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

Authors :
Sebastiano, Matteo Rossi
Hadano, Shinji
Cesca, Fabrizia
Ermondi, Giuseppe
Source :
Drug Discovery Today. Oct2024, Vol. 29 Issue 10, pN.PAG-N.PAG. 1p.
Publication Year :
2024

Abstract

• We provide guidelines for drug discovery campaigns for rare Hereditary spastic paraplegia (HSP). • Alternative models beyond traditional drug discovery paradigms are required. • Gene therapy and drug repurposing have different application domains in the delivery of targeted therapies. • In silico and specific experimental methods are suggested. • We provide concrete examples of the application of gene therapy and targeted therapy to treat Hereditary spastic paraplegia 50 (SPG50) and Infantile ascending hereditary spastic paralysis (IAHSP). 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
13596446
Volume :
29
Issue :
10
Database :
Academic Search Index
Journal :
Drug Discovery Today
Publication Type :
Academic Journal
Accession number :
179709497
Full Text :
https://doi.org/10.1016/j.drudis.2024.104138