Table 1 FXS targeted treatments in models and man

mGluR5 inhibition (MPEP, fenobam, STX107, AFQ056, RO4917523); MPEP used in models except where marked^a

Courtship behavior—immediate recall and short-term memory; mushroom body formation; odor-shock memory; survival on glutamate-containing food

Audiogenic seizures^a; Epileptiform bursts; open-field hyperactivity; dendritic spine morphology^a; amygdala mEPSP frequency; prepulse inhibition^a; marble burying^a

Fenobam—phase IIa single-dose open-label trial—PPI improved, anxiety reduced; AFQ056—phase II^b 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

Audiogenic seizures; dendritic spine density; excessive protein synthesis; abnormal growth pattern; ocular dominance plasticity; inhibitory avoidance extinction

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

Dendritic spine morphology; Cortical LTP deficits; open-field hyperactivity, repetitive behaviors, center field anxiety deficit; Fear conditioning

PI3K inhibition (LY294002)

Dendritic spine morphology; mTOR overactivity

ERK/MEK inhibition (SL327)

Audiogenic seizures; protein synthesis

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

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

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)

Audiogenic seizures

Anticholinesterase (donazepil)

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