人类朊病毒病:分子发病机制以及可能的治疗目标和策略。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Expert Opinion on Therapeutic Targets Pub Date : 2023-07-01 Epub Date: 2023-06-19 DOI:10.1080/14728222.2023.2199923
Simone Baiardi, Angela Mammana, Sabina Capellari, Piero Parchi
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引用次数: 0

摘要

导言:人类朊病毒疾病是一种与折叠错误的朊病毒蛋白(PrP)聚集和自我传播有关的异质性、通常进展迅速的传染性神经退行性疾病。尽管朊病毒病非常罕见,但其表型变异的范围很广,在分子水平上由折叠错误的 PrP 的不同构象和宿主基因型变异决定。此外,它们还以特发性、遗传决定性和获得性等不同病因形式独特地出现:本综述概述了朊病毒疾病潜在治疗靶点的最新情况,以及在细胞、动物模型和人体试验中取得的主要成果。还讨论了与开发有效疗法和临床试验相关的未决问题和挑战:目前测试的治疗策略以细胞PrP为目标,以防止形成折叠错误的PrP或促进其消除。其中,针对朊病毒蛋白 mRNA 的被动免疫和反义寡核苷酸基因疗法最有前景。然而,该疾病的罕见性、异质性和快速进展性使成功开展有实力的治疗试验和在无症状或早期脑损伤发生前识别患者的工作受到严重阻碍。因此,迄今为止最有希望的治疗目标是通过降低朊病毒蛋白的表达,预防或延缓致病基因突变携带者的表型转化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Human prion disease: molecular pathogenesis, and possible therapeutic targets and strategies.

Introduction: Human prion diseases are heterogeneous, and often rapidly progressive, transmissible neurodegenerative disorders associated with misfolded prion protein (PrP) aggregation and self-propagation. Despite their rarity, prion diseases comprise a broad spectrum of phenotypic variants determined at the molecular level by different conformers of misfolded PrP and host genotype variability. Moreover, they uniquely occur in idiopathic, genetically determined, and acquired forms with distinct etiologies.

Area covered: This review provides an up-to-date overview of potential therapeutic targets in prion diseases and the main results obtained in cell and animal models and human trials. The open issues and challenges associated with developing effective therapies and informative clinical trials are also discussed.

Expert opinion: Currently tested therapeutic strategies target the cellular PrP to prevent the formation of misfolded PrP or to favor its elimination. Among them, passive immunization and gene therapy with antisense oligonucleotides against prion protein mRNA are the most promising. However, the disease's rarity, heterogeneity, and rapid progression profoundly frustrate the successful undertaking of well-powered therapeutic trials and patient identification in the asymptomatic or early stage before the development of significant brain damage. Thus, the most promising therapeutic goal to date is preventing or delaying phenoconversion in carriers of pathogenic mutations by lowering prion protein expression.

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来源期刊
CiteScore
8.90
自引率
1.70%
发文量
58
审稿时长
3 months
期刊介绍: The journal evaluates molecules, signalling pathways, receptors and other therapeutic targets and their potential as candidates for drug development. Articles in this journal focus on the molecular level and early preclinical studies. Articles should not include clinical information including specific drugs and clinical trials. The Editors welcome: Reviews covering novel disease targets at the molecular level and information on early preclinical studies and their implications for future drug development. Articles should not include clinical information including specific drugs and clinical trials. Original research papers reporting results of target selection and validation studies and basic mechanism of action studies for investigative and marketed drugs. The audience consists of scientists, managers and decision makers in the pharmaceutical industry, academic researchers working in the field of molecular medicine and others closely involved in R&D.
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