OPERAT I NG REV I EW CON T I NU E D WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 10 20 30 Obesity Fat mass (g) WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 50 100 150 IGF-1 (ng/ml) Circulating IGF-1 levels WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 2 4 6 8 10 Cognition Time spent with the novel object (S) Obesity Circulating IGF-1 levels Cognition WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 50 100 150 Social preference Time spent with the mouse (S) WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 20 40 60 80 100 Social Interaction Sniffing events (n) WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 50 100 150 200 Anxiety Time (S) Social preference Social interaction Anxiety WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 2000 4000 6000 8000 10000 Hypoactivity (Open Field distance travelled) Distance travelled (cm) WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 200 400 600 800 Hypoactivity (Open Field time spent active) Time (S) WT + Vehicle Magel2-null + Vehicle WT+ NNZ2591 (low dose) Magel2-null + NNZ2591 (low dose) WT+ NNZ2591 (high dose) Magel2-null + NNZ2591 (high dose) 0 2 4 6 Daily living Nest Building quality (grade 1 to 5) Hypoactivity Hypoactiv ty Daily Living (Open Field distance travell d) (Open Field time spent active) Efficacy in mouse model of Prader-Willi (Magel2-null) Prader-Willi is caused by mutations in the 15q11-q13 region of chromosome 15. In the Magel2-null mouse model, which exhibits features of Prader-Willi in humans, wild type mice and knockout mice were treated with placebo (vehicle) or NNZ-2591 for 6 weeks. Treatment with NNZ-2591 normalized fat mass (obesity) insulin levels, IGF-1 levels and all the behavioral deficits in the knockout mice and had no effect on the wild type mice. Insulin levels (pM) WT plus vehicle Magel2-null plus vehicle WT plus NNZ-2591 low dose Magel2-null plus NNZ-2591 low dose WT plus NNZ-2591 high dose Magel2-null plus NNZ-2591 high dose 110 173 112 143 115 119 Neuren Pharmaceuticals Limited Annual Repor t 2022 11
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