BOSTON (Oct. 8, 2014)— Under a five-year, $6 million grant announced today by the National Institutes of Health, Boston Children's Hospital will lead 10 medical centers in studying three rare genetic syndromes that often cause autism spectrum disorder (ASD) and intellectual disability (ID). The study's ultimate goal is to launch clinical trials of new treatments and develop "biomarkers" that can be used to monitor treatment effectiveness—for the three rare syndromes and possibly for broader groups of ASD/ID patients.
Through the grant, from NIH's Rare Diseases Clinical Research Network (RDCRN), the 10 centers have formed the Developmental Synaptopathies Consortium (U54 NS092090). In addition to the NIH and Boston Children's, the Consortium includes Cincinnati Children's Hospital Medical Center, Cleveland Clinic, Icahn School of Medicine at Mount Sinai, Rush University Medical Center, Stanford University, University of Alabama at Birmingham, University of California at Los Angeles and University of Texas at Houston. (See below for a list of leading investigators.) Enrollment is projected to begin in the spring of 2015.
While both ASD and ID have a variety of known genetic causes, some of them have been shown to impair similar cellular pathways in the brain. The three conditions to be studied by the Consortium—tuberous sclerosis complex (caused by mutations in the TSC1 and TSC2 genes), Phelan-McDermid syndrome (caused by SHANK3 mutations) and PTEN Hamartoma Tumor Syndrome (caused by PTEN mutations)—seem to affect certain shared pathways influencing the development of brain connections, or synapses.
"To date, genetic studies indicate that there are about 500 to 1,000 genes that make people susceptible to ASD and ID," says Mustafa Sahin, MD, PhD, a pediatric neurologist at Boston Children's Hospital and the Consortium Director. "While it's very unlikely that a single therapy could treat disorders with so many distinct causes, we may be able to find certain groups of patients who share defects in similar biochemical pathways and may respond to treatment with the same agents."
For example, the finding that tuberous sclerosis complex results from disruption of the mTOR pathway have led Sahin and colleagues to test whether mTOR inhibitors can improve patients' neurocognition. The Consortium investigators now plan to begin testing mTOR inhibitors in PTEN patients, since mTOR has also been implicated in their disease.
Together, the sites will seek to enroll 100 patients with tuberous sclerosis, 90 with Phelan-McDermid syndrome and 140 with PTEN mutations, ages 3 to 21, and follow them for three to five years with physical examinations, neuropsychological testing and advanced brain imaging. Advocacy groups for each condition, including the Tuberous Sclerosis Alliance, Phelan McDermid Syndrome Foundation, PTEN World, PTEN Life and The Beatrice and Samuel A. Seaver Foundation, helped design the studies and are providing additional funding. Each group will notify its patient community when enrollment opens.
"Through comparative analysis of pathology caused by multiple genes, we may find that treatments developed for one disorder might be applicable to others," says Sahin, who also founded and directs the Multidisciplinary Tuberous Sclerosis Program at Boston Children's. "A deeper understanding of this shared biology may also be a gateway to understanding the broader mechanisms of ASD and ID."
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The RDCRN is an initiative of NIH's Office of Rare Disease Research (ORDR) and National Center for Advancing Translational Sciences. The Developmental Synaptopathies Consortium is funded through collaboration between NCATS, NIMH, NINDS and NICHD. Its lead investigators are:
- Mustafa Sahin, MD, PhD, Principal Investigator, Boston Children's Hospital
- Audrey Thurm, PhD, Principal Investigator, NIH
- Darcy Krueger, MD, PhD, Principal Investigator, Cincinnati Children's Hospital Medical Center
- Charis Eng, MD, PhD, Principal Investigator, and Thomas Frazier, PhD, co-investigator, Cleveland Clinic)
- Joseph Buxbaum, PhD, Administrative Director, and Alexander Kolevzon, MD, Principal Investigator, Icahn School of Medicine at Mount Sinai
- Elizabeth Berry-Kravis, MD, PhD, Co-Investigator, and Latha Soorya, PhD, Co-Investigator, Rush University Medical Center
- Antonio Hardan, MD, Principal Investigator, Stanford University
- Martina Bebin, MD, Principal Investigator, University of Alabama at Birmingham
- Joyce Wu, MD, Principal Investigator, and Julian Martinez, MD, Co-Investigator, University of California at Los Angeles
- Hope Northrup, MD, Principal Investigator, and Deborah Pearson, PhD, Co-investigator, University of Texas at Houston
About Boston Children's Hospital
Boston Children's Hospital is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 14 members of the Institute of Medicine and 14 members of the Howard Hughes Medical Institute comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's today is a 395-bed comprehensive center for pediatric and adolescent health care. Boston Children's is also the primary pediatric teaching affiliate of Harvard Medical School.
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