BACKGROUND:  The muscular dystrophies (MD) are a group of genetic diseases characterized by progressive weakness and degeneration of muscle tissue. The most common form is Duchenne MD, a lethal disease that affects all voluntary and involuntary muscles, including the heart, rendering survival beyond the early 30s being rare. It is known that this form of MD, as well as others, are caused by the absence of the protein dystrophin. In healthy muscle cells, dystrophin, membrane proteins and glycoproteins form the dystrophin-glycoprotein complex (DGC). Portions of the DGC are decorated with a variety of glycans that enable binding to the protein laminin, which is necessary for normal muscular function. It has been shown in a mouse model of dystrophin-deficient MD that overexpression of the enzyme β-1,4 N-acetylgalactosaminyl-transferase (also known as Galgt2 or CTGalNAcT) can rescue glycosylation and laminin binding, and revert muscular dystrophy. . Therefore, it is of interest to identify therapeutics that could specifically alter muscle cell glycosylation.

INNOVATION:  Researchers at UCLA have identified a protocol for high-throughput screening of small molecules to identify compounds that alter glycosylation at the desired sites. This assay is a sensitive and specific lectin binding assay using a mouse muscle cell line. Robust binding with a large dynamic range was achieved, so that significant changes in lectin binding between cells transfected with a CTGalNAcT plasmid and a control plasmid could be readily observed. As a proof of concept, a library of FDA approved compounds was screened and a lead compound was identified. This compound was found to increase surface glycosylation, enhance laminin binding, increase CTGalNAcT mRNA, and increase DGC levels in mouse cell lines and primary muscle cells.

POTENTIAL APPLICATIONS 

• Drug screening for MD and other muscle wasting disorders
• MD therapeutic

ADVANTAGES

• Assay is less expensive and less time consuming than other screening assays used to identify potential MD therapeutics.
• Lead compound has already been approved for use in humans by the FDA (for other therapeutic purposes).

DEVELOPMENT-TO-DATE:  A small molecule library was screened using the developed assay and a lead drug candidate was identified. The efficiency of this candidate has been established in vitro. The researchers are now planning in vivo efficiency studies.

Reference: UCLA Case No. 2008-833