In 2012, The John Merck Fund awarded a $1 million, four-year grant to the University of California, Davis, for Principal Investigator David Hessl’s research project, “Cognitive Training for Fragile X Syndrome.”
Fragile X syndrome (FXS) is the most common inherited cause of autism. Prevalence estimates are 1 in 4,000 to 8,000. The phenotype associated with FXS includes both behavioral and cognitive deficits in addition to physical features. The behavioral phenotype typically includes attention-deficit hyperactivity disorder, anxiety and intermittent aggression, which can cause significant difficulties for families. Individuals with Fragile X Syndrome demonstrate profound executive function deficits that interfere with learning, socialization, and emotion regulation.
Dr. Hessl’s study, the first non-pharmacological controlled trial for FXS, evaluated the efficacy of Cogmed, a cognitive training program that enhances working memory and executive function. The study provided evidence that children and adolescents with FXS can engage and make progress in an intensive web-based working memory training program, over a period of 5-6 weeks. The primary hypothesis that participants completing the publicly available adaptive training versions of the program will make significantly greater gains in standardized measures of working memory than those completing a non-adaptive “control” version was not confirmed. However, both groups improved on a variety of metrics. The John Merck Fund has made an additional $181,500 grant to enable Dr. Hessl to mine data from the original study to glean more insight about what factors contribute to improved working memory and executive function in study participants.
The Journal of Neurodevelopmental Disorders published a paper on Dr. Hessl’s research.
JMF’s grant to Dr. Hessl is part of our Developmental Disabilities Program’s Translational Research Program – supporting research with the potential for near-term positive impact on people with developmental disabilities and their families.
Xinyu Zhao, PhD, a grantee in The John Merck Fund’s Developmental Disabilities Program (along with her colleague Anita Bhattacharyya), received the 2018 National Fragile X Foundation (NFXF) Research Award for outstanding contributions to the understanding of Fragile X syndrome. Zhao is a professor of neuroscience and Waisman Center investigator at the University of Wisconsin-Madison. The award was presented at the 2018 national conference held in Cincinnati, Ohio, in July. Zhao also presented, “Bridging the Gap: How Human Stem Cells May Help Us to Find Treatments for Fragile X Syndrome” as a featured speaker at the conference.
Fragile X syndrome is the leading inherited cause of intellectual disability, as well as the source of many cases of learning disabilities and autism. Fragile X is caused by a repetitive genetic error on the long arm of the X chromosome. The mutation is in a single gene called FMR1. A small set of nucleotides (the building blocks of DNA) are repeated excessively, disrupting the structure of the gene and preventing the production of its normally encoded protein (FMRP). The mutation is passed through families and can occur more frequently or severely in future generations.
Zhao’s research focuses on the function of FMRP in neuronal development—the process important for learning, memory, cognition, and adaptation. She is also exploring reactivation of the silenced FMRI gene as a potential treatment option.
“I am honored to receive this award and be included among the previous recipients who have made such significant contributions to Fragile X research” says Zhao. “We share a commitment to expand and advance this research with the goal of improving the lives of individuals and families impacted by Fragile X syndrome.”
A new program offering free elective genetic testing for newborns, developed at RTI International, will become available to North Carolina parents starting in 2018, thanks to a grant from the National Institutes of Health.
The National Institutes of Health, through the National Center for Advancing Translational Sciences (NCATS), announced earlier this year that it will provide $1 million per year over five years to launch the Early Check program (also supported by JMF) statewide in North Carolina, offering testing for one or more genetic conditions to up to 120,000 families each year. Early Check will function as a research study, helping enable research on genetic conditions and potential treatments. This project is one of seven innovation awards funded by National Center for Advancing Translational Sciences.
“We hope to offer to every baby born in North Carolina the opportunity to participate in this study,” said Don Bailey, PhD, Distinguished Fellow at RTI and the project’s principal investigator.
Shortly after birth, most babies in the US go through a series of screenings for genetic disorders. The tests help doctors act quickly to help babies with conditions that can be treated, but that might otherwise go unnoticed and could be deadly.
The panel of conditions currently included in standard newborn screening tests leaves out some diseases, such as Fragile X syndrome, that could be detected early. In some cases, tests are available, but expensive.
“The conditions left out of standard newborn screening do not have enough evidence that early treatment changes outcomes, something necessary for a public health program that is done universally,” said Lisa Gehtland, MD, a physician and public health analyst at RTI and the Project Director. Early Check researchers will provide information about whether some of these conditions are appropriate for newborn screening.
“Early Check is an exciting and innovative project to not only improve health outcomes, but to expand our scientific knowledge about detection and new approaches to treatment,” said Alex Kemper, MD, a pediatrician who serves as the principal investigator at Duke.
Read more about Early Check in its feature on the NIH’s NCATS website here.
“Social-environmental factors have profound effects on neurodevelopment and behavior. We need to address the child’s social environment if treatments are to be successful.”
– Scott S. Hall, PhD, Stanford University
In 2015, The John Merck Fund awarded a $1 million, four-year grant to Scott Hall, Associate Professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, to explore the treatment of disruptive behaviors in Fragile X syndrome. Fragile X syndrome (FXS) is an intellectual disability that affects one in 4,000 males and one in 8,000 females and causes learning difficulties, hyperactivity, social anxiety, hypersensitivity to sensory stimuli, and autism and autism-related behaviors.
Many individuals with FXS, particularly boys, show severe disruptive behaviors, such as self-injury, property destruction, and aggression. These behaviors can be extremely distressing for families and severely impact the child’s quality of life and education. Currently available drug therapies for these behaviors have not been shown to be very effective.
Dr. Hall’s research explores how social-environmental factors play a role in the development and maintenance of these behaviors, and his project evaluates a behavioral, rather than pharmacological, treatment for children with FXS. Following in-home assessments, caregivers receive daily coaching over a twelve-week period via telemedicine, enabling them to implement a standardized treatment protocol to reduce problem behaviors. Each child’s treatment is based on an initial analysis of the function of the child’s disruptive behavior.
Dr. Hall and The John Merck Fund hope that his project will have a positive, near-term impact on children with FXS and their families by informing their treatment decisions and decreasing stress at home and at school. The novel use of telemedicine to deliver interventions for problem behavior in FXS may be especially beneficial, given that many families live hundreds of miles from an FXS clinic and disruptive behaviors can make face-to-face treatment a challenge. Results from this study may also set the stage for future combined pharmacological and behavioral intervention trials, and may be used as evidence in efforts to convince health care companies to cover behavioral treatment.
JMF’s grant to Dr. Hall is part of our Developmental Disabilities Program’s Translational Research Program – supporting research with the potential for near-term positive impact on people with developmental disabilities and their families.
Dr. Hall has a long history of novel research in Fragile X syndrome treatments. He and his research lab – the Translational Applied Behavior Analysis Laboratory – focus on understanding how biological and environmental factors affect the development of behavior disorders in children with FXS and other developmental disabilities. The goal of the lab is to develop syndrome-specific treatments based on the underlying biological and/or environmental factors that cause these behaviors.
“If you really want to study neurodevelopment, you have to study it in the brain, not just in a culture dish.”
Also pictured above: Dr. Meng Li.
In 2015, The John Merck Fund awarded grants to Xinyu Zhao, PhD, and Anita Bhattacharyya, PhD, from the University of Wisconsin-Madison Waisman Center, to explore cutting edge genetic treatments for Fragile X syndrome. Fragile X syndrome is an intellectual disability that affects one in 4,000 males and one in 8,000 females, and causes learning difficulties, hyperactivity, social anxiety, hypersensitivity to sensory stimuli, and autism and autism-related behaviors.
Just one single gene on the X chromosome, when shut off, causes Fragile X syndrome, and Xinyu and Anita are combining their expertise to find ways to reactivate this gene. While previous researchers have conducted their studies on mice, our grantees’ work will use human stem cells in order to draw more accurate conclusions about Fragile X syndrome treatments. Using a new genetic editing tool, they will insert a “reporter gene” allowing them to identify when new drugs succeed in reactivating the gene that causes Fragile X syndrome. Xinyu will also take stem cells and transplant them into mouse brains to more effectively study brain development and drug treatment.
JMF’s grant to Xinyu and Anita is part of our developmental disabilities Translational Research Program – supporting research with the potential for immediate impact on people with developmental disabilities and their families.
Both researchers have a long history of novel research in Fragile X syndrome treatments. Xinyu Zhao, PhD, and her research lab focus on the molecular mechanisms involved in neural stem cells and brain development to in order to treat neurological disorders and injuries. Anita Bhattacharyya, PhD, and her lab use stem cells to research Down and Fragile X syndromes with the hope of developing therapies to address these genetic developmental disabilities. Xinyu and Anita, along with The John Merck Fund, believe that this study will advance our understanding of Fragile X syndrome and open the door to future treatments.