基于 RNA 的肝脏代谢疾病疗法

IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut Pub Date : 2025-02-23 DOI:10.1136/gutjnl-2023-331742
Antonio Fontanellas, Pedro Berraondo, Francesco Urigo, Daniel Jericó, Paolo G V Martini, Fernando Pastor, Matias A Avila
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引用次数: 0

摘要

基于 RNA 的疗法在过去十年中迅速崛起,提供了一类与传统药物截然不同的新型药物。这些疗法可以通过编程来靶向或恢复有缺陷的基因,从而实现更个性化的治疗并减少副作用。值得注意的是,RNA疗法在治疗遗传性肝病方面取得了重大进展,例如治疗遗传性转甲状腺素淀粉样变性病的小干扰RNA疗法,该疗法采用GalNAc连接等肝脏靶向策略,提高了疗效和安全性。基于 RNA 的基因编辑技术,如碱基编辑器和质点编辑器簇状有规律间隔短回文重复序列系统,也显示出了将基因组重排和癌症风险降至最低的前景。虽然 RNA 疗法具有高精确性,但在优化给药方法、确保长期安全性和有效性方面仍存在挑战。脂质纳米粒子-RNA疗法,尤其是用于罕见病的蛋白质替代疗法,已从临床前的成功中获得了支持。与病毒基因疗法相比,mRNA 疗法更安全,可降低基因组整合和癌基因激活的风险。然而,临床试验,尤其是针对罕见病的临床试验,面临着样本量小、观察期短等限制。进一步的临床前研究(包括非人灵长类动物)对于完善试验设计至关重要。尽管RNA疗法潜力巨大,但其高昂的成本也带来了挑战,需要成本效益模型来指导定价和可及性。在此,我们将讨论基于RNA的疗法的基本方面,并展示遗传性肝脏代谢疾病方面最相关的临床前和临床研究进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
RNA-based therapies in liver metabolic diseases
RNA-based therapeutics have rapidly emerged over the past decade, offering a new class of medicines that differ significantly from conventional drugs. These therapies can be programmed to target or restore defective genes, allowing for more personalised treatments and reducing side effects. Notably, RNA therapies have made significant progress in the treatment of genetic liver diseases, exemplified by small interfering RNA treatments for hereditary transthyretin amyloidosis, which use liver-targeting strategies such as GalNAc conjugation to improve efficacy and safety. RNA-based gene-editing technologies, such as base editor and prime editor clustered regularly interspaced short palindromic repeats systems, also show promise with their ability to minimise genomic rearrangements and cancer risk. While RNA therapies offer high precision, challenges remain in optimising delivery methods and ensuring long-term safety and efficacy. Lipid nanoparticle-mRNA therapeutics, particularly for protein replacement in rare diseases, have gained support from preclinical successes. Compared with viral gene therapies, mRNA therapies present a safer profile with reduced risks of genomic integration and oncogene activation. However, clinical trials, especially for rare diseases, face limitations such as small sample sizes and short observation periods. Further preclinical studies, including non-human primates, will be essential for refining trial designs. Despite their potential, the high costs of RNA therapies pose a challenge that will require cost–utility models to guide pricing and accessibility. Here, we discuss the fundamental aspects of RNA-based therapeutics and showcase the most relevant preclinical and clinical developments in genetic liver metabolic diseases.
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来源期刊
Gut
Gut 医学-胃肠肝病学
CiteScore
45.70
自引率
2.40%
发文量
284
审稿时长
1.5 months
期刊介绍: Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
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