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DSRTF Awards $1.4 Million for New Research Grants to Advance Cognition Research and Potential New Therapies in Down Syndrome
November, 2009

The Down Syndrome Research and Treatment Foundation (DSRTF) announces the award of $1.4 million in funding for five new DSRTF Research Grants. Researchers at Johns Hopkins University School of Medicine, University of California, San Diego School of Medicine, Stanford University School of Medicine and the University of Arizona are the recipients of this latest round of DSRTF grant funding. This represents the highest annual grant funding level since DSRTF’s founding in 2004.

The focus of the new DSRTF Research Grants for 2009-2010 is to significantly build upon the DSRTF-supported research that has led to dramatic breakthroughs in defining specific mechanisms responsible for cognitive impairment in Down syndrome, as well as the identification and pursuit of five new potential drug targets for improving cognitive function. The new grants will also focus on overcoming potential critical challenges for new clinical trials.

The new 2009-2010 DSRTF Research Grants include:

JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE
$450,000 DSRTF Research Center Grant to Principal Investigator Dr. Roger Reeves, Professor, Department of Physiology and McKusick Nathans Institute for Genetic Medicine.

• Pursuit of two novel potential therapeutic targets
• Enables establishment of new Down Syndrome “Virtual” Center for Basic and Translational Studies
• Initiation of Down syndrome Cognition Project and Network
• More than $860,000 total DSRTF Research Grant funding since 2007

This new DSRTF grant extends support for the investigation of a novel and promising therapeutic target associated with neurogenesis (nerve cell growth and development) to ameliorate cognitive impairment in Down syndrome. Based on the discovery by Dr. Reeves and his colleagues that specific neuronal cell populations in a Down syndrome mouse model have a reduced response to a specific signaling growth factor, termed Shh (“Sonic hedgehog”), which results in less growth of specific brain regions, his research group is treating these mouse models with drug compounds that stimulate the Shh pathway. They are assessing whether neurogenesis in the cerebellum and hippocampus is restored to the expected pattern by Shh activators and produces measurable positive effects on brain functions, including learning and memory.

A second supported project, with Dr. Reeves and co-Principal Investigators, Constance Smith-Hicks, MD, PhD, Instructor, Department of Neurology, and Paul Worley, MD, Professor of Neuroscience, continues investigation of their recent discovery that a protein product of the Arc gene, critically involved in synaptic plasticity associated with learning and memory, may be mis-regulated in Down syndrome. Tightly regulated changes in the expression of Arc play a crucial role in hippocampal-based learning and memory. Its over-expression can result in many of the features that are classically described in Down syndrome central nervous system, including changes in synaptic structure. Under this new DSRTF grant the researchers are working to understand how the Arc gene becomes mis-regulated, explore mechanisms that might restore normal function in nerve cells and identify drugs acting on these mechanisms as potential new therapies to improve cognition in individuals with Down syndrome.

As a major new initiative, this DSRTF grant is enabling the establishment of a new Down Syndrome “Virtual” Center for Basic and Translational Studies with an initial network of co-Principal Investigators spanning multiple research institutions. In addition to Dr. Reeves, this “virtual” center  includes Drs. Constance Smith-Hicks and Paul Worley (Johns Hopkins), Iser DeLeon and George Capone (Kennedy Krieger Institute), Lynn Nadel and Jamie Edgin (University of Arizona), and Stephanie Sherman (Emory University School of Medicine). With funding from this DSRTF grant, these researchers have initiated the Down Syndrome Cognition Project employing a newly developed Down syndrome-specific Cognitive Test Battery (see University of Arizona DSRTF Research Grant below) to assess and define cognitive variability in a large-set of individuals with Down syndrome.  As part of this project, the researchers are establishing a Down syndrome Biobank enabling correlations to be drawn between cognition and genetic variability. This new information could provide the basis for genetic analyses to identify new potential targets for therapeutic intervention. Importantly, this project also aims to further establish the utility of the new DS Cognitive Test Battery for measuring efficacy of potential new drugs in clinical trials along with establishment of collaborating clinical sites representing an initial scaffold for a clinical trials network for translation of research discoveries to effective new therapies.

UNIVERSITY OF CALIFORNIA, SAN DIEGO SCHOOL OF MEDICINE
$350,000 DSRTF Innovation Research Grant to Principal Investigator Dr. William Mobley, Professor and Chair, Department of Neurosciences.

• Pursuit of three novel potential therapeutic targets
• Identification of age-related behavioral and cognitive changes

With Dr. Mobley’s recent relocation to the University of California, San Diego, this new DSRTF Innovation Research Grant extends funding to further characterize previously identified potential therapeutic approaches and drug targets for improving cognition and/or overcoming neurodegeneration in mouse models for Down syndrome. These potential therapeutic approaches include further investigations of APP (reduction of expression addressing Alzheimer’s disease pathology and associated memory loss), GABA-B receptor blockade, and increasing the levels of the neurotransmitter norepinephrine through the use of the developmental drug, L-DOPS.  Both blockade of the GABA-B receptor and the L-DOPS mediated increase in norepinephrine have been shown to significantly improve learning and memory in a mouse model for Down syndrome. The results of these new studies are expected to provide additional data and information critical to determining potential for advancement toward preclinical and clinical studies. The research will also investigate the role of increased expression of Girk2 (a human chromosome 21 gene encoding a potassium ion channel that modulates neural circuit activity) in mediating inhibitory-excitatory imbalance and cognition as well as its potential as an additional therapeutic/drug target complementary to GABA-B receptors. Additional initiatives in the supported research program will focus to identifying age-related behavioral and cognitive changes in mouse models for Down syndrome for potential insight and relevance in humans.

STANFORD UNIVERSITY SCHOOL OF MEDICINE
$250,000 DSRTF Innovation Research Grant to co-Principal Investigators Drs. H. Craig Heller, Lokey/Business Professor Department of Biology, and Craig Garner, Professor Department of Psychiatry and Behavioral Sciences, and co-Directors Stanford Down Syndrome Research Center; additional $200,000 for 2009 extension of DSRTF Research Center Grant to co-Principal Investigators Drs. William Mobley, Craig Garner, Dan Madison and Isabella Graef, Stanford Down Syndrome Research Center.

• Pursuit of a novel potential therapeutic target
• Exploring mechanisms involved in cognitive dysfunction in Down syndrome and technologies to identify new potential therapeutic targets
• More than $4 million total DSRTF Research Grant funding since 2004

The new DSRTF Research Grant award to Drs. Heller and Garner continues to fund the further characterization and investigations of the earlier identified GABA-A receptor as a potential therapeutic/drug target for improving cognition in mouse models of Down syndrome through characterization of different GABA-A receptor-subtype specific compounds. Previous DSRTF-supported research demonstrated that GABA-A blockers are able to significantly improve learning and memory in a mouse model for Down syndrome. These new studies are expected to provide additional data and information critical to determining potential of specific drugs, including examples with lower side-effect potential (e.g., seizures), for advancement toward preclinical and clinical studies.

Under this new grant the researchers are also using a recently developed microscopic technique, designated array tomography, to investigate possible inhibitory and excitatory neural network changes in the hippocampus of mouse models of Down syndrome as well as any changes in response to GABA-A receptor blockers. This research may provide insight to adaptive and relatively long lasting cognitive improvement produced by GABA-A blocking drug compounds, which may be an important aspect for a potential therapeutic mechanism and clinical studies.

UNIVERSITY OF ARIZONA
$150,000 DSRTF Innovation Research Grant to co-Principal Investigators Drs. Lynn Nadel, Regent’s Professor, and Jamie Edgin, Research Associate, Department of Psychology.
Development and validation of new Down syndrome-specific Cognitive Test Battery

• Exploration of sleep-cognition correlations in Down syndrome
• More than $260,000 total DSRTF Grant funding since 2008

With this new DSRTF Innovation Research grant, Drs. Nadel and Edgin will continue and complete development and initial validation a multi-part specific cognitive test battery for children, ages 4-18 years, with Down syndrome. They further plan to tailor and extend the cognitive test battery to adults with Down syndrome to detect emergence of additional cognitive decline associated with aging and Alzheimer’s disease pathology. This new cognitive test battery represents the first-ever specifically developed for detailed assessment of cognition in individuals with Down syndrome. The tests in the battery have been designed to assess cognitive function in the prefrontal cortex, hippocampus and cerebellum – all brain areas demonstrated to be involved in cognitive impairment in Down syndrome. In addition, the tests were developed to be fundamentally non-verbal based in order to separate neuropsychological skills from language demands and variability.  Identifying the factors influencing the variability in cognitive outcomes may be central to the formulation and development of successful new therapies to improve cognition in children and adults with Down syndrome. This includes the identification of potential new therapeutic targets, and critically, establishing efficacy protocols for clinical trials.

The researchers are also continuing their investigation of specific relationships and correlations between sleep, cognition and behaviors in children with Down syndrome. Such systematic studies, involving quantitative assessment of sleep problems, including sleep apnea, hypoxemia and fragmentation in correlation with the new Down syndrome-specific Cognitive Test Battery, may provide insight to new research directions, therapeutic targets and strategies to ameliorate specific aspects of cognitive impairment in individuals with Down syndrome.

Since its founding in 2004, DSRTF has generated more than $5.6 million to fund and support major new results-driven research programs at Stanford University School of Medicine, Johns Hopkins School of Medicine, the University of Arizona, and now, the University of California, San Diego School of Medicine. This represents part of the targeted expansion of the Foundation's strategy to stimulate and facilitate the most promising biomedical research that will accelerate development of treatments to significantly improve cognition, including memory, learning and speech, for children and adults with Down syndrome.