Zebrafish Duchenne Muscular Dystrophia Models

Duchenne muscular dystrophy (DMD) is a progressive muscle dysfunction disease characterized by delayed motor development in infancy, progressing to loss of ambulation, and culminating in respiratory or cardiac failure in young adulthood. DMD is an X-linked monogenic neuromuscular disease caused by mutations in the DMD gene, which encodes dystrophin. Dystrophin, together with sarcoglycans and dystroglycan, maintains sarcolemma integrity and stability by interacting with intracellular actin and extracellular laminin. The present standard of care is corticosteroid treatment, which delays the progression of skeletal muscle and cardiac dysfunction but also has serious side effects. The potential for novel drug combination therapies for DMD has not been completely explored.

Animal models have helped advance our knowledge of potential pharmacological therapies for DMD. In particular, the zebrafish animal model offers many advantages for drug discovery and understanding drug mechanisms of action for DMD therapies. Similar to dystrophin in humans, zebrafish dystrophin originally localizes to the peripheral ends of the myofibres at the myotendinous junction and gradually shifts to non-junctional sites. Dystrophin deficiency in zebrafish is characterized by extensive muscle degeneration, muscle progenitor proliferation, fibrosis, and greater variation in myofibre cross-sectional areas. Zebrafish combine effective breeding with cost-efficient husbandry and the embryos’ yolk enables rapid development without the need for feeding in the first week. What's more, the translucent embryos are amenable for microscopic observation and the birefringent muscle readily enables assessment of the muscle integrity under polarized light.

Creative Biogene, a zebrafish research company with experienced scientists, has established zebrafish as a preclinical translation model for evaluating new drug therapies for DMD. Our zebrafish models of DMD such as the sapje mutants have implications for the development of suitable treatments for the human disease. We can systematically evaluate a set of drug combination therapies using the zebrafish DMD model. We can also test for mRNA biomarkers associated with disease progression and drug-induced disease amelioration by qRT-PCR and RNA-seq on DMD zebrafish. Besides, we are also equipped with tools specific to measuring muscle abnormality in the zebrafish DMD model and allows for high-throughput screening for DMD therapies, either individually or in combination.

Figure 1. Example of a strategy for testing pharmacological rescue of a zebrafish DMD model.

Advantages

• The zebrafish model more closely resembles human DMD in symptom severity.
• Drug efficacy can be established in studies with duration as short as four days.
• Both cardiac and skeletal muscle phenotypes and other biomarkers can be easily monitored.
• Can perform large-scale drug screens for small molecules.

Our zebrafish DMD model services will help you to identify the novel drug combinations that are beneficial for DMD. Contact us today to discuss your objectives and how we can reach them.

References

1. Gintjee T J J, et al. High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics. Biology, 2014, 3(4): 752-780.
2. Berger J. Duchenne Muscular Dystrophy from a Zebrafish’s Perspective. Austin Journal of Musculoskeletal Disorders, 2015, 2(2): 1019-1020.
3. Widrick J J, et al. Muscle dysfunction in a zebrafish model of Duchenne muscular dystrophy. Physiological genomics, 2016, 48(11): 850-860.
4. Maves L. Recent advances using zebrafish animal models for muscle disease drug discovery. Expert opinion on drug discovery, 2014, 9(9): 1033-1045.
5. Widrick J J, et al. Discovery of novel therapeutics for muscular dystrophies using zebrafish phenotypic screens. Journal of neuromuscular diseases, 2019 (Preprint): 1-17.

For research use only. Not intended for any clinical use.