小柯机器人

美国加州理工学院Sarkis K. Mazmanian、Axial Therapeutics公司A. Stewart Campbell等研究人员合作完成口服小分子螯合剂对自闭症谱系障碍青少年的安全性和目标参与的临床试验。2022年2月14日，《自然—医学》杂志在线发表了这项成果。

研究人员表示，自闭症谱系障碍（ASD）的定义是涉及减少沟通和社会互动的标志性行为，以及重复性活动和限制性兴趣。ASD代表了一个广泛的谱系，从受影响最小的个体到需要强烈支持的个体，其他表现通常包括焦虑、易怒/攻击性和感官处理的改变。胃肠道（GI）问题在ASD中也很常见，研究发现ASD患者的肠道微生物组与对照组相比有变化，补充了最近发现的粪便和循环中的肠道衍生代谢物的差异。然而，消化道或微生物组在ASD中的作用仍有争议。

研究人员报告了一种口服限制消化道的吸附剂（AB-2004），它对小的芳香族或酚类分子有亲和力，可以缓解小鼠的焦虑样行为，这些行为是由肠道微生物代谢物驱动的。因此，设计并完成了一项试验性人体研究，以评估AB-2004在一项开放标签、单组、多级剂量的临床试验中的安全性，该试验在新西兰和澳大利亚招募了30名患有ASD和消化道症状的青少年。试验表明，AB-2004在所有剂量水平上都具有良好的安全性和耐受性，没有发现与药物有关的严重不良事件。在AB-2004治疗的基线和结束期间，研究人员观察到特定的尿液和血浆中的肠道细菌代谢物水平明显下降，表明可能靶向参与。

此外，研究人员观察到多个探索性行为终点的改善，在治疗8周后的焦虑和烦躁以及消化道健康的事后分析中最为明显。这些来自开放标签研究（试验注册号：ACTRN12618001956291）的结果表明，用口服吸附剂靶向肠道代谢物是一种安全且耐受性良好的方法，可以改善与ASD相关的症状，从而为更大规模的安慰剂对照试验增加信心。

附：英文原文

Title: Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial

Author: 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.

Issue&Volume: 2022-02-14

Abstract: 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.

DOI: 10.1038/s41591-022-01683-9

Source: https://www.nature.com/articles/s41591-022-01683-9

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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