Small Molecules To Target r(CGG) Expansions to Treat Fragile X Syndrome

With a 2-year, $90,000 grant from FRAXA Research Foundation, Dr.’s Matthew Disney and Wang-Yong Yang worked to correct the underlying problem in fragile X: the silencing of the fragile X gene (FMR1) and the resulting lack of FMRP (Fragile X Mental Retardation Protein). Their approach was to use novel small molecules to target the abnormal CGG repeats before the FMR1 gene.

Social Behavior as an Outcome Measure for Fragile X Clinical Trials

One of the features of the fragile X mouse model which is relevant to the human fragile X syndrome (and autism) is social behavior. Several tests show consistent social behavioral abnormalities in the fragile X mouse model. With a $140,000 grant from FRAXA Research Foundation in 2012-2013, Dr. Willemsen at Erasmus University used social behavior tests to measure the effectiveness of several drug strategies.

Tori Shaeffer

Development of a Novel GABA-A Agonist in Fragile X Syndrome

Of the many genes known to be regulated by FMRP, the gamma-aminobutyric acid receptor A (GABA(A)), is gaining attention as a potential target for the treatment of FXS. Mounting evidence suggests decreased expression and functioning of GABA(A) is involved in the pathophysiology of FXS. Non-selective GABA(A) agonism in animal models of FXS has been associated with normalization of morphological features, GABA(A) expression, and behavior. However, the clinical use of these agents in fragile X is associated with unwanted side-effects, such as sedation, dulling of cognition, and occasional paradoxical agitation, which limits their use. Given the limitations in available GABA(A)-based treatment of FXS, this group plans to investigate a novel selective GABA(A) agonist in a mouse model of FXS. This agent has the potential to relieve many symptoms of fragile X without the unwanted side effects.

Kendal Broadie

Matrix Metalloproteinase Therapeutic Treatments for Fragile X Syndrome

With a $157,000 grant from the FRAXA Research Foundation in 201202013, Dr. Kendal Broadie and Dr. Cheryl Gatto worked to define the distinct but also overlapping roles for MMP-1 and MMP-2 in synaptic structural and functional development. In drug studies with fragile X fruit flies, they will be testing a range of MMPIs in drug treatments to compare effectiveness during development and at maturity, in order to define the contributions of FXS developmental impairments and adult recovery/plasticity.

Kimberly Huber, Ph.D., FRAXA Investigator

Evaluation of CamKII Dependent Regulation of mGluR5-Homer Scaffolds as a Potential Therapeutic for Fragile X Syndrome

Dr. Huber made the original discovery of the mGluR Theory of Fragile X when she was a postdoctoral fellow in the lab of Dr. Mark Bear, with her first FRAXA grant in 2000. Dr. Huber has received $474,300 in grants from FRAXA Research Foundation since then, researching molecular mechanisms and developmental switches in fragile X syndrome. She has worked with 4 FRAXA Postdoctoral Fellows (Elena Nosyreva, PhD in 2006; Jennifer Roseni, PhD in 2007; Tong Zang, PhD in 2010-2011; and Weirui Guo, PhD in 2012-2013) and has received supporting funds from The Meadows Foundation of/for Texas.