A prodrug targeting CIM6P/IGF2R enhances memory in healthy mice and reverses deficits in an Angelman syndrome mouse model.

Devastating diseases of the central nervous system (CNS), such as neurodevelopmental disorders and neurodegenerative diseases, carry severe neurological symptoms, including cognitive impairment -a decline characterized by learning and memory problems. Currently, no efficacious treatment is available for preventing or treating these diseases; therefore, there is a great unmet need to find novel, effective therapeutics. Previous studies have shown that insulin-like growth factor 2 (IGF2) and mannose 6-phosphate (M6P), two major ligands of the cation-independent M6P/IGF2 receptor (CIM6P/IGF2R), significantly enhance memory and prevent forgetting in healthy animals. Furthermore, they reverse most core symptoms in mouse models of neurodevelopmental disorders, such as Angelman syndrome (AS mice) and autism spectrum disorder, and of neurodegenerative diseases. Starting from the M6P chemical structure, we designed the novel prodrug PMP1. We tested its effects on learning and memory in healthy mice as well as on behavioral deficits in AS mice. We report that both subcutaneous and oral administrations of PMP1 significantly enhance memory strength and persistence in healthy mice. Furthermore, they reverse memory impairments and motor deficits in AS mice. The effect of PMP1 requires the expression of CIM6P/IGF2R in the hippocampus, and the treatment does not elicit any detectable adverse effects. The highest effects were achieved with the same PMP1 maximum effective dose via either route of administration; however, oral administration produced a more prolonged effect. Thus, the novel small-molecule prodrug PMP1, through CIM6P/IGF2R, is a promising therapeutic candidate for Angelman syndrome and an effective memory enhancer.