Scientists have discovered that an enzyme known as prohormone covertase (PC1) is deficient in the brain of people who suffer from the Prader-Willi syndrome, a rare obesity syndrome. This discovery may pave the way for the development of new therapeutic options for these patients.
The Prader-Willi syndrome affects roughly 1 in 15,000 individuals and is characterised by insatiable hunger and extreme obesity, as well as by reduced growth, and a tendency to develop diabetes.
Past scientific studies had already identified potential genetic causes of the syndrome. Anomalies in a small region of chromosome 15 are thought to be involved in its development, causing a dysfunction in the part of the brain known as the hypothalamus, which regulates hunger and satiety. Patients are also known to have excessive level of the ghrelin hormone, which triggers hunger.
Yet, uncertainties remained about how these genes were really connected to the clinical phenotype of the Prader-Willi syndrome. Few treatments have been effective to date, so in their research published in the Journal of Clinical Investigation, the scientists wanted to investigate the molecular mechanisms that may be involved to come up with new therapeutic options for patients.
"Many treatments have been tried over the years, but none have been very effective. Giving growth hormones does help with with growth problems, but not with the regulation of food intake. Ketogenic diets – low carbs and high fat diets – were also promising but in the end they had little clinical impact, they didn't confer much benefits to these patients", senior author Dr. Rudolph Leibel told IBTimes UK.
The promise of stem cells
The team, from Columbia University Medical Center and supported by the Foundation for Prader-Willi Research, converted skin stem cells from Prader-Willi patients and from healthy controls into brain cells. Compared with the controls' stem cell-derived neurons, the neurons of Prader-Willi patients presented reduced levels of the PC1 enzyme.
"What stem cells enable us to do is to see the brain cells of these patients in ways that would have been impossible otherwise. It will potentially allow us to to identify therapeutic agents that might help us rectify the phenotype of the children with Prader-Willi syndrome", Leibel said.
To investigate their findings further, and confirm the role of the PC1 deficiency in the development of the syndrome, the researchers used transgenic mice that did not express one of the gene deleted on the area of chromosome 15 involved in the Prader-Willi syndrome. They found out that the mice were deficient in PC1 and displayed most of the hormone-related problems seen in people who have the disease.
This discovery could help researchers in their quest to find drug candidates that could activate the PC1 enzyme and raise its levels – drugs that have already been developed and that are safe to use could be tested and re-purposed.
The scientists could also continue working with stem cells to screen a larger library of molecules that could also function by raising the levels of PC1. Levo Therapeutics, a small pharmaceutical company founded by the parents of a child suffering from the Prader-Willi syndrome, is currently working with the researchers to find therapeutic applications to their findings.