Preclinical alternative drug discovery programs for monogenic rare diseases. Should small molecules or gene therapy be used? The case of hereditary spastic paraplegias.

Autor: Sebastiano MR; University of Torino, Molecular Biotechnology and Health Sciences Department, CASSMedChem, Piazza Nizza, 10138 Torino, Italy., Hadano S; Molecular Neuropathobiology Laboratory, Department of Physiology, Tokai University School of Medicine, Isehara, Japan., Cesca F; Department of Life Sciences, University of Trieste, 34127 Trieste, Italy., Ermondi G; University of Torino, Molecular Biotechnology and Health Sciences Department, CASSMedChem, Piazza Nizza, 10138 Torino, Italy. Electronic address: giuseppe.ermondi@unito.it.
Jazyk: angličtina
Zdroj: Drug discovery today [Drug Discov Today] 2024 Oct; Vol. 29 (10), pp. 104138. Date of Electronic Publication: 2024 Aug 19.
DOI: 10.1016/j.drudis.2024.104138
Abstrakt: Patients diagnosed with rare diseases and their and families search desperately to organize drug discovery campaigns. Alternative models that differ from default paradigms offer real opportunities. There are, however, no clear guidelines for the development of such models, which reduces success rates and raises costs. We address the main challenges in making the discovery of new preclinical treatments more accessible, using rare hereditary paraplegia as a paradigmatic case. First, we discuss the necessary expertise, and the patients' clinical and genetic data. Then, we revisit gene therapy, de novo drug development, and drug repurposing, discussing their applicability. Moreover, we explore a pool of recommended in silico tools for pathogenic variant and protein structure prediction, virtual screening, and experimental validation methods, discussing their strengths and weaknesses. Finally, we focus on successful case applications.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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