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CMCC 2396

Discovery of GSK3ß inhibitors to treat neuromuscular diseases through novel zebrafish screening platform

Inventors: Leonard Zon, Cong Xu, Emily Price, Amy Wagers, Ronald Kahn

Invention Types: Research Tool, Therapeutics

Research Areas: Musculoskeletal, Neurology/Neuroscience

Keywords: Animal Model (zebra fish), Drug Screening, Small Molecule/Drug

For More Information Contact:  Meyer, Abbie

 

Invention Description:

The Zon lab has developed a novel zebrafish blastomere culture system to examine the influence of chemical compounds on myogenesis, ultimately identifying molecular pathways that regulate muscle specification and satellite cell expansion. This method was achieved by exploiting the unique chemical genetics of the zebrafish to reveal conserved mechanisms controlling the specification and expansion of myogenic progenitor cells.

Using this zebrafish embryo culture system with reporters of early and late skeletal muscle differentiation, Dr. Zon's lab and collaborators examined the influence of 2,400 chemicals on myogenesis and identified six that expanded muscle progenitors, including three GSK3ß inhibitors, two calpain inhibitors and one adenylyl cyclase activator forskolin. Forskolin also enhanced proliferation of mouse satellite cells in culture and maintained their ability to engraft in vivo. A combination of bFGF, forskolin and the GSK3ß inhibitor BIO induced skeletal muscle differentiation in human induced pluripotent stem cells (iPSCs) and produced engraftable myogenic progenitors that contributed to muscle repair in vivo.

This screening system provides new insights into skeletal muscle biology and may lead to novel therapies for metabolic and neuromuscular diseases.

Applications:

- GSK3ß inhibitor treatment for muscular dystrophy or other neuromuscular disease.
- Rapid and novel drug screening method on muscle cell proliferation.
- Rapid and novel drug screening method for any cell lineage to identify chemicals for cell-based

Competitive Advantages:

- Compared to traditional ESC/iPSC differentiation screens chemical screening methods using zebrafish embryos, this system takes one sixth of the time and uses one tenth of the number of embryos.
- This screening system does not require culture mainten

Business Opportunity:

Sponsored research or licensing opportunity

Key Publications:
Xu C, Tabebordbar M, Iovino S, et al. A zebrafish embryo culture system defines factors that promote vertebrate myogenesis across species. Cell. 2013 Nov 7; 155(4):909-921.

IPStatus: Patented