A phase I trial with Transgenic bacteria expressing interleukin-10 in Crohn's disease
A phase I trial with Transgenic bacteria expressing interleukin-10 in Crohn's disease
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DOI：
10.1016/j.cgh.2006.03.028
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发表时间：
2006-06-01
影响因子：
12.6
通讯作者：
Steidler, Lothar
中科院分区：
文献类型：
--
作者：
Braat, Henri;Rottiers, Pieter;Steidler, Lothar
背景与目的：利用活的转基因细菌是局部递送免疫调节蛋白的有效途径。这种策略避免了全身副作用，并允许长期治疗慢性疾病。然而，用活的转基因细菌治疗患者，对人类受试者本身的安全性和转基因的生物遏制提出了问题。方法：我们用基因修饰的乳酸乳球菌（LL-Thy12）治疗克罗恩病患者，其中胸腺苷酸合成酶基因被合成的编码成熟人白细胞介素-10的序列所取代。10名患者被纳入了一项安慰剂对照试验。通过直接询问和评估疾病活动性，每天评估患者是否存在潜在的不良反应。我们通过常规培养和定量聚合酶链反应来评估LL-Thy12在患者粪便中的存在和释放动力学。结果：使用LL-Thy12治疗是安全的，因为只有轻微的不良事件存在，并且观察到疾病活动性降低。此外，粪便回收的LL-Thy12细菌依赖胸腺嘧啶生长和产生白细胞介素-10，表明遏制策略是有效的。结论：在这里，我们表明使用转基因细菌进行蛋白质的粘膜递送在人类中是可行的策略。这种新颖的策略避免了系统性副作用，并具有生物抑制作用；因此适合作为慢性肠道疾病的维持治疗。
Background & Aims: The use of living, genetically modified bacteria is an effective approach for topical delivery of immunomodulatory proteins. This strategy circumvents systemic side effects and allows long-term treatment of chronic diseases. However, treatment of patients with a living, genetically modified bacterium raises questions about the safety for human subjects per se and the biologic containment of the transgene. Methods: We treated Crohn's disease patients with genetically modified Lactococcus lactis (LL-Thy12) in which the thymidylate synthase gene was replaced with a synthetic sequence encoding mature human interleukin-10. Ten patients were included in a placebo-uncontrolled trial. Patients were assessed daily for the presence of potential adverse effects by direct questioning and assessment of disease activity. We evaluated the presence and kinetics of LL-Thy12 release in the stool of patients by conventional culturing and quantitative polymerase chain reaction of LL-Thy12 gene sequences. Results:Treatment with LL-Thy12 was safe because only minor adverse events were present, and a decrease in disease activity was observed. Moreover, fecally recovered LL-Thy12 bacteria were dependent on thymidine for growth and interleukin-10 production, indicating that the containment strategy was effective. Conclusions: Here we show that the use of genetically modified bacteria for mucosal delivery of proteins is a feasible strategy in human beings. This novel strategy avoids systemic side effects and is biologically contained; therefore it is suitable as maintenance treatment for chronic intestinal disease.