Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice

Autor: Yetrib Hathout, Utkarsh J. Dang, Eric P. Hoffman, Molly Barkhouse, Mamta Giri, Heather Gordish-Dressman, Kitipong Uaesoontrachoon, Michael Ziemba, Kanneboyina Nagaraju
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Proteomics
Male
mdx mouse
Serum Proteins
Protein Folding
Heredity
Aminoisobutyric Acids
Genetic Linkage
Duchenne muscular dystrophy
Duchenne Muscular Dystrophy
Pharmacology
Biochemistry
Muscular Dystrophies
Dystrophin
Mice
Medical Conditions
Fibrosis
Medicine and Health Sciences
Macromolecular Structure Analysis
Pregnadienediols
Multidisciplinary
biology
Pharmaceutics
Animal Models
Blood proteins
Experimental Organism Systems
Neurology
X-Linked Traits
Sex Linkage
Prednisolone
Biomarker (medicine)
Medicine
Protein Interaction Networks
Rituximab
Network Analysis
medicine.drug
Research Article
Protein Structure
Computer and Information Sciences
Combination therapy
Science
Mouse Models
Research and Analysis Methods
Model Organisms
Drug Therapy
medicine
Genetics
Animals
Molecular Biology
Clinical Genetics
business.industry
Drug Repositioning
Biology and Life Sciences
Proteins
Muscular Dystrophy
Animal
medicine.disease
Muscular Dystrophy
Duchenne
Cytoskeletal Proteins
Disease Models
Animal
biology.protein
Animal Studies
Mice
Inbred mdx
business
Biomarkers
Zdroj: PLoS ONE, Vol 16, Iss 2, p e0246507 (2021)
PLoS ONE
ISSN: 1932-6203
Popis: Duchenne muscular dystrophy is initiated by dystrophin deficiency, but downstream pathophysiological pathways such as membrane instability, NFĸB activation, mitochondrial dysfunction, and induction of TGFβ fibrosis pathways are thought to drive the disability. Dystrophin replacement strategies are hopeful for addressing upstream dystrophin deficiency; however, all methods to date use semi-functional dystrophin proteins that are likely to trigger downstream pathways. Thus, combination therapies that can target multiple downstream pathways are important in treating DMD, even for dystrophin-replacement strategies. We sought to define blood pharmacodynamic biomarkers of drug response in the mdx mouse model of Duchenne muscular dystrophy using a series of repurposed drugs. Four-week-old mdx mice were treated for four weeks with four different drugs singly and in combination: vehicle, prednisolone, vamorolone, rituximab, β-aminoisobutyric acid (BAIBA) (11 treatment groups; n = 6/group). Blood was collected via cardiac puncture at study termination, and proteomic profiling was carried out using SOMAscan aptamer panels (1,310 proteins assayed). Prednisolone was tested alone and in combination with other drugs. It was found to have a good concordance of prednisolone-responsive biomarkers (56 increased by prednisolone, 39 decreased) focused on NFκB and TGFβ cascades. Vamorolone shared 45 (80%) of increased biomarkers and 13 (33%) of decreased biomarkers with prednisolone. Comparison of published human corticosteroid-responsive biomarkers to our mdx data showed 14% (3/22) concordance between mouse and human. Rituximab showed fewer drug-associated biomarkers, with the most significant being human IgG. On the other hand, BAIBA treatment (high and low dose) showed a drug-associated increase in 40 serum proteins and decreased 5 serum proteins. Our results suggest that a biomarker approach could be employed for assessing drug combinations in both mouse and human studies.
Databáze: OpenAIRE
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