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Autism Speaks grant boosts Rett syndrome research

Jan. 23, 2014, 9:48 AM

Colleen Niswender, Ph.D., research associate professor of Pharmacology, has received a three-year, $450,000 grant from the autism science and advocacy organization Autism Speaks to support studies investigating a possible new treatment for Rett syndrome.

Colleen Niswender, Ph.D.

Niswender’s grant was one of 13 new research projects that received nearly $2.7 million in funding this year through Autism Speaks’ Early Access to Care initiative. Its goal is to lower the average age of diagnosis of autism spectrum disorders (ASD) and increase access to high-quality early interventions.

“We are extremely excited to have been given the opportunity to pursue the development of new therapeutics for Rett syndrome with support from Autism Speaks,” said Niswender, who is also director of molecular pharmacology in the Vanderbilt Center for Neuroscience Drug Discovery (VCNDD).

Preliminary data suggest that compounds targeting the metabotropic glutamate receptor 5 subtype (mGlu5) can reverse manifestations of the disease in a mouse model, she said.

Rett syndrome is a neurodevelopmental disorder that has significant symptom overlap with ASD, and is one of the most common causes of intellectual disabilities in females. Genetically, the disease results from mutations in the Mecp2 gene, which disrupt neurotransmitter signaling, including signals mediated by the excitatory transmitter glutamate.

“Excitingly, recent evidence from mouse models of the disease has demonstrated that many of the symptoms of Rett syndrome can be reversed, even at advanced stages,” Niswender said. “This suggests that Rett syndrome does not have to exist as a lifelong condition and that the disorder is ripe for therapeutic intervention.”

Niswender’s team is using compounds discovered at Vanderbilt called positive allosteric modulators to “turn up” receptor activity when glutamate binds to the mGlu5 receptor, similar to a dimmer switch in an electrical circuit.

Previous studies have suggested that enhancing neurotransmission via this mechanism may increase the already high risk of seizures in Rett patients.

The researchers overcame this challenge by identifying novel compounds that, in addition to correcting multiple deficits in adult Mecp2 mutant mice, do not appear to induce or enhance seizure risk even after multiple weeks of chronic dosing.

The grant from Autism Speaks will allow them to examine the ability of mGlu5 modulation to relieve symptoms at each stage of disease progression.

“It is our hope that this work will make important contributions to the world-wide effort to develop new treatments for devastating diseases like Rett syndrome and ASD,” Niswender said.

In addition to Autism Speaks, Niswender has received support from the International Rett Syndrome Foundation and National Institutes of Health grants MH062646 and NS031373. VCNDD director P. Jeffrey Conn, Ph.D., is principal investigator of the NIH grants.

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