a rare disease) widely-available outcome measures of G1D encephalopathy. An additional hypothesis, prerequisite for future combined- or comparative-therapy research, is that the addition of C7 to the ketogenic diet does not interfere with it analytically or clinically. These expectations will be tested in G1D patients who are already receiving (i.e., prior to enrollment) either a regular diet or a ketogenic diet. The proposal is significant because its go/no-go perspective and criteria will address whether C7 can be developed as a medical food treatment for G1D. Particularly innovative is the investigation of brain anaplerotic therapy, which can be expanded to disorders associated with deficient brain glucose states such as those identified by fludeoxyglucose-PET scan (for example, head trauma, dementia and lesional epilepsy). The ethical dimensions and projection of this research are underscored by its use of a broadly verifiable (i.e., accessible and reproducible) food-grade intervention for a severe, hardly treatable disease. If successful, this work may thus catalyze a medical practice transformation.

脑葡萄糖转运蛋白I型（G1 D）的部分缺陷仍然被认为是一种罕见的疾病，在各种各样的脑病中被诊断出的频率越来越高。其最常见的形式-也是对公共卫生影响最大的形式-是与神经心理障碍相关的儿童期发作的癫痫（在所有癫痫病例中），这是抗癫痫药物难治性的，因此25年来几乎与生酮饮食疗法密不可分。尚未对G1 D进行临床试验，但限制碳水化合物的生酮饮食（在G1 D相关癫痫中推荐，以最大化酮症并滋养大脑）导致大脑可用的血糖生理性和直观上适得其反的降低。我们的主要目的是评估用三庚酸甘油酯（C7，一种广泛使用的食品级合成甘油三酯，广泛用于人类消费应用）部分饮食替代是否可以安全地调节G1 D癫痫患者的神经心理学表现（特别是注意力评分）。为了支持这一目标，我们公布的数据为本文选择的这一结果指标和其他结果指标提供了信息。科学动机是解释脑葡萄糖代谢的两个方面：（1）通过三羧酸（TCA）循环将葡萄糖完全降解为CO2和水;以及（2）通过碳供体反应补充天然TCA前体损失来刺激TCA循环（通过另一种葡萄糖部分，约占所有脑葡萄糖的20%） 统称回补。在这种情况下，生酮饮食的另一个局限性是其组成性脂肪酸和衍生酮体缺乏回补能力，因此如（1）中所述被消耗而不会有助于（2）。我们和其他两个实验室的结果表明，C7代谢物在啮齿动物中具有回补作用，满足（1）和（2）。C7代谢还有利地影响癫痫小鼠模型（包括G1 D）中的神经元兴奋性和惊厥。这是C7将被检查的机制框架。因此，我们的主要假设是，常规饮食的C7补充影响（这是罕见疾病的关键）G1 D脑病的广泛可用的结局指标。另一个假设是，未来联合或比较治疗研究的先决条件是，在生酮饮食中添加C7不会在分析或临床上干扰它。这些预期将在已经接受（即，在登记之前）常规饮食或生酮饮食。该提案意义重大，因为其去/不去的观点和标准将解决C7是否可以作为G1 D的医疗食品治疗开发。特别创新的是对脑回补疗法的研究，该疗法可以扩展到与脑葡萄糖缺乏状态相关的疾病，例如通过氟脱氧葡萄糖-PET扫描确定的疾病（例如，头部创伤、痴呆和病灶性癫痫）。这项研究的伦理方面和预测是通过使用一个广泛可核实的（即，可获得和可重复的）食品级干预措施，用于治疗严重的、难以治愈的疾病。如果成功的话，这项工作可能会促进医疗实践的转变。