Mid-Atlantic Consortium Newsletter Summer 2013

Joint Center Would Integrate In-depth Studies of Fragile X Syndrome

Boy with Fragile x syndrome

A boy with Fragile x syndrome. Picture courtesy of the Elwyn Fragile X Center.

Researchers in Philadelphia and Baltimore are planning a new center focused on improving outcomes for individuals with Fragile X syndrome.

The proposed center, to be operated by the University of Pennsylvania Perelman School of Medicine (Penn), the Children’s Hospital of Philadelphia (CHOP), and the Kennedy Krieger Institute (KKI) in Baltimore, would integrate efforts to improve drug treatments, better describe how the disease affects individuals, and seek biomarkers to facilitate diagnosis and treatment. A funding proposal has been submitted to the National Institutes of Health.

“It’s time to accelerate this kind of collaborative approach to the most common cause of intellectual impairment,” says Tom Jongens, Ph.D., associate professor of genetics at Penn and proposed director of the center. “We’re poised to improve behavioral and cognitive assessments of Fragile X, look at rapid identification of drugs in mouse models, and enhance the definition of the condition.”

Fragile X is caused by loss of the FMR1 gene function, which encodes the Fragile X Mental Retardation Protein (FMRP). Individuals with the syndrome exhibit a range of difficulties, including impaired cognition and high rates of autism spectrum disorders, anxiety disorders and attention deficit/hyperactivity disorders.

A major challenge with clinical trials of drugs for patients with Fragile X is that most involve novel compounds that have no history of use in humans, Jongens says. Therefore, these trials require extremely careful monitoring for safety, are very costly, and usually only examine short-term effects (over a period of a day to several weeks), providing little time for improvements to occur in the underlying disease and to observe positive outcomes, especially in cognition.

At the proposed center, one of several goals is to select drugs already approved for other conditions (e.g., that target the signaling pathway for insulin, for example) that show initial promise in fruit fly models of Fragile X, and test them in mouse models. Because the drugs are Food and Drug Administration-approved and have minimal side effects in children, successful animal tests could make them excellent candidates for longer clinical trials in affected individuals, combined with educational and behavioral interventions, Jongens says. Investigators also hope to identify the most effective timing for treatment by testing mice at different ages.

Center investigators also will work to identify potential biomarkers of FMR1-related conditions. Basic research from fly and mouse Fragile X models suggests that hyperactivation of the excitatory (glutamate) pathway, and diminished levels of the inhibitory (GABA) pathway exist in the brains of individuals with Fragile X, though data are limited. At KKI, researchers will use powerful magnetic resonance imaging tools to study levels of the neurotransmitters glutamate, GABA, and glycine in children with Fragile X, says Michael Johnston, M.D., executive vice president and chief medical officer for KKI, and principal investigator for KKI’s work in the center.

Another core project of the proposed center would seek to better define the features and clinical symptoms of Fragile X patients, says Judith Miller, Ph.D., a clinical psychologist with CHOP’s Center for Autism Research, and principal investigator for this area. She and her colleagues plan to recruit Fragile X patients at three locations – KKI; Geisinger Health System in Danville, PA.; and Elwyn Inc. in the Philadelphia suburbs – for in-depth assessment of their levels of autism, anxiety, attentiveness and IQ/cognition. The ultimate goal is to “understand how these pieces fit together for individual patients, so we’ll know what the drugs are targeting,” Miller says.

Yet another center project would compare testing and outcomes between animal models of Fragile X and patients. “We aim to understand the behavioral characteristics of Fragile X in a more complete way than ever before,” Johnston says. “And mostly, we hope this collaboration will more efficiently obtain quality data from mouse studies to help us get new treatments to the clinic as quickly as possible.”

For more information or to be listed in a Fragile X database maintained by CHOP, call Julianne Fretz at 1-866-570-6524, or see http://www.centerforautismresearch.com.

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