A High-dose Folinic Acid Treatment for Core and Associated Symptoms of Autism

高剂量亚叶酸治疗自闭症核心及相关症状

• 批准号: 10205120
• 负责人: RICHARD Eugene FRYE
• 金额: $ 50.67万
• 依托单位: PHOENIX CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205120
• 关键词: Address; Affect; Age; Antibodies; Arkansas; Attention; Autoantibodies; Behavior Therapy; Biological; Biological Markers; Blood - brain barrier anatomy; Brain; Centers for Disease Control and Prevention (U.S.); Child; Childhood; Clinical; Communication; Data; Disease; Dose; Double-Blind Method; Educational Intervention; Equation; FOLR1 gene; Family; Folic Acid; Functional disorder; Genes; Genetic Markers; Genetic Polymorphism; Glutathione; Goals; Health; High Prevalence; Hyperactivity; Immune; Immunologic Markers; Immunologic Tests; Individual; Infrastructure; Insurance; Intervention; Language; Language Tests; Lethargies; Leucovorin; Life; Medical; Metabolic; Metabolic Pathway; Metabolism; Methylation; Neural Pathways; Neurodevelopmental Disorder; Occupational Therapy; Outcome; Oxidation-Reduction; Pathway interactions; Pediatric Hospitals; Pharmaceutical Preparations; Phase; Physiological; Placebos; Prevalence; Probability; Psychopharmacology; Randomized; Recovery; Research; Site; Social Functioning; Special Education; Speech Therapy; Stereotyped Behavior; Subgroup; Supportive care; Symptoms; System; Testing; United States; Universities; Validation; Work; associated symptom; autism spectrum disorder; autistic children; biological systems; clinical predictors; communication behavior; critical developmental period; double-blind placebo controlled trial; enzyme pathway; evaluation/testing; folic acid metabolism; impression; improved; individuals with autism spectrum disorder; innovation; instrument; language impairment; open label; overtreatment; placebo controlled study; predicting response; predictive marker; primary outcome; repetitive behavior; research clinical testing; response; social communication; standard of care; treatment group; treatment response

Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder that affects 1-2% of individuals in the United States. However, no effective medical treatment has been developed to address core (communication, social function, stereotyped behavior) or associated (attention, hyperactivity, irritability) ASD symptoms and/or underlying pathophysiological abnormalities associated with ASD. The goal of this work is to develop a safe, well-tolerated medical treatment with efficacy for improving core and associated ASD symptoms and pathophysiological abnormalities associated with ASD. Such an innovative treatment would have the potential to be disease-modifying and could augment on-going standard-of-care educational and behavioral therapies. Studies have demonstrated the importance of folate metabolism in children with ASD. Several folate-dependent metabolic systems, including methylation and glutathione redox metabolism, demonstrate abnormalities in individuals with ASD. Several detrimental polymorphisms in folate and folate- related pathway genes have been associated with ASD. Autoantibodies to the folate receptor alpha have a high prevalence in children with ASD and can interfere with folate transport into the brain. Most importantly, we have demonstrated that a reduced form of folate, known as folinic acid, may have efficacy in improving both core and associated symptoms of ASD and physiological abnormalities associated with ASD. Most notable, in a small double-blind placebo-controlled study, we have demonstrated that folinic acid significantly improves language in children with ASD with a medium-to-large effect size, confirming findings from our earlier open- label studies. This effect appears to be particularly strong in children with ASD who manifest folate receptor alpha autoantibodies with a large effect sizes and number needed to treat of about 2. Hyperactivity, lethargy and irritability were also found to significantly improve. We propose to conduct a large (N=162) multicenter double-blind placebo-controlled study to confirm the efficacy of high-dose folinic acid on core and associated symptoms of ASD using centers and infrastructure developed as part of the Research Units on Pediatric Psychopharmacology (RUPP) Autism Network which has conducted many of the major ASD drug trials, including Emory and Harvard University sites in addition to Arkansas Children's Hospital. This study will also examine whether immune (folate receptor alpha autoantibodies) and genetic (polymorphism in folate-related metabolic pathways) biomarkers can predict response to treatment in order to better identify the individuals that will benefit from this treatment. This project is innovative as it investigates a treatment that addresses both ASD symptoms and underlying pathophysiological abnormalities associated with ASD, and aims to define biomarkers that identify subgroups of children with ASD who will response to the treatment. Given that physiological abnormalities in folate-related systems are rather pervasive in ASD, this project has the potential to improve the health of a substantial proportion of individuals with ASD.

自闭症谱系障碍（ASD）是一种破坏性的神经发育障碍，影响1-2%的个人 在美国然而，尚未开发出有效的医学治疗来解决核心问题。 （沟通、社会功能、刻板行为）或相关（注意力、多动、易怒）ASD 症状和/或与ASD相关的潜在病理生理异常。这项工作的目标是 开发一种安全、耐受性良好的药物治疗，有效改善核心和相关ASD 与ASD相关的症状和病理生理异常。这种创新的治疗方法将 具有改善疾病的潜力，可以增强正在进行的护理标准教育和 行为疗法研究表明叶酸代谢在ASD儿童中的重要性。 几种叶酸依赖性代谢系统，包括甲基化和谷胱甘肽氧化还原代谢， 在ASD患者中表现出异常。叶酸和叶酸盐的几种有害多态性- 相关通路基因与ASD相关。叶酸受体α的自身抗体具有 在ASD儿童中的患病率很高，并且可以干扰叶酸转运到大脑中。最重要的是我们 已经证明，一种还原形式的叶酸，称为亚叶酸，可以有效地改善这两个方面， ASD的核心和相关症状以及与ASD相关的生理异常。最值得注意的是， 一项小型的双盲安慰剂对照研究，我们已经证明亚叶酸可以显著改善 语言在ASD儿童中具有中等至大的效应量，证实了我们早期开放式研究的结果， 标签研究。这种效应在表现出叶酸受体的ASD儿童中表现得特别强烈 α自身抗体具有大的效应大小，治疗所需的数量约为2.活动过度，嗜睡 和易怒也被发现显着改善。我们建议进行一项大型（N=162）多中心 一项双盲安慰剂对照研究，以证实高剂量亚叶酸对核心和相关 ASD的症状使用中心和基础设施开发的儿科研究单位的一部分， 精神药理学（RUPP）自闭症网络已经进行了许多主要的ASD药物试验， 包括埃默里大学和哈佛大学以及阿肯色州儿童医院。本研究还将 检查是否免疫（叶酸受体α自身抗体）和遗传（叶酸相关的多态性） 代谢途径）生物标志物可以预测对治疗的反应，以便更好地鉴定个体 会从这种治疗中受益。这个项目是创新的，因为它调查了一种治疗方法， ASD症状和与ASD相关的潜在病理生理异常，旨在定义 这些生物标志物用于识别ASD儿童的亚组，这些亚组将对治疗产生反应。鉴于 叶酸相关系统的生理异常在ASD中相当普遍，该项目具有潜在的 改善大部分ASD患者的健康状况。

项目成果

The Soluble Folate Receptor in Autism Spectrum Disorder: Relation to Autism Severity and Leucovorin Treatment.

• DOI: 10.3390/jpm12122033
• 发表时间: 2022-12-08
• 期刊: JOURNAL OF PERSONALIZED MEDICINE
• 作者: Frye, Richard E.;Lane, Alison;Worner, Ashley;Werner, Brianna A.;McCarty, Patrick J.;Scheck, Adrienne C.;Collins, Heidi L.;Adelman, Steven J.;Quadros, Edward V.;Rossignol, Daniel A.
• 通讯作者: Rossignol, Daniel A.