Disentangling ingestive behavior-related phenotypes in Prader-Willi syndrome: Integrating information from nonclinical studies and clinical trials to better understand the pathophysiology of hyperphagia and obesity

Abstract

Prader-Willi syndrome (PWS) is a rare genetic form of hyperphagia leading to severe obesity, accompanied by endocrine, musculoskeletal, and neurological dysfunction. PWS is caused by the inactivation of contiguous genes on chromosome 15q11-q13, and mice with gene-targeted mutations in one or more of these PWS genes recapitulate PWS-like phenotypes. In addition to evaluating the potential effectiveness of a therapeutic for the treatment of PWS, animal models can be used to elucidate the deficiencies in appetitive and energy balance pathways that lead to hyperphagia and obesity. Various therapeutics have been tested for their effects on ingestive behavior, hyperphagia, and obesity in clinical trials for PWS, with encouraging preliminary results on small groups of participants with PWS. Here, we summarize ingestive behavior-related therapeutics tested in PWS animal models and summarize published data from clinical trials that have evaluated the effect of therapeutics on ingestive behavior in individuals with PWS. We then discuss strategies to accelerate the discovery and translation of therapies into clinical practice in PWS.

Keywords: Clinical trials; Diazoxide; Exenetide; GLP-1; Ghrelin; Growth hormone; Leptin; MAGEL2; Melanocortin; Mouse models of disease; Nonclinical studies; Oxytocin; Prader–Willi syndrome; Preclinical studies.