利用 omics 解决体外神经变性问题:通往新目标和新药物之路。

IF 3.5 3区 医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-06-17 eCollection Date: 2024-01-01 DOI:10.3389/fnmol.2024.1414886
Caterina Carraro, Jessica V Montgomery, Julien Klimmt, Dominik Paquet, Joachim L Schultze, Marc D Beyer
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引用次数: 0

摘要

药物研发通常是一个低效和资本密集型的过程。对于神经退行性疾病(NDDs)而言,考虑到后期候选药物失败的案例不胜枚举,开发新型疗法显得尤为迫切。尽管我们对驱动神经退行性变的致病机制的了解在不断加深,但要更好地、最终全面地了解 NDD 的病理生理学基础,还需要付出更多的努力。除了 NDD 的病因是多因素的异质性病因外,目前的实验模型只能部分再现在人类身上观察到的主要表型这一事实也使这一过程变得更加复杂。在这种情况下,多组学方法有可能加快鉴定针对驱动 NDDs 的多种潜在机制的新药或改用药物。在药物发现过程中采用多组学方法的一个主要优势是,这些总体工具能够通过对不同分子层(即基因组、转录组、蛋白质组)的全面表征来分解疾病状态和模型扰动,直至单细胞分辨率。由于最近的进步提高了这些技术的可负担性和可扩展性,利用 omics 技术推动药物发现的工作刚刚起步,但在神经科学领域正在迅速扩展。结合日益先进的体外模型,特别是受益于人类 iPSCs 的引入,多组学正在塑造一种新的 NDD 药物发现范式,从疾病特征描述到治疗预测和实验筛选。在这篇综述中,我们将讨论使用多组学方法体外发现 NDDs 靶点和疗法的实例、主要优势和面临的挑战。
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Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs.

Drug discovery is a generally inefficient and capital-intensive process. For neurodegenerative diseases (NDDs), the development of novel therapeutics is particularly urgent considering the long list of late-stage drug candidate failures. Although our knowledge on the pathogenic mechanisms driving neurodegeneration is growing, additional efforts are required to achieve a better and ultimately complete understanding of the pathophysiological underpinnings of NDDs. Beyond the etiology of NDDs being heterogeneous and multifactorial, this process is further complicated by the fact that current experimental models only partially recapitulate the major phenotypes observed in humans. In such a scenario, multi-omic approaches have the potential to accelerate the identification of new or repurposed drugs against a multitude of the underlying mechanisms driving NDDs. One major advantage for the implementation of multi-omic approaches in the drug discovery process is that these overarching tools are able to disentangle disease states and model perturbations through the comprehensive characterization of distinct molecular layers (i.e., genome, transcriptome, proteome) up to a single-cell resolution. Because of recent advances increasing their affordability and scalability, the use of omics technologies to drive drug discovery is nascent, but rapidly expanding in the neuroscience field. Combined with increasingly advanced in vitro models, which particularly benefited from the introduction of human iPSCs, multi-omics are shaping a new paradigm in drug discovery for NDDs, from disease characterization to therapeutics prediction and experimental screening. In this review, we discuss examples, main advantages and open challenges in the use of multi-omic approaches for the in vitro discovery of targets and therapies against NDDs.

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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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