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.

Public Health Relevance

Autism spectrum disorder (ASD) is a devastating neurodevelopmental disorder with life-long consequences that is estimated to affect 1 out of 68 individuals in the United States. Despite the dramatic rise in ASD over the past two decades there remains no effective medical treatment for its core symptoms. A reduced form of folate, called folinic acid, may be able to both improve core and associated symptoms of ASD as well as improve underlying biological abnormalities, thereby substantially helping millions of individuals with ASD.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Behavioral Genetics and Epidemiology Study Section (BGES)
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Kau, Alice S
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Arkansas Children's Hospital Research Institute
Little Rock
United States
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