Methionine is an essential proteinogenic amino acid, but its excess can lead to deleterious effects. Inborn errors of methionine metabolism resulting from loss of function in cystathionine β-synthase (CBS) cause classic homocystinuria (HCU), which is managed by a methionine-restricted diet. Synthetic biotics are gastrointestinal tract-targeted live biotherapeutics that can be engineered to replicate the benefits of dietary restriction. In this study, we assess whether SYNB1353, an Nissle 1917 derivative, impacts circulating methionine and homocysteine levels in animals and healthy volunteers. In both mice and nonhuman primates (NHPs), SYNB1353 blunts the appearance of plasma methionine and plasma homocysteine in response to an oral methionine load. A phase 1 clinical study conducted in healthy volunteers subjected to an oral methionine challenge demonstrates that SYNB1353 is well tolerated and blunts plasma methionine by 26%. Overall, SYNB1353 represents a promising approach for methionine reduction with potential utility for the treatment of HCU.

中文翻译：

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活生物治疗药物 SYNB1353 通过在动物模型和健康志愿者中的直接降解来降低血浆蛋氨酸

蛋氨酸是一种必需的蛋白质氨基酸，但过量会导致有害影响。由于胱硫醚 β-合酶 (CBS) 功能丧失而导致的先天性蛋氨酸代谢缺陷会导致典型的同型半胱氨酸尿症 (HCU)，可通过限制蛋氨酸饮食来控制。合成生物素是针对胃肠道的活生物治疗药物，经过改造可以复制饮食限制的益处。在这项研究中，我们评估了 SYNB1353（一种 Nissle 1917 衍生物）是否影响动物和健康志愿者的循环蛋氨酸和同型半胱氨酸水平。在小鼠和非人灵长类动物 (NHP) 中，SYNB1353 会减弱口服蛋氨酸负荷后血浆蛋氨酸和血浆同型半胱氨酸的出现。在接受口服蛋氨酸挑战的健康志愿者中进行的 1 期临床研究表明，SYNB1353 具有良好的耐受性，可使血浆蛋氨酸降低 26%。总体而言，SYNB1353 代表了一种有前途的减少蛋氨酸的方法，具有治疗 HCU 的潜在用途。