RT Journal Article
T1 A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease
A1 Esteban-Martos, Alvaro
A1 Brokate-Llanos, Ana María
A1 Real-Navarrete, Luis Miguel
A1 Melgar-Locatelli, Sonia
A1 De Rojas, Itziar
A1 Castro-Zavala, Adriana
A1 Bravo-Romero, María José
A1 Mañas-Padilla, María del Carmen
A1 García-González, Pablo
A1 Ruiz-Galdón, Maximiliano
A1 Pacheco-Sánchez, Beatriz
A1 Polvillo, Rocío
A1 Rodriguez-de-Fonseca, Fernando
A1 González, Irene
A1 Castilla-Ortega, María Estela
A1 Muñoz-Gómez, Manuel
A1 Rivera-González, Patricia
A1 Reyes-Engel, Armando
A1 Ruiz, Agustín
A1 Royo-Sánchez-Palencia, José Luis
AB 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.
PB MDPI
YR 2023
FD 2023
LK https://hdl.handle.net/10630/28761
UL https://hdl.handle.net/10630/28761
LA eng
NO Esteban-Martos, A., Brokate-Llanos, A. M., Real, L. M., Melgar-Locatelli, S., de Rojas, I., Castro-Zavala, A., ... & Royo, J. L. (2023). A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease. International Journal of Molecular Sciences, 24(15), 12079.
NO Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s/n, 29071 Malaga, SpainDepartamento 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, SpainCentro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, SpainInstituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, SpainDepartamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, 29071 Malaga, SpainResearch Center and Memory Clinic, Ace Alzheimer Center Barcelona—Universitat Internacional de Catalunya, 08017 Barcelona, SpainNetwork Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, SpainUnidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, SpainFunding for open Access charge: Universidad de Málaga / CBUA
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026