Potential drug appears to ease effects of Prader-Willi syndrome

December 26, 2016, Duke University Medical Center

Duke Health researchers have identified a drug-like small molecule that, in animal experiments, appears to be an effective treatment for a genetic disorder called Prader-Willi syndrome.

Prader-Willi syndrome is characterized by poor feeding, growth and weak muscles in infancy, followed by excessive eating, obesity and behavioral problems in childhood. It occurs in about one of every 15,000 births and has no cure.

If the findings by the Duke-led team bear out in human studies, the drug could become the first treatment option for Prader-Willi syndrome. The concept proven in this study could also apply immediately to other similar type of genomic imprinting disorders in which children only inherit an active copy of a gene from one parent.

"Our findings are promising and indicate that we may have a path forward for the first time to treat the severe, life-limiting features of this genetic disorder," said Yong-hui Jiang, M.D., Ph.D., associate professor in Duke's departments of Pediatrics and Neurobiology. Jiang is senior author of a study published online Dec. 26 in the journal Nature Medicine.

In most cases of Prader-Willi syndrome, the responsible gene in the region of chromosome 15 from the father is missing and the mother's copy is silent. Jiang and colleagues focused their work on finding a way to activate the silent gene from the mother's chromosome to recover the necessary gene function that would ordinarily be performed by the father's gene.

The researchers—including Bryan Roth, M.D., Ph.D, at the University of North Carolina at Chapel Hill and co-first authors Yuna Kim, Ph.D., and Hyeong-min Lee, Ph.D.—conducted screenings of more than 9,000 compounds. Using fluorescent marker in mouse embryonic fibroblasts, the researchers were able to see whether any of the small molecules triggered the cells to glow, which indicated they were capable of activating the maternal copy of the Prader-Willi gene.

A class of small molecule that are known as G9a inhibitors were successful, both in the mouse model of Prader-Willi syndrome and in human cells from patients with the disorder. G9a is an enzyme that is important for gene regulation.

The G9a inhibitors also appeared to have a therapeutic effect. When mice with Prader-Willi syndrome were treated with these small molecule drugs during infancy, they lived longer and had more normal growth.

"Our findings suggest that G9a inhibitors may play a role in regulating the silencing of parental chromosomes on certain genes that require an imprinting process for normal function," Jiang said. "This could provide a new insight for the molecular mechanism of genomic imprinting."

In addition to Jiang, Kim, Lee and Roth, study authors include Yan Xiong, Noah Sciaky, Samuel W. Hulbert, Xinyu Cao, Jeffrey I. Everitt and Jian Jin.

Explore further: Major breakthrough in understanding Prader-Willi syndrome, a parental imprinting disorder

More information: Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome, Nature Medicine, nature.com/articles/doi:10.1038/nm.4257

Related Stories

Major breakthrough in understanding Prader-Willi syndrome, a parental imprinting disorder

May 11, 2014
(Medical Xpress)—Scientists at the Hebrew University of Jerusalem have reported a major breakthrough in understanding the molecular basis for Prader-Willi syndrome (PWS), perhaps the most studied among the class of diseases ...

Rare obesity syndrome therapeutic target identified

December 12, 2016
Columbia University Medical Center (CUMC) researchers have discovered that a deficiency of the enzyme prohormone covertase (PC1) in the brain is linked to most of the neuro-hormonal abnormalities in Prader-Willi syndrome, ...

Seeing cell to cell differences for first time explains symptoms of rare genetic disorders

April 1, 2016
Every cell in the body has two genomes, one from the mother and one from the father. Until now, researchers have lacked the tools to examine—in a single cell —the exact readout from each genome to make RNA. Using a new ...

New insights uncovered into Prader-Willi syndrome

June 14, 2016
A study published in the journal Human Molecular Genetics by researchers at Children's Hospital Los Angeles (CHLA) provides novel insights into the brain mechanisms underlying the insatiable hunger and subsequent obesity ...

Recommended for you

Doctors may be able to enlist a mysterious enzyme to stop internal bleeding

August 14, 2018
Blood platelets are like the sand bags of the body. Got a cut? Platelets pile in to clog the hole and stop the bleeding.

Byproducts of 'junk DNA' implicated in cancer spread

August 14, 2018
The more scientists explore so-called "junk" DNA, the less the label seems to fit.

Artificial placenta created in the laboratory

August 14, 2018
In order to better understand important biological membranes, it is necessary to explore new methods. Researchers at Vienna University of Technology (Vienna) have succeeded in creating an artificial placental barrier on a ...

Using DeepMind's neural network learning system to diagnose eye diseases

August 14, 2018
Three institutions working together have applied DeepMind's neural network learning system to the task of discovering and diagnosing eye diseases. Moorfields Eye Hospital has been working with Google's DeepMind Health subsidiary ...

3-D printed biomaterials for bone tissue engineering

August 13, 2018
When skeletal defects are unable to heal on their own, bone tissue engineering (BTE), a developing field in orthopedics can combine materials science, tissue engineering and regenerative medicine to facilitate bone repair. ...

Artificial intelligence platform screens for acute neurological illnesses

August 13, 2018
An artificial intelligence platform designed to identify a broad range of acute neurological illnesses, such as stroke, hemorrhage, and hydrocephalus, was shown to identify disease in CT scans in 1.2 seconds, faster than ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.