Agent/target | Â | Phenotypes reversed | Translational progress | |
---|---|---|---|---|
 | dfmr mutant fly | Fmr1 KO mouse | Humans with FXS | |
(1)a Block translational signaling pathway—external | ||||
 | mGluR5 inhibition (MPEP, fenobam, STX107, AFQ056, RO4917523); MPEP used in models except where markeda | Courtship behavior—immediate recall and short-term memory; mushroom body formation; odor-shock memory; survival on glutamate-containing food | Audiogenic seizuresa; Epileptiform bursts; open-field hyperactivity; dendritic spine morphologya; amygdala mEPSP frequency; prepulse inhibitiona; marble buryinga | Fenobam—phase IIa single-dose open-label trial—PPI improved, anxiety reduced; AFQ056—phase IIb trial completed with improvement in fully methylated patients, phase III trial being initiated; RO4917523—phase II trial in progress STX107—phase I completed |
mGluR5 inhibition by genetic reduction of mGluR5 receptors | Â | Audiogenic seizures; dendritic spine density; excessive protein synthesis; abnormal growth pattern; ocular dominance plasticity; inhibitory avoidance extinction | Â | |
(1)b Block translational signaling pathway- internal | ||||
 | Lithium (inhibition of GSK3β and PI turnover) | Courtship behavior—immediate recall and short-term memory; mushroom body formation | Audiogenic seizures; open-field hyperactivity; dendritic spine morphology; learning and anxiety deficits in the elevated plus maze, elevated zero maze, passive avoidance; social interaction deficit with new mice and anxiety-related behaviors during social interaction | Open label trial—behavioral improvement, some adaptive skills and verbal memory improved; ERK biomarker normalized |
GSK3β inhibition (AR-A014418 or SB-216763) |  | Audiogenic seizures |  | |
PAK inhibition by genetic reduction of PAK | Â | Dendritic spine morphology; Cortical LTP deficits; open-field hyperactivity, repetitive behaviors, center field anxiety deficit; Fear conditioning | Â | |
PI3K inhibition (LY294002) | Â | Dendritic spine morphology; mTOR overactivity | Â | |
ERK/MEK inhibition (SL327) | Â | Audiogenic seizures; protein synthesis | Â | |
(2) Inhibit activity of individual FMRP-regulated proteins | ||||
 | Inhibit MMP9 (minocycline) |  | Dendritic spine morphology; anxiety in elevated plus maze; exploratory behavior in Y maze | Improvement in behavior in small open-label trial |
Inhibit APP/Aβ with antibody or by genetic reduction of APP | Audiogenic seizures; dendritic spine morphology; marble burying |  | ||
Inhibit STEP by genetic reduction of STEP | AMPA receptor internalization; audiogenic seizures; open-field hyperactivity | Â | ||
(3) Activate surface AMPA receptors | ||||
 | Ampakines (CX516, CX614) |  | CX614 increases BDNF which reverses impairments in hippocampal TBS-LTP | CX516—phase II trial—no cognitive or behavioral effects overall—dose too low but may have helped subjects co-treated with antipsychotics |
(4) Other synaptic receptors/proteins | ||||
 | GABA-B agonists (baclofen, R-baclofen) | Survival on glutamate-containing food; memory deficits | Audiogenic seizures; open-field hyperactivity; marble burying | R-baclofen phase II trial—improvement in overall function, social and language function in more socially impaired subject group |
GABA-A agonists (ganaxolone) | Â | Audiogenic seizures | Â | |
Anticholinesterase (donazepil) | Â | Â | Open label trial -behavioral and social improvement | |
NMDA antagonists (memantine, acamprosate) |  |  | Memantine—small open-label trial—no overall improvement | |
 |  |  | Acamprosate—open-label trial in 3 patients with improved language and socialization | |
Glutamate uptake inhibition (riluzole) |  |  | Riluzole—small open-label trial—no overall improvement, ERK biomarker normalized |