Down Syndrome Cognition Research 101: An Introduction
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An introduction to topics in Down syndrome cognition research, including current initiatives DSRTF supports and clinical trials now underway. Presenters: DSRTF board member Sarah Wernikoff; DSRTF ...

An introduction to topics in Down syndrome cognition research, including current initiatives DSRTF supports and clinical trials now underway. Presenters: DSRTF board member Sarah Wernikoff; DSRTF Chief Scientific Officer Dr. Michael Harpold; and Roche Pharmaceuticals' Dr. Omar Khwaja.

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  • Five Potential Drug TargetsThe results from the Discovery research phase are the most significant. Before DSRTF’s founding there were no brain mechanisms identified to be associated with cognitive impairment in Down syndrome. By funding work at Stanford University and Johns Hopkins University DSRTF helped to identify five new potential drug targets.Three Candidate DrugsThe Target Validation and Drug Discovery phase is where the basic discoveries are more rigorously tested and the molecules and compounds that have shown potential in the target validation stage advance to the drug discovery phase, where important aspects such as dosage, efficacy and initial safety assessments are made. The promising results of the Discovery phase have enabled DSRTF to fund a number of projects in this phase. Three of which can now be considered ‘candidate drugs.’
  • About 250,000 people in the United States have Down syndrome, but despite its relative frequency of occurrence, the government provides less in funding for DS research than it spends for similar disibilities30 times less — only $55 per individual with DS annually.  And without the money to pay for it, the promise of DS cognition research may go unfulfilled.
  • * Being investigated for enhancing cognitive functions in Down Syndrome. We are investigating if attention, language and memory could be improved which could eventually results in an improvement in communication, behavior or daily living of the subject. * The mechanism of action of the drug addresses the imbalance of excitatory and inhibitory neurotransmission:In animal models of Down Syndrome, an imbalance between excitatory and inhibitory neurotransmission in the brain is believed to underlie the cognitive problems in individuals with Down SyndromeRoche’s investigational drug is being assessed for its ability to address this imbalance by targeting one of neurotransmission systems, the GABAergic system* The drug has been tested in 97 healthy volunteers. The safety and tolerability profile allow for continuing clinical trials in adults with Down Syndrome. The drug was administered up to 1000mg twice daily for 13 days. The protocol was submitted to the FDA and an IND was opened to investigate this investigational drug in Down Syndrome. The common adverse events seen in the healthy volunteer studies are discussed during the consenting process with the investigator. We now need to investigate that this drug is also well tolerated in people with Down Syndrome.
  • * Being investigated for enhancing cognitive functions in Down Syndrome. We are investigating if attention, language and memory could be improved which could eventually results in an improvement in communication, behavior or daily living of the subject. * The mechanism of action of the drug addresses the imbalance of excitatory and inhibitory neurotransmission:In animal models of Down Syndrome, an imbalance between excitatory and inhibitory neurotransmission in the brain is believed to underlie the cognitive problems in individuals with Down SyndromeRoche’s investigational drug is being assessed for its ability to address this imbalance by targeting one of neurotransmission systems, the GABAergic system* The drug has been tested in 97 healthy volunteers. The safety and tolerability profile allow for continuing clinical trials in adults with Down Syndrome. The drug was administered up to 1000mg twice daily for 13 days. The protocol was submitted to the FDA and an IND was opened to investigate this investigational drug in Down Syndrome. The common adverse events seen in the healthy volunteer studies are discussed during the consenting process with the investigator. We now need to investigate that this drug is also well tolerated in people with Down Syndrome.

Down Syndrome Cognition Research 101: An Introduction Presentation Transcript

  • 1. Down Syndrome Cognition Research 101: An Introduction March 21, 2013 World Down Syndrome DaySarah Wernikoff Dr. Michael Harpold, Ph.D. Dr. Omar Khwaja, M.D., Ph.D.Board Chair, DSRTF Chief Science Officer, DSRTF Translational Medicine Leader Roche
  • 2. World DS Day March 21st 2013AGENDA1. Introduction, About DSRTF – Sarah Wernikoff, DSRTF • Mission, Organization and Research History • Goals, Strategy and Results • NIH Funding Gap2. Research Overview – Dr. Michael Harpold, DSRTF3. Roche Clinical Trials – Dr. Omar Khwaja, Roche4. Participant Q&A
  • 3. World DS Day March 21st 2013Overview: The DSRTF MissionThe mission of DSRTF is to….• Stimulate and fund cognition research to improve learning, memory, and speech for individuals with Down syndrome• Translation of research to deliver treatments to allow individuals to: • Participate more successfully in school • Lead more active and independent lives • Prevent or delay early cognitive decline (i.e. Alzheimer’s Disease)
  • 4. World DS Day March 21st 2013Overview: History2003 Decoding of human genome opens door to cognitive research2004 Mouse model for DS developed by researchers in London; DSRTF is founded2005 DSRTF awards first grant to Dr. William Mobley of Stanford University2006 First drug target, the APP gene, identified by Dr. William Mobley and his team, linking cognitive impairment in DS to the cognitive decline experienced in Alzheimer’s disease2007 DSRTF establishes it’s Scientific Advisory Board, the only scientific board in the US dedicated exclusively to cognition research for DS2008 DSRTF announces supporters had held over 50 events in over 20 states since the organizations founding2008-2010 DSRTF expands grant awards to include Johns Hopkins University, UC San Diego, University of Arizona, University of Texas, and the VA Hospital of Palo Alto2011 Roche Pharmaceuticals begins clinical trial of the first potential therapy designed to improve cognition and adaptive behavior in individuals with Down syndrome2012 TODAY: Over $9M in funding provided, 8 drug targets identified and 3 clinical trials underway
  • 5. World DS Day March 21st 2013Overview: Organization Board of Directors Currently 9 members from NY, Boston, Chicago, Kansas City, San Francisco and LA Lori Morton Carolyn Cronin Director of Philanthropy Executive Director & Operations Michael Harpold, Ph.D Chief Scientific Officer Scientific Advisory Board Currently 6 members
  • 6. World DS Day March 21st 2013Overview: Why Cognition Research? • Life expectancy of individuals with Down syndrome have more than doubled in the last 30 years – from 25 to nearly 60 years old. • The majority of those with DS experience mild-to-moderate cognitive impairment, thus a small improvement = great impact to independence. • Cognitive challenges are are limiting throughout these longer lives, and typically increase with age: Nearly 90% of individuals with DS develop the neuropathology of Alzheimer’s disease by the age of 40. • The decoding of the human genome in 2003 made this research possible, and last 8 years of progress tells us treatments are probable.
  • 7. Overview: Our Goal Moving the Curve Toward Greater Independence Dependent Living Independent Living
  • 8. Overview: Our Strategy FOCUS An exclusive focus on cognition research RESOURCES Attracting and retaining talented researchers into the field COLLABORATION Fostering interdisciplinary coordination and communication TRANSLATION Accelerating the move from research into treatments
  • 9. DSACF Lunch & Learn January 14th 2013Our Results and Clinical TrialsAt DSRTF we are proud of our achievements during our initial 8 years….. • Identification of eight drug targets, leading to three drug candidates. • Catalyst for the research that has lead to the Roche clinical trials (one of five targets identified through our research). • Over $9M in funding at the following research institutions: o Stanford University o VA Palo Alto Healthcare System o University of California San Diego School of Medicine o Johns Hopkins University School of Medicine o University of Arizona o University of Texas, Austin • A Scientific Advisory Board focused exclusively on identifying the most promising DS cognition research in the U.S.
  • 10. DSACF Lunch & Learn January 14th 2013 NIH Funding Gap Dollars Spent by the NIH per Capita 52X Relative to Other Disorders 39X 6X 27X 13X 3X 28X 2X 5XPopulation size in US: 250K 1.5M 400K 1.5M 400K 45K 17.5K 30K 30K 30K
  • 11. World Down Syndrome Day Webinar – 2013 Down Syndrome Cognition Research OverviewMajor Progress in Translating Discoveries into New Therapies Michael M. Harpold, PhD Chief Scientific Officer & Chair, Scientific Advisory Board Down Syndrome Research and Treatment Foundation
  • 12. World DS Day March 21st 2013 Down Syndrome Research and Treatment Foundation DSRTF Founded in 2004 501(c)(3) Organization MissionTo stimulate biomedical research that will accelerate development of treatments to significantly improve cognition, including memory, learning and speech, for children and adults with Down syndrome. Creating New Opportunities for All Individuals with Down Syndrome • To lead more independent lives • To participate more successfully in schools & employment • To prevent additional early cognitive decline with aging & Alzheimer’s disease
  • 13. World DS Day March 21st 2013 The Research Strategy & Grants Program Creating New Opportunities for All Individuals with Down Syndrome Through Cognition Research Rapid success and validation of the new Research Strategy achieved  More than $9.0 million in new research funding since 2004  Established critical biomedical expertise – Highly distinguished, accomplished & proactive Scientific Advisory Board, researchers & new collaborations  Defined multiple mechanisms involved in cognitive impairment associated with Down syndrome  Identified and pursuing at least eight new potential therapeutic drug targets
  • 14. World DS Day March 21st 2013 The Research Strategy & Grants Program Creating New Opportunities for All Individuals with Down Syndrome Through Cognition Research Rapid success and validation of the new Research Strategy achieved  Targeted grants to advance new therapeutic targets through drug R&D pipeline, including target validation, identification and evaluation of effective drug candidates  Focused on accelerating toward innovative, safe and effective clinical trials together with the development of effective new therapies and new opportunities for all individuals with Down syndrome  ** New clinical trials - Biopharma engagement **  Roche RG1662 Clinical Trials – Initiated September, 2011  Balance Therapeutics BD-001 Clinical Trial – Initiated August, 2012  AC Immune ACI-24 Clinical Trial in Down syndrome IND Approved by FDA – January, 2013  Leveraged >$7 million in additional research funding from NIH, universities & other foundations  Partnerships & collaborations in achieving breakthroughs
  • 15. World DS Day March 21st 2013 Cognition, Learning Memory & Speech in Down Syndrome Why Cognition Research in Down Syndrome? Neurological manifestations of Down syndrome are disabling. Early developmental & sustained cognitive disability & issues are most significant: • Extending across the lifespan • Development is globally slowed • Generally, mild to moderate cognitive impairment with marked involvement of memory, learning and speech • Significant related life issues: independence, speech/communication, sleep problems Majority of individuals with Down syndrome show the neuropathology of Alzheimer’s disease by the age of 40, and majority show further cognitive decline New biomedical research can significantly advance more detailed understanding of cognition in Down syndrome to not only yield safe and effective new therapies, but also new and more effective interventional strategies in education, employment and independence.
  • 16. World DS Day March 21st 2013Cognition, Learning Memory & Speech in Down Syndrome Memory Systems: Hippocampus • Detects and stores novel information- allowing for quick adaptation • Binds together pieces of information • “Talks” to the rest of the brain to store and update knowledge • Helps construct a “map” of the world in our brain. Memories are best One target system- recalled when this map is intact. hippocampus and surrounding cortex
  • 17. World DS Day March 21st 2013Cognition, Learning Memory & Speech in Down Syndrome Memory Systems: Frontal Cortex • Involved in “working memory”- keeping information online and working with it. • Alloway (2009) found working memory was a better predictor of school performance than IQ. • Allows for flexibility; less “getting stuck” on a way of solving a problem • Helps to plan actions- the CEO of the brain • Regulates attention and keeps behavior inFrontal cortex is the brain’s check CEO • Abstract thinking (e.g., concept of time)
  • 18. World DS Day March 21st 2013 Cognition, Learning Memory & Speech in Down SyndromeWhat impact could changing these “memory systems” have in Down Syndrome? Behavior Better school Improvement- Greater progress e.g., “less connections Better stubborn” More More Attention andAssociations Flexibility Greater in their Task “Juggling” Faster at knowledge ability & processing willingness to and initiating try new activities strategies
  • 19. World DS Day March 21st 2013 Cognition, Learning Memory & Speech in Down Syndrome Evidence for links between memory and learning in Down Syndrome• Binding of information on “hippocampal tasks” relates to adaptive behavior scores• Memory for complex objects relates to language ability• Auditory working memory is highly related to IQReviewed in Edgin et al. (2012). Merging human and mouse cognitive phenotypes in DS: Implications forAssessment. Progress in Brain Research.
  • 20. World DS Day March 21st 2013 Cognition, Learning Memory & Speech in Down Syndrome Bottom line: If we don’t try, we won’t know what could be• There is no “language” or “everyday tasks” section of our brain that can be targeted.• These skills are supported by memory systems – the same systems we are modifying in mouse models such as hippocampus and the frontal cortex.• Changes in these systems can have a big impact in the human. Only through regulated evidence-based clinical trials will we know if these drugs work and how big the impact might be.
  • 21. World DS Day March 21st 2013 The Research Strategy & Grants Program Discovery, Development & Approval of New Therapies to Improve Cognition in Individuals with Down Syndrome Key Strategic Drivers - Questions That Must Be Addressed Successful development and approval of effective new therapies, including essential enlistment of Biopharma companies and their expertise, requires answers to at least 3 key questions  Are there evidence-based dysfunctional cognitive mechanisms together with associated validated specific drug targets & drug candidates to ameliorate that dysfunction?  Are there specific assessment tools that can measure meaningful improvements (efficacy) resulting from treatment with new potential drugs – can success be demonstrated?  Are there potential clinical trial capable sites and patient participants that can be sufficiently and efficiently recruited for successful new drug development and FDA approval? As recently as 2004 there were no answers to any of these questions…
  • 22. World DS Day March 21st 2013 The Research Strategy & Grants ProgramCoordinating, Integrating & Accelerating Progress Throughout Drug R&D Pipeline
  • 23. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Defining dysfunctional cognitive mechanisms & drug targets – Question #1At least 8 new potential therapeutic drug targets have been discovered and shown to overcome specific impairments to improve cognition in mouse models for Down syndrome, a major step toward development of effective new therapies.
  • 24. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Defining dysfunctional cognitive mechanisms & drug targets – Question #1 Targeting Early Developmental & Sustained Cognitive Disability in Down Syndrome Impaired connections and communications in brain neuronal circuits: 3 Targets  GABAA Receptor (Stanford/UCSD grants) • Drugs specifically reducing GABAA receptor-mediated neurotransmission overcome excitatory-inhibitory imbalance in neural circuits and improve specific forms of learning and memory. • ** Target of New Drugs in Roche & Balance Therapeutics Clinical Trials **  GABAB Receptor & GIRK2 (UCSD grants) • Drugs specifically reducing GABAB receptor-mediated neurotransmission and/or GIRK2 overcome excitatory-inhibitory imbalance in neural circuits and improve specific forms of learning and memory.
  • 25. World DS Day The Research Strategy & Grants Program March 21st 2013 Defining dysfunctional cognitive mechanisms & drug targets – Question #1 Impaired connections and communications in brain neuronal circuits: 3 Targets Greater Inhibition in Hippocampus Excitatory-Inhibitory Imbalance GABA-A Receptor GABA-B Receptor Inhibitors Inhibitors Decreased Synaptic GIRK 2 Blockers Plasticity Improved Synaptic PlasticitySuppression of Learning & Memory Improved Learning & Memory
  • 26. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Defining dysfunctional cognitive mechanisms & drug targets – Question #1 Targeting Earlier Development of Alzheimer’s Disease in Down Syndrome Brain neuronal cell and circuit degeneration – Alzheimer’s disease connections: 4 Targets  APP & its products - Produced by over-expressed human chromosome 21 gene (UCSD/Stanford grants) • Lowering the levels of APP and its products reduces the degeneration of specific neural circuits involved in both learning and memory found in both Down syndrome and Alzheimer’s disease with aging. • ** Target of AC Immune’s New Drug & Planned Clinical Trial **  Norepinephrine Neurotransmitter Restoration (UCSD/Stanford/VA Palo Alto grants) • Drugs increasing norepinephrine (NE) levels in the brain overcome effects of degeneration of specific NE neural circuits and improve contextual learning and memory.
  • 27. World DS Day The Research Strategy & Grants Program March 21st 2013 Defining dysfunctional cognitive mechanisms & drug targets – Question #1 Brain neuronal cell and circuit degeneration – Alzheimer’s disease connections: 4 Targets Increased APP Decrease APP and/or ProductsDecreased Synaptic Function Improved Synaptic Function Neurodegeneration Halt Neurodegeneration Cognitive Loss & Improved & Maintained Dysfunction L-DOPS-mediated NE Cognitive Function Increase
  • 28. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Defining dysfunctional cognitive mechanisms & drug targets – Question #1Targeting Early Developmental & Sustained Cognitive Disability in Down Syndrome Neurogenesis – Impairment in formation of brain neuronal circuits: 1 Target  SHH Pathway (Johns Hopkins grants) • Drugs activating the brain SHH signaling pathway restore development of cerebellum and improve specific form of hippocampal-mediated learning and memory.
  • 29. World DS Day The Research Strategy & Grants Program March 21st 2013 Defining dysfunctional cognitive mechanisms & drug targets – Question #1 Neurogenesis – Impairment in formation of brain neuronal circuits: 1 Target Impaired Neurogenesis in Cerebellum & Hippocampus Shh ActivatorsImpaired Development of Neuronal Circuits Corrected Development of Neuronal Circuits Motor, Learning & Improved Motor, Learning Memory Dysfunction & Memory Functions
  • 30. World DS Day The Research Strategy & Grants Program March 21st 2013 ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Measurement of cognitive improvement through new therapies & establishing clinical trials – Questions #2 & 3 Translational research initiatives address gaps and potential roadblocks in discovery and clinical R&D  Down Syndrome-specific Cognitive Test Battery – The Arizona Cognitive Test Battery (ACTB; University of Arizona grants) • Development of the ACTB – the first Down syndrome-specific cognitive test battery - to significantly enable efficacy determination in clinical trials.  DS Cognition Project - network of collaborating researchers with 9 US institutions (Johns Hopkins Research Center grants) • Creating scaffold for effective Down syndrome clinical trials network.
  • 31. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Measurement of cognitive improvement through new therapies & establishing clinical trials – Questions #2 & 3 Translational research initiatives address gaps and potential roadblocks in discovery and clinical R&D  BioPharma Industry Engagement • Roche, the multi-national pharmaceutical company, initiated major new clinical trial in September, 2011 • “A Study of RG1662 in Individuals With Down Syndrome” • New investigational drug, RG1662, targeting amelioration of inhibitory-excitatory imbalance in DS • Addresses overcoming cognitive and behavioral impairments in individuals with Down syndrome • Phase I (18-30 yrs of age) being conducted at 9 clinical trial sites across the US; 1 site in the UK • http://www.roche-trials.com/trialDetailsGet.action?studyNumber=BP25543&diseaseCategoryId=266 • 2 additional supporting DS clinical trials initiated in 2012
  • 32. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Measurement of cognitive improvement through new therapies & establishing clinical trials – Questions #2 & 3 Translational research initiatives address gaps and potential roadblocks in discovery and clinical R&D  BioPharma Industry Engagement • Balance Therapeutics, Inc. initiated significant new clinical trial in August, 2012 • “Study of the Drug BTD-001 in Young Adults and Adolescents with Down Syndrome." • Investigational drug, BD-001, targeting amelioration of inhibitory-excitatory imbalance in DS • Addresses overcoming cognitive and behavioral impairments in individuals with Down syndrome • Phase I (12-35 yrs of age) being conducted at clinical trial sites in Australia • https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000652875
  • 33. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Measurement of cognitive improvement through new therapies & establishing clinical trials – Questions #2 & 3 Translational research initiatives address gaps and potential roadblocks in discovery and clinical R&D  BioPharma Industry Engagement • AC Immune SA received FDA approval in January, 2013 for IND for new clinical trial in adults with Down syndrome • Investigational drug, ACI-24, targeting amelioration of Alzheimer’s disease (AD) neuropathology in DS • Addressing reduction in AD “plaques” & overcoming associated memory impairments in individuals with Down syndrome
  • 34. World DS Day March 21st 2013 The Research Strategy & Grants Program Coordinating, Integrating & Accelerating Progress Throughout R&D Pipeline Grants Program 2012-13 For additional research details on these research projects: http://www.dsrtf.org/pages/our-research/2012-2013-grant-awards Johns Hopkins University of Texas UCSD Research Research Center & Research Pilot Grant Center Grant Network Grant TARGET PRECLINICAL CLINICAL TRIALS FDA VALIDATION LEAD DEVELOPMENT DISCOVERY REVIEW & COMPOUND & PHASES RESEARCH & DRUG OPTIMIZATION IND I-III APPROVAL DISCOVERYVA Palo Alto Health Continuing Strategic Stanford Research University of Arizona Engagement with System Research Grant Research Grant Pilot Grant Biopharma Companies Roche, Balance Therapeutics & AC Immune Clinical Trials
  • 35. World DS Day March 21st 2013 The Research Strategy & Grants Program ‘Unprecedented’ Progress in Down Syndrome Biomedical Research Proactive advisory and strategic dialogue with NIH and Congress to enhance comprehensive new Down syndrome research, maximize synergy, and increase Federal funding.  NIH Down Syndrome Consortium with Down Syndrome Organizations  Down Syndrome Patient Registry  Launch Goal: mid-2013  NIH Down Syndrome Research Strategic Plan
  • 36. World DS Day March 21st 2013 Down Syndrome Biomedical Research Why is it important for the wider community? Alzheimer’s Disease  Because of the shared neuropathology and higher incidence of earlier age onset of Alzheimer’s disease (AD) in individuals with Down syndrome, the Down syndrome population may benefit from drugs developed in AD research.  Significantly for the same reasons, greater understanding of AD and new drugs to treat AD for the wider population can also result from Down syndrome biomedical research. Solid Tumor Cancers  Research has documented a lower incidence of a variety of solid tumors in Down syndrome – Why?  Initial evidence is emerging showing human chromosome 21 gene(s) which when present in three copies suppresses tumor formation  Down syndrome research may lead to widely applicable new therapies for solid tumor cancers. Atherosclerosis  Research has suggested a lower incidence of atherosclerosis in Down syndrome – Why?  Down syndrome research may lead to widely applicable new therapies for atherosclerosis. Individuals with Down syndrome are uniquely contributing to all of us!
  • 37. World DS Day March 21st 2013What Will Be Required to Sustain and Expand the Momentum to Further Accelerate the Development of Effective New Therapies? How Can You Be Involved and Make a Real Difference? Continue to become well educated supporters and “consumers” of evidence-based Down syndrome biomedical research.  Partnership together for leveraging resources to accelerate realization of effective new therapies & new opportunities for all individuals with Down syndrome Critical need for participation in validated evidence-based clinical studies  ** New Therapeutic Drug Clinical Trials **  ** New Down Syndrome Patient Registry **  Down Syndrome Heart Project  Down Syndrome Cognition Project
  • 38. World DS Day Down Syndrome Biomedical Research March 21st 2013 Creating New Opportunities for All Individuals with Down Syndrome Through Cognition Research “Seize-the-moment” – Unusually Significant Opportunity Now The ‘unprecedented’ results and progress achieved signify that effective new treatments and greater independence are within reach for people with Down syndrome. Understanding and Treating Down Syndrome Is:  No longer too complex or difficult – New research and tools, increased understanding and progress  Not too late - Cognitive function can be modified, even in adults Compelling case for significant and proportionate increase in funding & investment in more fundamental & translational Down syndrome research to build upon new momentum  Significantly more promising & needed new research than current resources available Requires building upon & increasing cooperation, collaborations & partnerships  Researchers, clinicians, their institutions, the Down syndrome community and organizations, Federal agencies including across the different NIH institutes, and Biopharma companies
  • 39. World DS Day March 21st 2013 The Research Strategy & Grants ProgramCreating New Opportunities for All Individuals with Down Syndrome Through Cognition Research Building major new momentum in Down syndrome research for new opportunities for children and adults with Down syndrome to further realize their dreams! Join together with us in partnership and… Be a part of the breakthroughs !!! www.dsrtf.org www.dsrtf.org/plus15
  • 40. Developing a new molecule for treatment ofintellectual disability associated with Downsyndrome Omar Khwaja Translational Medicine Leader for Neuroscience World Down Syndrome Day 2013
  • 41. Given the appropriate support andopportunity, all individuals living with Downsyndrome can achieve their potential, realisetheir human rights on an equal basis withothers and make an important contribution tosociety. We must therefore intensify ourefforts to create conditions of empowermentthat allow meaningful participation of personswith Down syndrome.
  • 42. 46
  • 43. Ts65Dn mouse modelDown syndrome 60 *** *** TS veh *** *** *** *** *** CO veh *** Latency (s) 40 p<0.001 250 20 225 % of control EPSP slope 200 0 175 0 1 2 3 4 5 6 7 8GABAA Receptor 150 Session 125 Behaviour 100 75 -20 0 20 40 60 80 Circuitry Time (min) Physiology 49
  • 44. 50
  • 45. Effective learning and memoryrequires balance between inhibition and excitation in the brain GABA Glu
  • 46. In Down syndrome there appears to be excessive inhibition by GABA neurons Glu GABA
  • 47. Fernandez etal, 2007
  • 48. About the investigational Roche drug RG1662• Being investigated for enhancing cognition and memory functions in Down Syndrome• Mechanism of action: GABA system- highly selective for the alpha 5 subunit
  • 49. 57
  • 50. Roche is currently conducting 3 trials• BP25543 – Drug study in people with DS• BP25612 – Non-drug study in people with DS• WP25611
  • 51. Study BP25543 Objectives Primary Objective • Assess the safety and tolerability of RG1662 in young adults 18-30 with Down Syndrome Secondary Objective •How is the drug handled by the body? (pharmacokinetics) Exploratory objectives •Explore the effect of RG1662 on cognition •Explore biomarkers
  • 52. Selected Inclusion Criteria• Men and women aged 18 to 30 with Down Syndrome• Able to give assent• Have verbal skills to participate in assessments
  • 53. Exploratory Efficacy Assessments• Attention – Reaction times via a computerized test• Memory – Immediate memory – Short term memory – Delayed memory• Language – Fluency – Associations• Adaptive Function
  • 54. Study BP25612 Objectives (Non-Drug Study) Primary Objective • To assess the performance and reliability of scales and measures of • Cognitive function • Memory • Adaptive behavior • Activities of Daily Living • Impact on Caregivers
  • 55. Overview of Study Design• France, Spain, UK and US• 90 participants• Teenagers and adults with DS 12-30 years• Study duration = up to 27 weeks• Approximately 3 visits
  • 56. Study WP25611 Objectives (PET/fMRI Study) to the same parts •Whether the drug gets of the brain in people with Down Syndrome as we have found in people without Down Syndrome •Whether the brains of people with Down Syndrome have the same number of receptors (targets) where we think the drug works •Whether giving the study drug makes a difference to the way in which the brains of people with Down Syndrome work
  • 57. Who Can Take Part In This Study?Young men and women of 18-30 years old: - With Down Syndrome - Without Down SyndromeIf this applies to your child/ward with Down Syndrome, why might they-If they have epilepsy- If they are taking some types of medication that would affect the stud-If you (as their carer) or they don’t think they can lie quite still and relOR- If they have major Depression that is not adequately controlled by par-If they have dementia-If they have Thyroid problems not controlled by treatment-If they have heart or blood pressure problems
  • 58. Thank you for your attending 70
  • 59. We Innovate Healthcare
  • 60. World DS Day March 21st 2013 3:1 Matchof all donations made today at www.dsrtf.org …Your $100 becomes $400, your $500 becomes $2000, and so on...
  • 61. World DS Day March 21st 2013Open Discussion and Q&A