Newly Discovered Drug Molecule Offers Hope of Treatment for Prader-Willi Syndrome

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Highlights

• Researchers from Duke University have identified a drug like molecule that inhibits G9a, an enzyme that is important for gene regulation
• If this molecules if found to be effective in further clinical trials, it is the first ever treatment for Prader Willi, a rare genetic disorder
• G9a has been implicated in many diseases and the effectiveness of this newly discovered drug could aid in treating many genetic disorders

A drug like molecule has been identified by researchers from Duke University which is found to be effective against a genetic disorder called Prader Willi syndrome.

Prader-Willi Syndrome

This is a rare genetic disorder that is characterized by poor muscle tone, low level of sex hormone and extreme hunger. The feeling of fullness of satiety response is poor in people with this disorder resulting in overeating and obesity.

‘First ever treatment for Prader Willi syndrome offers hope to the many affected by the condition. A drug like molecule that inhibits G9a, an enzyme that is important for gene regulation has been found.’

The classic symptoms of this disorder include:

• Floppiness and an inability to suck in newborns
• Undescended testis
• Poor motor skills
• Weight gain
• Mild learning difficulties

There is no known cure for this condition and obesity is controlled using exercises and diet. People with this condition need to be monitored for the rest of their lives and need special support.

Potential Treatment in Sight

In majority of the cases of Prader-Willi syndrome, the individual gets a copy from the mother that is silent while the gene copy in chromosome 15 is missing from the father. Under normal circumstances, the gene in the father's copy of the chromosome would carry out the necessary function, however, since this gene is missing, the researchers from Duke University tried to activate the silent gene from the mother to carry out the functions.

Identifying G9a Inhibitors

Dr. Bryan Roth from The University of North Carolina and colleagues screened more than 9,000 compounds which could activate the silent gene. Fluorescent markers were used to identify whether any of the compounds triggered the cells to glow, indicating that the compound successfully activated the silent gene.

A class of molecules called the G9a inhibitors was successful in both mouse models as well as in the human cells from patients with the disorder. The enzyme G9a is important in gene regulation.

Mice that were treated with the G9a inhibitors during the stage of infancy showed normal development and lived longer. Dr. Yong-hui Jiang, who is an associate professor in Duke's departments of Pediatrics and Neurobiology said "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. This could provide a new insight for the molecular mechanism of genomic imprinting."

In a study published by Ana Fiszbein et al in the journal Cell Reports, it was found that alternate splicing of G9a lead to neuronal differentiation. G9a is an important enzyme that is required for neuron differentiation. This important enzyme has been implicated in the growth and differentiation of a variety of cells and tissues, including thenocytes and skeletal muscles. In the nervous system it has been found that G9a controls cognition as well as controlling adaptive responses by repressing non neuronal genes.

In the study by Chen WL and colleagues titled "G9a- An antineoplastic target" published in the Journal Current Cancer Drug Targets, the mounting evidence of G9a catalyzing histone and non-histone proteins are detailed. Another study by Fransesco Casciello titled "Functional Role of G9a Histone Methyltransferase in Cancer" published in the Journal Frontiers in Immunology focusses on the gene regulation of G9a and its role in cancer progression and differentiation. G9a inhibition is found to inhibit cell proliferation in many cell lines and its presence is found to increase growth and proliferation of solid tumours.

The study on Prader Willi syndrome is one of the first few studies that focus on the treatment for this rare genetic disorder. If the animal studies can be replicated in human studies, then the compound used to inhibit G9a could be an effective means of treatment for Prader Willi, the very first treatment for this condition.

Apart from Prader Willi syndrome, the G9a inhibitor identified in the current study can be used for other similar genetic disorders. The incidence of Prader Willi syndrome is only 1 in 15,000 but it can result in shorter life span and greater dependency on caregivers for support. The identification of the drug like compound that inhibits G9a enzyme could help treat the condition and lead to a longer lifespan with a better quality of life.

References:

1. Functional Role of G9a Histone Methyltransferase in Cancer - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC4585248/)
2. Prader-Willi Syndrome - (https:medlineplus.gov/praderwillisyndrome.html)
3. Yuna Kim, Hyeong-Min Lee, Yan Xiong, Noah Sciaky, Samuel W Hulbert, Xinyu Cao, Jeffrey I Everitt, Jian Jin, Bryan L Roth, Yong-hui Jiang. Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader-Willi syndrome. Nature Medicine, 2016; DOI: 10.1038/nm.4257

Source: Medindia

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