Small Rho GTPases, a Potential Therapeutic Target for Fragile X Syndrome

With a $384,345 in grants FRAXA Research Foundation over 5 years, Dr. MariVi Tejada from the University of Houston focused on Rac1, a promising point of intervention in pathways of brain receptors, and tested several compounds in an attempt to rescue function in the mouse model of fragile X.


$384,345 Grant
MariVi Tejada-Simon, PhD
Principal Investigator
University of Houston
2011-13 FRAXA Research Grant
2008-9 FRAXA Research Grant
$384,345 over 5 Years

Dr. Tejada-Simon investigated the role of the enzyme Rac1 in the pathology of fragile X. The seminal work of Dr. Kim Huber (currently of UT Southwestern) has shown that excessive signaling through metabotropic glutamate receptors (especially mGluR5) causes much of the brain dysfunction in fragile X. However, the “mGluR Theory of Fragile X” did not attempt to explain why the function of this pathway was found to be excessive. Indeed, it known that there is a normal amount of mGluR5 itself, and most components of the signaling pathway are also present in normal amounts. Dr. Tejada-Simon showed that Rac1, the enzyme which initiates the signaling cascade following stimulation of metabotropic receptors, is increased in quantity and level of activity in fragile X, thus offering mechanistic support for the mGluR Theory, and an opportunity to target the specific abnormality in fragile X.

During the first year of this project, she characterized the extent of this abnormality and began testing compounds which can inhibit Rac1. In the second year of work, she thoroughly tested 3 major treatment strategies which inhibit Rac1, and assessed their ability to rescue the anatomic and behavioral deficits in the fragile X mouse model. Two of the compounds tested are investigational agents, but the third is an available drug called a statin. Numerous statins are available as treatments for high cholesterol, such as lovastatin (Mevacor) and simvastatin (Zocor); these are well-tested drugs with an excellent safety profile, so this work offers the prospect of an off-the-shelf disease-modifying treatment for fragile X.