A zebrafish platform for DMD drug-combination testing

PI: Lisa Maves, PhD

Institution: Seattle Children’s Research Institute

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Basic research using animal models of Duchenne muscular dystrophy (DMD) has identified many classes of drugs that show promise in improving the progressive muscle degeneration of DMD. Some animal studies have found that combinations of drugs can have increased benefits for DMD relative to individual drugs. This is encouraging, because drug combinations have shown great benefits for other diseases, such as cancer and HIV infection. A barrier to identifying therapies for DMD is determining which drugs or drug combinations are the most promising and should be tested in clinical trials. The zebrafish DMD model offers several advantages for testing drug combinations. The goal of this project is to establish zebrafish as a preclinical model for identifying new drug combination therapies for DMD. We have tested a new set of drug combination treatments on DMD zebrafish. We used a novel drug-pooling strategy that allows us to test every drug in an 86-molecule library in combination with each other. We screened the drug pools for their ability to improve muscle degeneration defects in DMD zebrafish. Our efforts have identified a new drug combination that has beneficial effects on zebrafish DMD symptoms. Our study, for the first time, provides an example of testing a library of drugs in combination for improvement of DMD symptoms and provides a model for the future use of zebrafish as a preclinical drug combination testing model for different drug classes. This project will advance DMD research and help DMD patients by identifying novel drug combinations that potentially represent an improvement over the current steroid treatments for DMD.