FRAXA-funded scientists created small molecules that target the CGG repeat “off-switch” in Fragile X, aiming to restore the missing FMRP protein at its source.
Study pinpointed presynaptic calcium dysfunction as the driver of STP defects in Fragile X, and BK channel activation restored normal synaptic signaling.
Dr. Jope found that lithium (at usual therapeutic doses) and investigational GSK3 inhibitors can reverse a number of cognitive deficits in FMR1 knockout mice.
Dr. Broadie showed that MMP enzymes disrupt synapse development in Fragile X. MMP inhibitors (e.g. minocycline) improved connectivity and behavior in fruit flies.
FRAXA-funded studies found faulty endocannabinoid signaling in Fragile X brain circuits for reward and emotion, and boosting 2-AG restored normal function.
With FRAXA funding the team found that activating 5-HT7 receptors reversed excess mGluR-LTD in Fragile X mice, pointing to a new route to fix synapses.
Dr. MariVi Tejada from the University of Houston tested several potential therapeutic compounds in an attempt to rescue function in the mouse model of Fragile X.
This work found amyloid precursor protein (APP) overexpression and increased β-amyloid in Fragile X mice, implicating Alzheimer-related pathways in FXS pathology.
JNK kinase is abnormally active in Fragile X model mice and directly regulates mGluR-dependent translation of FMRP targets, pointing to JNK as a therapeutic target.
Loss of FMRP leads to excess synthesis of the scaffold protein Shank1 at dendrites. Elevated Shank1 may impair synaptic pruning and drive Fragile X spine pathology.
Fragile X mice show reduced basal cAMP and exaggerated mGluR-LTD; boosting cAMP or blocking specific adenylyl cyclases rescues synaptic and behavioral defects.
Fragile X mice show weakened GABAergic inhibition in key brain regions like the amygdala. Enhancing GABA_A receptor activity reduced hyperactivity and improved inhibition.
The Richter lab found that CPEB1 knockdown in Fmr1 KO mice normalized excessive protein synthesis and improved synaptic and memory problems tied to Fragile X.
With $282,000 in funding from FRAXA Research Foundation, Dr. Leonard Kaczmarek and colleagues explored association of Slack channels with the Fragile X protein (FMRP).
With a $219,500 FRAXA grant, Dr. Stephen Haggarty at Harvard/MIT used patient-derived stem cells to screen drugs targeting GSK3, aiming to enhance lithium therapy.
With a $10,000 FRAXA grant, Dr. David Hessl at UC Davis analyzed the Aberrant Behavior Checklist as a key outcome measure for Fragile X. Results were published.
FRAXA-funded research by Dr. Anita Bhattacharyya at the Waisman Center revealed key insights into cyclic AMP signaling in Fragile X. Findings were published.
