There is some data suggesting that one of the systems that regulates appetite and weight in the brain, the melanocortin-4 receptor pathway, may be disrupted in PWS. This study will examine a new class of drugs targeting this pathway, in a mouse model of PWS. The drugs will be tested alone and in combination with other drugs currently being evaluated for PWS-associated hyperphagia.
ABSTRACT: While hyperphagia and obesity are but two of the symptoms of Prader-Willi Syndrome, treatment of these symptoms will significantly improve the quality of life for PWS patients and families, and reduce the high incidence of metabolic diseases in PWS patients. The MAGEL2 gene has been shown to be deleted in patients with PWS, and a mouse model of this gene deletion shows an increase in adipose mass. Interestingly, these mice are resistant to the ability of the adipose hormone leptin to inhibit food intake, and are hypersensitive to the actions of a downstream effector of leptin, a neuropeptide called alpha-MSH that acts through the melanocortin-4 receptor (MC4R). This suggests that PWS patients may respond well to treatment with MC4R based drugs, and this is the basis for the current clinical trial in PWS patients of setmelanotide, a peptide analogue of alpha-MSH administered by injection. The long term goal of this work is to develop small molecule orally available therapeutics for the treatment of the hyperphagia and obesity in PWS. Towards this end, we have recently developed a set of potent small molecule positive allosteric modulators of MC4R (MC4R PAMs) that inhibit food intake and weight gain in wild type mice. In this research program, we will test the hypothesis that these compounds may be particularly potent in reduction of food intake and induction of weight loss in the Magel 2 knockout model of PWS. Further, we will test if this class of drugs can enhance the activity of alpha-MSH compounds currently in clinical trials for PWS, such as the RM511 analogue, setmelanotide. These findings may further inform the development of therapeutics for the hyperphagia and obesity of PWS.
Research Outcomes: Project Summary
The Magel2KO mouse does indeed seem to be hypersensitive to enhanced melanocortin signaling, as induced by administration of the MC4R PAM GSK3397744. The clear stress-induced anorexia seen in the Magel2KO mouse, however, confounds the interpretation of the result.
Roger Cone, PhD
University of Michigan