A Forward Genetic Screen to Identify Druggable Modulators of MECP2 Levels

Huda Zoghbi, MD | Baylor College of Medicine

$1,485,949 AWARDED

MECP2-duplication syndrome (MDS) occurs when there are one or more extra copies of the MECP2 gene. The excessive MeCP2 protein made by the extra copy of the gene severely affects brain function. During the previous RSRT-funded project, the Zoghbi lab discovered that MDS symptoms can be eliminated in mice if MeCP2 levels are corrected. A drug to lower MeCP2 would be the simplest way to do this for patients, so for this project the goal is to find drugs that can reduce MeCP2 protein levels or identify good drug targets that can be used to design drugs to treat MDS.

Two major approaches to find drugs that lower MeCP2 are being pursued.

1. Testing almost all of the current FDA-approved drugs to see if any of them can affect MeCP2 levels. Such strategies have worked to find treatments for other diseases, and if one is found, the path to clinical use will be dramatically accelerated since the drug will already be available and its safety profile will be known.

2. Testing every gene in the genome to identify those that regulate MeCP2 levels. Once MeCP2 regulators are identified efforts to find drugs that might inhibit them can then be sought. This approach was pilot tested and indeed several MeCP2 regulators were found. A drug to inhibit one of regulators was then tested in MDS mice and some of the mice’s symptoms were improved. For this project, all the regulators will be followed up as well as any new ones discovered, with additional mouse studies to determine which are the best drug targets and if they can work even better when used in combination.

The Zoghbi lab is trying to find as many drug targets and drugs as possible to maximize chances of finding those that are most effective and safe, and can be brought to the clinic to treat ­MECP2-duplication syndrome.

Current Projects