Biomarker-focused multi-drug combination therapy and repurposing trial in mdx mice
Open Access
- 22 February 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (2), e0246507
- https://doi.org/10.1371/journal.pone.0246507
Abstract
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.Funding Information
- Foundation to Eradicate Duchenne (2018)
This publication has 34 references indexed in Scilit:
- Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History StudyNeurology, 2015
- Immune-mediated pathology in Duchenne muscular dystrophyScience Translational Medicine, 2015
- Large-scale serum protein biomarker discovery in Duchenne muscular dystrophyProceedings of the National Academy of Sciences of the United States of America, 2015
- Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophyThe Journal of cell biology, 2014
- β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk FactorsCell Metabolism, 2014
- Sparing of the Dystrophin-Deficient Cranial Sartorius Muscle Is Associated with Classical and Novel Hypertrophy Pathways in GRMD DogsThe American Journal of Pathology, 2013
- VBP15, a novel anti‐inflammatory and membrane‐stabilizer, improves muscular dystrophy without side effectsEMBO Molecular Medicine, 2013
- The Paradox of Muscle Hypertrophy in Muscular DystrophyPhysical Medicine and Rehabilitation Clinics of North America, 2012
- From SOMAmer-Based Biomarker Discovery to Diagnostic and Clinical Applications: A SOMAmer-Based, Streamlined Multiplex Proteomic AssayPLOS ONE, 2011
- Rituximab Targets Podocytes in Recurrent Focal Segmental GlomerulosclerosisScience Translational Medicine, 2011