2. Academic Validation
  3. A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer's Disease

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer's Disease

  • Int J Mol Sci. 2023 Jul 28;24(15):12079. doi: 10.3390/ijms241512079.
Alvaro Esteban-Martos 1,  Ana Maria Brokate-Llanos 2,  Luis Miguel Real 1 3,  Sonia Melgar-Locatelli 4 5,  Itziar de Rojas 6 7,  Adriana Castro-Zavala 4 5,  Maria Jose Bravo 1,  Maria Del Carmen Mañas-Padilla 4 5,  Pablo García-González 6 7,  Maximiliano Ruiz-Galdon 1,  Beatriz Pacheco-Sánchez 4 8,  Rocío Polvillo 2,  Fernando Rodriguez de Fonseca 4 8,  Irene González 1,  Estela Castilla-Ortega 4 5,  Manuel J Muñoz 2,  Patricia Rivera 4 8,  Armando Reyes-Engel 1,  Agustin Ruiz 6 7,  Jose Luis Royo 1
Affiliations

Affiliations

  • 1 Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s/n, 29071 Malaga, Spain.
  • 2 Departamento de Biología Molecular e Ingeniería Bioquímica, Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO/CSIC/JA, Ctra Utrera Km1, 41013 Sevilla, Spain.
  • 3 Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain.
  • 4 Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain.
  • 5 Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, 29071 Malaga, Spain.
  • 6 Research Center and Memory Clinic, Ace Alzheimer Center Barcelona-Universitat Internacional de Catalunya, 08017 Barcelona, Spain.
  • 7 Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, Spain.
  • 8 Unidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, Spain.
PMID: 37569459 DOI: 10.3390/ijms241512079
Abstract

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer's disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin's effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.

Keywords

Alzheimer’s disease; GWAS pipeline; drug discovery; midostaurin.

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