Tackling neurodegeneration in vitro with omics: a path towards new targets and drugs

Front Mol Neurosci. 2024 Jun 17:17:1414886. doi: 10.3389/fnmol.2024.1414886. eCollection 2024.

Abstract

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.

Keywords: AD; PD; drug discovery; drug repurposing; in vitro; multi-omics; neurodegeneration; single-cell.

Publication types

  • Review

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by grants from RIA HORIZON Research and Innovation Actions HORIZON-HLTH-2021-DISEASE-04-07 Grant Agreement no. 101057775 (NEUROCOV, to MDB and JLS), the European Union’s Horizon 2020 Research and 672 Innovation Programme under Grant Agreement no. 945539 (HBP SGA3, to MDB) and no. 785907 673 (HBP SGA2, to MDB), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198), Vascular Dementia Research Foundation, and the donors of the ADR AD2019604S, a program of the BrightFocus Foundation (to DP).