Stewart Campbell A, Needham Brittany D, Meyer Christopher R, Tan Joanna, Conrad Mary, Preston Gregory M, Bolognani Federico, Rao Srinivas G, Heussler Helen, Griffith Rebecca, Guastella Adam J, Janes Amy C, Frederick Blaise, Donabedian David H, Mazmanian Sarkis K
Axial Therapeutics, Woburn, MA, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Nat Med. 2022 Mar;28(3):528-534. doi: 10.1038/s41591-022-01683-9. Epub 2022 Feb 14.
Autism spectrum disorder (ASD) is defined by hallmark behaviors involving reduced communication and social interaction as well as repetitive activities and restricted interests. ASD represents a broad spectrum, from minimally affected individuals to those requiring intense support, with additional manifestations often including anxiety, irritability/aggression and altered sensory processing. Gastrointestinal (GI) issues are also common in ASD, and studies have identified changes in the gut microbiome of individuals with ASD compared to control populations, complementing recent findings of differences in gut-derived metabolites in feces and circulation. However, a role for the GI tract or microbiome in ASD remains controversial. Here we report that an oral GI-restricted adsorbent (AB-2004) that has affinity for small aromatic or phenolic molecules relieves anxiety-like behaviors that are driven by a gut microbial metabolite in mice. Accordingly, a pilot human study was designed and completed to evaluate the safety of AB-2004 in an open-label, single-cohort, multiple-ascending-dose clinical trial that enrolled 30 adolescents with ASD and GI symptoms in New Zealand and Australia. AB-2004 was shown to have good safety and tolerability across all dose levels, and no drug-related serious adverse events were identified. Significant reductions in specific urinary and plasma levels of gut bacterial metabolites were observed between baseline and end of AB-2004 treatment, demonstrating likely target engagement. Furthermore, we observed improvements in multiple exploratory behavioral endpoints, most significantly in post hoc analysis of anxiety and irritability, as well as GI health, after 8 weeks of treatment. These results from an open-label study (trial registration no. ACTRN12618001956291) suggest that targeting gut-derived metabolites with an oral adsorbent is a safe and well-tolerated approach to improving symptoms associated with ASD, thereby emboldening larger placebo-controlled trials.
自闭症谱系障碍（ASD）的定义特征包括沟通和社交互动减少，以及重复行为和兴趣受限。ASD涵盖范围广泛，从受影响最小的个体到需要高强度支持的个体，其额外表现通常包括焦虑、易怒/攻击性以及感觉处理改变。胃肠道（GI）问题在ASD中也很常见，研究已确定与对照组人群相比，ASD个体的肠道微生物群存在变化，这与近期在粪便和循环中发现的肠道衍生代谢物差异相呼应。然而，胃肠道或微生物群在ASD中的作用仍存在争议。在此，我们报告一种对小芳香或酚类分子具有亲和力的口服胃肠道限制吸附剂（AB - 2004）可缓解小鼠肠道微生物代谢物驱动的焦虑样行为。因此，我们设计并完成了一项初步人体研究，以在一项开放标签、单队列、多剂量递增的临床试验中评估AB - 2004的安全性，该试验在新西兰和澳大利亚招募了30名患有ASD和胃肠道症状的青少年。结果显示，AB - 2004在所有剂量水平下均具有良好的安全性和耐受性，未发现与药物相关的严重不良事件。在AB - 2004治疗基线和结束之间，观察到肠道细菌代谢物的特定尿液和血浆水平显著降低，表明可能实现了靶点作用。此外，在治疗8周后，我们观察到多个探索性行为终点有所改善，最显著的是在焦虑和易怒的事后分析以及胃肠道健康方面。这项开放标签研究（试验注册号：ACTRN12618001956291）的结果表明，用口服吸附剂靶向肠道衍生代谢物是一种安全且耐受性良好的方法，可改善与ASD相关的症状，从而为更大规模的安慰剂对照试验提供了支持。
