November 23, 2004
ALSA Funds Rapid Screen for Agents to Inhibit Mutant SOD1
The ALS Association (ALSA) today announced funding of a new ALSA-initiated project that will rapidly pan for new agents that lower cellular stores of mutant SOD1, the protein implicated in an inherited form of ALS. The grant to Wendy Broom, Ph.D., and Robert Brown Jr., D.Phil., M.D., both of the Massachusetts General Institute of Neurodegeneration in Charlestown, Mass., funds the use of laboratory grown cells to screen for new ALS therapeutics that act by either slowing production of mutant SOD1, or hastening its destruction within the cell.
The goal of the project, said Broom and Brown, is to prioritize compounds with favorable pharmacokinetic properties prior to testing in animal models. Ultimately, the investigators intend that these studies will lead to profound and powerful strategies to treat inherited forms of ALS.
The investigators use PC12 cells. They have engineered the cells to express a reporter protein when the SOD1 gene is activated. With an automated screening assay, the investigators will test compounds in these cells, to see if any agents will change activation of the SOD1 gene. The investigators have also generated PC12 cells that express the SOD1 protein jointly with a reporter protein. Any compound that lowers cellular levels of this construct protein might be hastening the cells’ ability to get rid of mutant SOD1.
Once the rapid, automated screening process finds potentially active compounds, these “hits” will be tested again. The researchers will check that the hit compounds are actually changing the levels of SOD1. They will also determine the doses active in the cells, consider ability to enter target tissue, and will prioritize compounds with the most promise as therapeutic agents.
Changes in the gene coding for SOD1 are evident in 20 percent of ALS patients who have family history of the disorder. About ten percent of all cases of ALS appear to be inherited. The investigators predict that measures that reduce the levels of mutant SOD1 proteins will provide therapeutic benefit in ALS mice and potentially in patients with SOD1-mediated ALS.
