Fatty acid supplements alter biological signatures in children with Autism Spectrum Disorder

摘要 脂肪酸补充剂是自闭症谱系障碍（ASD）儿童消费的最受欢迎的补充产品之一，这是由轶事证据和一些小规模的RCT证明的益处，这些RCT证明了外化行为的改善。因为没有批准的药物可以治疗ASD的核心症状，善意的父母正在寻求任何可能帮助他们孩子的产品。这意味着，在没有任何证据基础的情况下，向儿童提供脂肪酸补充剂，以说明其功能，作用机制，有效剂量或益处与危害。非处方（OTC）脂肪酸补充剂是丰富的，由不同的脂肪酸组成，通常含有其他成分。我们小组和其他人最近的证据表明，与其他配方相比，鱼油和琉璃苣油的组合提供DHA，EPA和GLA（“Omega 3-6”）的补充特别有前途。在开展严格的全面疗效试验之前，迫切需要评估Omega 3-6的最佳剂量以及与ASD症状相关的生理学相关生物特征的变化。我们的目标是评估更高剂量的Omega 3-6对预先指定的生物特征的影响。我们的总体假设是，Omega 3-6的最佳剂量将以与ASD相关行为改善相关的方式改变生物特征。该提案的R61阶段将测试Omega 3-6将在一种或多种炎症标志物IL-1β，IL-2和IFNγ中产生临床显著降低（改善）的假设，并且我们的更高剂量将证明生物利用度，安全性和耐受性。该提案的R33阶段将测试对生物特征的影响与Omega 3-6剂量相关的假设，可以在新的患者样本中复制，并且关键炎症标志物的变化与补充后的核心ASD症状相关。在完成这个拟议的2阶段项目后，我们预计已经确定了Omega 3-6对炎症以及随后对儿童ASD症状发挥作用的最佳剂量范围。这些结果预计将产生重要的积极影响，为全面的疗效试验奠定必要的基础，以评估Omega 3-6对ASD症状改善的影响。

ABSTRACT Fatty acid supplements are among the most popular complementary products consumed by children with Autism Spectrum Disorder (ASD), driven by anecdotal evidence of benefit and a few small RCTs that demonstrated improvements in externalizing behaviors. Because no approved drugs exist to treat the core symptoms of ASD, well-intentioned parents are reaching for any product that may help their child. The implications are that fatty acid supplements are given to children without any evidence base as to their function, mechanism of action, effective dose, or benefits versus harms. Over-the-counter (OTC) fatty acid supplements are plentiful and consist of varying fatty acid compositions and often contain other ingredients. Recent evidence from our group and others suggest a combination of fish and borage oils providing supplementation of DHA, EPA and GLA (“Omega 3-6”) is particularly promising compared to other formulations. A critical need exists to evaluate Omega 3-6 for optimal dosing and changes in a physiologically relevant biological signature related to ASD symptoms, before a rigorous, full-scale efficacy trial can be launched. Our objective is to evaluate the effects of higher doses of Omega 3-6 on pre-specified biological signatures Our overall hypothesis is that optimal dosing of Omega 3-6 will alter biological signatures in a manner that correlates with improvements in ASD-related behaviors. The R61 phase of this proposal will test the hypothesis that Omega 3-6 will produce a clinically-significant reduction (improvement) in one or more the inflammatory markers IL-1β, IL-2, and IFNγ and our higher doses will demonstrate bioavailability, safety, and tolerability. The R33 phase of this proposal will test the hypothesis that the impact on biological signatures correlates with Omega 3-6 dose, can be replicated in a new sample of patients, and the change in key inflammatory marker(s) are correlated with core ASD symptoms after supplementation. Upon completion of this proposed 2-phase project, we expect to have identified an optimal dosing range for which Omega 3-6 exerts its effect on inflammation and, subsequently, on ASD symptoms in children. Such results are expected to have an important positive impact by laying the necessary groundwork for a full-scale efficacy trial to evaluate the effect of Omega 3-6 on ASD symptom improvement.