Ricerche finanziate da FAST ITALIA

Abstract at Society for Neuroscience, 2023

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder that affects approximately 1 on 12,000 children. AS is caused by genetic alterations of the 15q11.2-q13.1 chromosome region, which leads to several neuropsychiatric symptoms, including cognitive impairments and motor deficits. To date, the treatments available for AS patients are limited to symptomatic management. Our previous works on a mouse model of AS showed that the insulin like growth factor 2 receptor (IGF2R) ligands IGF2 and mannose 6 phosphate (M6P) reverse several behavioral defects of AS mice. Here we identified and synthesized a new small molecule compound (PMP1), designed as a prodrug derivative of M6P, that could provide long-lasting behavioral effects and could be administered orally. We tested PMP1 by subcutaneous (s.c.) injection into healthy mice (WT mice) and found that a single injection results in significant memory enhancement, tested with both aversive and non-aversive memory tasks.  We also found that PMP1 reversed memory and motor impairment in AS mice. PMP1 compared to IGF2 and M6P, in both WT and AS mice, emerged as more effective as memory enhancer in WT mice and in reversing memory and motor deficits in AS mice. We also found that PMP1 works effectively via oral administration in both WT and AS mice, and the effects are long lasting. Finally, we determined that the effect of PMP1 in memory enhancement requires IGF2R. Together, these data lead to the conclusion that PMP1 represents a new potential molecule for the treatment of AS and potentially of other diseases of cognitive impairments.