R21HD115119

Efficacy of novel melanocortin and gut-peptide dual agonists for childhood obesity treatment - Summary

The high prevalence of pediatric obesity requires new anti-obesity agents with increased efficacy, safety, and tolerance.

Recent treatments based on endogenous gut peptides such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective at inducing weight loss through a suppression of food intake, but they are often associated with nausea/malaise and gastrointestinal ailments, leading to poor compliance with, or discontinuation of, treatment, particularly in children and adolescents.

The melanocortin (MC) pathway, in particular central MC4-receptor (MC4R) signaling, has been implicated in the regulation of energy homeostasis.

Previous evidence, including our own, has shown that treatment with MCR agonists is effective at inducing weight loss in obese patients caused by deficient hypothalamic MC signaling, including patients with genetic obesity and forms of hypothalamic injury-related obesity, in part, by increasing energy expenditure.

While treatment with the MC4R agonist setmelanotide (SETMEL) is effective, as a monotherapy it is limited, and there may also be unwanted off-target effects such as non-selective MC1R-mediated melanocyte stimulation and hyperpigmentation.

Our group has therefore focused on the development of a new generation of therapeutics that target multiple receptors of complementary neurocircuits regulating energy balance to induce greater weight loss, with minimal side effects.

In support of this, our recently published findings show that our first tri-agonist GEP44, which targets the GLP-1R and the neuropeptide receptors Y1R and anorexigenic Y2-R, reduces feeding and body weight in diet-induced obese (DIO) rodents and shrews more potently than GLP-1RAs exendin-4 and liraglutide, but without nausea and emesis.

Based on these findings, we recently developed a novel GLP-1R/MC4R dual agonist (KCEM1) and our preliminary data show that treatment of DIO rats with KCEM1 reduced food intake and body weight, and improved glycemic control compared to controls, and these effects were stronger vs. equimolar injections of the GLP-1RA liraglutide, and semaglutide, respectively.

The goal of this research is to: 1) fully characterize and develop our GLP-1R/MC4R monomeric peptide dual agonists with improved efficacy by optimizing specific MC4R binding (over MC1/2/3/5Rs), and 2) create two novel neuropeptide Y receptor Y2R/MC4R agonists, which act independently of the GLP-1R pathway entirely thus avoiding associated side effects.

Specific aim 1 will test the hypothesis that KCEM1 both prevents and reverses DIO and improves glucoregulation relative to vehicle and FDA-approved single agonists.

Comprehensive measures of energy homeostasis will be supported by the Nutrition Obesity Research Center Energy Balance Core at the University of Washington.

Specific aim 2 (exploratory) will develop novel GLP-1R/MC4R and Y2R/MC4R dual agonists including long-acting lipidated multiagonists, and elucidate their penetration into the brain, receptor binding, and tissue-specific mechanisms in brain areas of energy homeostasis and peripheral tissues.

Together, this work is expected to identify novel, safe, and effective treatments for pediatric obesity.

Seattle Children's Hospital

TO CONDUCT AND SUPPORT LABORATORY RESEARCH, CLINICAL TRIALS, AND STUDIES WITH PEOPLE THAT EXPLORE HEALTH PROCESSES. NICHD RESEARCHERS EXAMINE GROWTH AND DEVELOPMENT, BIOLOGIC AND REPRODUCTIVE FUNCTIONS, BEHAVIOR PATTERNS, AND POPULATION DYNAMICS TO PROTECT AND MAINTAIN THE HEALTH OF ALL PEOPLE. TO EXAMINE THE IMPACT OF DISABILITIES, DISEASES, AND DEFECTS ON THE LIVES OF INDIVIDUALS. WITH THIS INFORMATION, THE NICHD HOPES TO RESTORE, INCREASE, AND MAXIMIZE THE CAPABILITIES OF PEOPLE AFFECTED BY DISEASE AND INJURY. TO SPONSOR TRAINING PROGRAMS FOR SCIENTISTS, DOCTORS, AND RESEARCHERS TO ENSURE THAT NICHD RESEARCH CAN CONTINUE. BY TRAINING THESE PROFESSIONALS IN THE LATEST RESEARCH METHODS AND TECHNOLOGIES, THE NICHD WILL BE ABLE TO CONDUCT ITS RESEARCH AND MAKE HEALTH RESEARCH PROGRESS UNTIL ALL CHILDREN, ADULTS, FAMILIES, AND POPULATIONS ENJOY GOOD HEALTH. THE MISSION OF THE NICHD IS TO ENSURE THAT EVERY PERSON IS BORN HEALTHY AND WANTED, THAT WOMEN SUFFER NO HARMFUL EFFECTS FROM REPRODUCTIVE PROCESSES, AND THAT ALL CHILDREN HAVE THE CHANCE TO ACHIEVE THEIR FULL POTENTIAL FOR HEALTHY AND PRODUCTIVE LIVES, FREE FROM DISEASE OR DISABILITY, AND TO ENSURE THE HEALTH, PRODUCTIVITY, INDEPENDENCE, AND WELL-BEING OF ALL PEOPLE THROUGH OPTIMAL REHABILITATION.

93.865 - Child Health and Human Development Extramural Research

National Institute of Child Health and Human Development (NICHD) [HHS - NIH]

Seattle, Washington 981011304 United States

Single Zip Code

NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed) (PA-20-195)