Genetic defects in cystathionine beta-synthase (CBS), a key enzyme of organic sulfur metabolism, result in deficiency of CBS activity and a rare inborn error of metabolism called classical homocystinuria (HCU). HCU is characterized by massive accumulation of homocysteine, an intermediate of methionine metabolism, and multisystemic clinical symptoms. Current treatment options for HCU are very limited and often inefficient, partially due to a low patient compliance with very strict dietary regimen. Novel therapeutic approaches are needed to cope with the toxic accumulation of homocysteine and restoration of a healthy metabolic balance. Human CBS is a complex intracellular multimeric enzyme that relies on three cofactors (heme, pyridoxal-5'-phosphate and S-adenosylmethionine) for proper function. Engineering and chemical modification of human CBS yielded OT-58, a first-in-class enzyme therapy candidate for HCU. Pre-clinical testing of OT-58 showed its substantial efficacy in lowering plasma and tissue concentrations of homocysteine, improving metabolic balance and correcting clinical symptoms of HCU. In addition, OT-58 showed great safety and toxicity profile when administered to non-human primates. Overwhelmingly positive and extensive pre-clinical package propelled OT-58 into a first-in-human clinical trial, which started on January 2019. In a meantime, other enzyme therapies based on modified human cystathionine gamma-lyase or erythrocyte-encapsulated bacterial methionine gamma-lyase have shown efficacy in decreasing plasma homocysteine in HCU mice. In addition, gene therapy approaches using adenovirus or minicircle DNA have been evaluated in HCU. In this review, we summarize the current efforts developing novel therapies for HCU to address a high unmet medical need among HCU patients.

中文翻译：

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经典的高胱氨酸尿症：从胱硫醚β合酶缺乏症到新型酶疗法。

胱硫醚β-合酶（CBS）是有机硫代谢的关键酶，其遗传缺陷导致CBS活性不足和罕见的先天性代谢错误，称为经典高半胱氨酸尿症（HCU）。HCU的特征是高半胱氨酸（蛋氨酸代谢的中间产物）的大量积累和多系统性临床症状。当前HCU的治疗选择非常有限，而且通常效率不高，部分原因是患者对非常严格的饮食方案的依从性较低。需要新颖的治疗方法来应对同型半胱氨酸的毒性积累和恢复健康的代谢平衡。人CBS是一种复杂的细胞内多聚酶，它依赖于三种辅助因子（血红素，5'-磷酸吡ido醛和S-腺苷甲硫氨酸）才能发挥正常功能。对人类CBS的工程改造和化学修饰产生了OT-58，这是HCU的一流酶治疗候选物。OT-58的临床前测试表明，它在降低血浆和组织中同型半胱氨酸的浓度，改善代谢平衡和纠正HCU的临床症状方面具有显着的功效。此外，OT-58对非人类灵长类动物给药时，显示出极大的安全性和毒性。极度积极和广泛的临床前包装使OT-58进入了首次于人的临床试验，该试验于2019年1月开始。与此同时，其他基于修饰的人胱硫醚γ-裂合酶或红细胞包裹的细菌蛋氨酸γ的酶疗法β-裂合酶已显示出降低HCU小鼠血浆同型半胱氨酸的功效。此外，在HCU中已经评估了使用腺病毒或小环DNA的基因治疗方法。在这篇综述中，我们总结了当前为HCU开发新疗法以解决HCU患者中高度未满足的医疗需求的努力。