活体生物药在代谢类疾病中的研究

doi:10.12211/2096-8280.2025-024

摘要/Abstract

摘要：

合成生物学技术的持续发展促进了益生菌的改造，进而推动了活体生物药（live biotherapeutic products， LBP）在疾病治疗领域的研究。近年来，LBP在多种疾病治疗剂的开发上有所应用。目前，选择合适的底盘细胞并进行工程化改造，以及为特定疾病设计专门的功能基因模块，已成为活体生物药开发的一般流程。尽管临床实验中针对代谢性疾病的LBP治疗结果尚未完全达到预期，但相关疗法正逐步向临床治疗迈进。本文全面综述了活体生物药在代谢性疾病治疗领域的最新进展，详细阐述了苯丙酮尿症、高尿酸血症和肠源性高草酸尿症等疾病的治疗剂开发。同时，还讨论了基于合成生物学技术的LBP开发策略。最后，总结了活体生物药当前面临的问题，包括安全性、疗效和个体化差异等，并提出了合理的展望，如拓展活体生物药概念、开发个性化活体生物药等。

关键词: 活体生物药, 代谢类疾病, 合成生物学, 微生物, 益生菌

Abstract:

The continuous advancement of synthetic biology technology has significantly facilitated the transformation of probiotics, thereby enhancing the potential research of live biotherapeutic products (LBP) in therapeutic agents.In recent years, the use of LBP has been extensively applied as a promising approach for treating a wide array of diseases, including metabolic diseases. The standardization of procedures in the development of live biotherapeutic products—such as the careful selection of suitable chassis cells, the execution of precise engineering transformations, and the design of specialized genetic circuits tailored for specific diseases—has become a general process of this emerging field. Although clinical trials involving LBP for the treatment of metabolic diseases have not always yielded the anticipated results, they are gradually progressing toward clinical application. This article provides a comprehensive review of the latest advancements in live biotherapeutic products within the context of metabolic disease treatment, detailing the significant research progress made in addressing conditions such as phenylketonuria, hyperuricemia, and enteric hyperoxaluria, where LBPs are being explored as innovative therapeutic options. Furthermore, the article discusses the strategic development of LBP based on synthetic biology technology, highlighting the potential of these technologies to create sophisticated and targeted therapies capable of addressing complex metabolic pathways. However, it also acknowledges the challenges that lie ahead for live biotherapeutic products, including concerns related to safety, efficacy, and individual variability. These factors are crucial for the successful translation of live biotherapeutic products from the laboratory to the clinic. In addressing these challenges, the article summarizes ongoing efforts to ensure the safety and efficacy of live biotherapeutic products, as well as the development of personalized treatments that can accommodate the unique genetic and metabolic profiles of individual patients. Finally, the article presents a forward-looking perspective on the future development of live biotherapeutic products, anticipating the breakthroughs and advancements that will shape the next generation of metabolic disease treatments and the potential impact these biotherapeutics could have on improving patient outcomes and quality of life.

Key words: live biotherapeutic products, metabolic diseases, synthetic biology, microorganism, probiotics

中图分类号:

Q819

匡家奇, 章素秀, 江晗, 魏韬. 活体生物药在代谢类疾病中的研究[J]. 合成生物学, DOI: 10.12211/2096-8280.2025-024.

KUANG Jiaqi, ZHANG Suxiu, JIANG Han, WEI Tao. Research on live biotherapeutic products in metabolic diseases[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2025-024.

图/表 4

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公司名称	所应用的适应症	产品名称	现状	参考文献
Synlogic	苯丙酮尿症	SYNB1618和SYNB1934	已在美国完成单臂2期研究和Ⅰ期临床试验，目前已停产	[17,41]
	同型胱氨酸尿症	SYNB1353	完成研发，已在美国完成Ⅰ期临床试验	[38,42]
	高氨血症	SYNB1020	完成研发，已在美国完成Ⅰ期临床试验，目前已停产	[43-44]
	肠源性高草酸尿症	SYNB8802	完成研发，已在美国完成1b临床研究	[45]
	痛风	SYNB2081	研发中	[46]
	胱氨酸尿症	尚未公布	尚未公布	[47]
ActoBio Therapeutics	糖尿病	AG019	完成研发，已在美国完成1b/2a期临床实验，最新进展未公布	[48]
和度生物医药（上海）有限公司	胆固醇过高	尚未公布	完成研发，未公布最新进展	[49]
和度生物医药（上海）有限公司	苯丙酮尿症	CBT-102	完成研发，正开展临床研究	[50]
苏州优信合生技术有限公司	苯丙酮尿症	UR101	完成研发，正开展临床前研究	[51]
	H氨基酸代谢病	UR102	完成研发，正开展临床前研究	[51]
	M氨基酸代谢病	UR103	完成研发，正开展临床前研究	[51]

公司名称	所应用的适应症	产品名称	现状	参考文献
Synlogic	苯丙酮尿症	SYNB1618和SYNB1934	已在美国完成单臂2期研究和Ⅰ期临床试验，目前已停产	[17,41]
	同型胱氨酸尿症	SYNB1353	完成研发，已在美国完成Ⅰ期临床试验	[38,42]
	高氨血症	SYNB1020	完成研发，已在美国完成Ⅰ期临床试验，目前已停产	[43-44]
	肠源性高草酸尿症	SYNB8802	完成研发，已在美国完成1b临床研究	[45]
	痛风	SYNB2081	研发中	[46]
	胱氨酸尿症	尚未公布	尚未公布	[47]
ActoBio Therapeutics	糖尿病	AG019	完成研发，已在美国完成1b/2a期临床实验，最新进展未公布	[48]
和度生物医药（上海）有限公司	胆固醇过高	尚未公布	完成研发，未公布最新进展	[49]
和度生物医药（上海）有限公司	苯丙酮尿症	CBT-102	完成研发，正开展临床研究	[50]
苏州优信合生技术有限公司	苯丙酮尿症	UR101	完成研发，正开展临床前研究	[51]
	H氨基酸代谢病	UR102	完成研发，正开展临床前研究	[51]
	M氨基酸代谢病	UR103	完成研发，正开展临床前研究	[51]

底盘细胞	拉丁文学名	所开发LBP的适应症	开发程度
大肠杆菌Nissle 1917	Escherichia coli Nissle 1917	苯丙酮尿症、高尿酸血症、肠源性高草酸尿症、慢性肾病、高氨酸血症、同型胱氨酸尿症、肥胖、果糖诱发的代谢综合征及糖尿病等	完成基因组注释^[56,92]；开发内源性隐匿质粒作为表达载体^[59-60,93]；开发阻止耐药基因转移的CRISPR系统^[94]；开发靶向特异性递送系统^[95]
乳酸杆菌	Lactobacillus	苯丙酮尿症^[96]、糖尿病^[97]	开发多种基因白编辑工具，如CRISPR系统和cre-lox系统^[69,98-99]
丁酸梭菌	Clostridium butyricum	糖尿病^[86]	开发CRISPR-Cas系统^[90]；完成不同株系的遗传学特性和生理特性分析^[100]
布拉氏酵母	Saccharomyces boulardii	高尿酸血症^[87]	修复乳糖代谢途径，构建多种诱导表达系统^[89]；构建反式激活系统^[88]

底盘细胞	拉丁文学名	所开发LBP的适应症	开发程度
大肠杆菌Nissle 1917	Escherichia coli Nissle 1917	苯丙酮尿症、高尿酸血症、肠源性高草酸尿症、慢性肾病、高氨酸血症、同型胱氨酸尿症、肥胖、果糖诱发的代谢综合征及糖尿病等	完成基因组注释^[56,92]；开发内源性隐匿质粒作为表达载体^[59-60,93]；开发阻止耐药基因转移的CRISPR系统^[94]；开发靶向特异性递送系统^[95]
乳酸杆菌	Lactobacillus	苯丙酮尿症^[96]、糖尿病^[97]	开发多种基因白编辑工具，如CRISPR系统和cre-lox系统^[69,98-99]
丁酸梭菌	Clostridium butyricum	糖尿病^[86]	开发CRISPR-Cas系统^[90]；完成不同株系的遗传学特性和生理特性分析^[100]
布拉氏酵母	Saccharomyces boulardii	高尿酸血症^[87]	修复乳糖代谢途径，构建多种诱导表达系统^[89]；构建反式激活系统^[88]

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