Whats happening in the Research World of Down syndrome? Overview of - PowerPoint PPT Presentation

What’s happening in the Research World of Down syndrome? Overview of research in Down Syndrome: Guided by the NIH Down Syndrome Research Plan

What is our common goal? • Increase quality of life of those with Down syndrome • Decrease health effects of extra chromosome 21 Why is this a challenge? • Not a change in a single gene • Increased dosage of many genes

Trisomy 21: increased dosage of chromosome 21 genes 1959 2016 1986

Your needs guide the research priorities Your participation combined with new research tools help to reach those goals

Research Tools Human chr21 Mouse chr16 Models systems are critical for understanding Mouse chr17 pathophysiology and disease progression Mouse chr10 https://www.nih.gov/news-events/nih-research-matters/comparing-mouse-human-genomes

Research Tools: Mouse models Human chr21 Ts65Dn

Research Tools: Mouse models Mouse models Human chr21 CHD + + + (ND) - + - -

Research Tools: Induced pluripotent stem cells (IPSC) Body cell

Reaching our goals through an iterative process Effect of chr21 gene dosage Treatment targets Pathophysiology Drug screening Disease progression Treatment effects Effect of genetic variants

Understanding the consequences of trisomy 21 Down Syndrome Directions National Institutes of Health Research Plan on Down Syndrome • Pathophysiology and Disease Progression • Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures • Down Syndrome and Aging • Treatment and Management • Research Infrastructure

• Pathophysiology and Disease Progression Use model systems to characterize: • Synaptic function • Vesicular trafficking • Mitochondrial function • Neuronal spine development • APP processing and signaling pathways

Memory and learning systems impaired in Down syndrome: Hippocampal defect • Detects and stores new information • Binds together pieces of information • “Talks” to the rest of the brain to store and update knowledge • Helps make a “map” of the world in our brain. Memories are best recalled when this map is in place One target - hippocampus and surrounding brain cortex

Memory and learning systems impaired in Down syndrome: Hippocampal defect Wild type mouse Excitatory neurons DS mouse Inhibitory neurons Dierssen, 2012

Understand the genes involved in alteration of brain formation: e.g., DYRK1A Dierssen, 2012

Gardiner, 2008

• Pathophysiology and Disease Progression Identify factors that explain variation in outcomes Survival to term Birth defects Alzheimer disease and aging Cognition and behavior

What contributes to the severity of the clinical outcomes? http://www.cdc.gov/genomics/public/features/cancer_causes.htm

Understand the factors that lead to variation in cognition and behavior

Understand the factors that lead to variation in cognition and behavior 250 participants Environmental Genetic factors factors Identify affected biological pathways Develop interventions that target imbalance

Environmental Genetic factors factors Identify affected biological pathways Develop interventions that target imbalance

• Birth defects Tarek Alsaeid, MD Genetic • Days in NICU Cincinnati Children’s Hospital Medical Center factors • Hospitalization Does congenital heart disease affect neurodevelopmental • … outcomes in children with Down syndrome? Identify affected biological pathways Develop interventions that target imbalance

Understanding the consequences of trisomy 21 Down Syndrome Directions National Institutes of Health Research Plan on Down Syndrome • Pathophysiology and Disease Progression • Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures • Down Syndrome and Aging • Treatment and Management • Research Infrastructure

• Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures Refine and develop specific outcome measures: • Sensitive cognition & behavior in DS • Identify change in clinical trials • Measure dementia, depression, autism in the background of ID • Imaging: MRI, fMRI, DTI, PET…new non-invasive methods

• Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures

Understanding the consequences of trisomy 21 Down Syndrome Directions National Institutes of Health Research Plan on Down Syndrome • Pathophysiology and Disease Progression • Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures • Down Syndrome and Aging • Treatment and Management • Research Infrastructure

• Down Syndrome and Aging Experience of an adult clinic for DS in Madrid, Spain (Real de Asua et al., 2015)

Clinical Findings Early-onset aging process: • Cataracts • Dementia • Musculoskeletal disorders Age-related cardiovascular conditions: • Absent • High prevalence of overweight/obesity • Lack of activity in the older groups More work is needed: • How to get care? • How to treat?

• Down Syndrome and Aging Identify factors associated with: • Onset and progression of dementia • Need for hormone therapy for older women • Mortality • Social needs of adult with DS and their families Treatment

• Down Syndrome and Aging Ben Handen, PhD University of Pittsburgh School of Medicine Neurodegeneration in Aging Down Syndrome Fred Schmitt, PhD & Elizabeth Head, PhD University of Kentucky The University of Kentucky Down syndrome Aging Study: What are we learning from bench studies of the brain?

Understanding the consequences of trisomy 21 Down Syndrome Directions National Institutes of Health Research Plan on Down Syndrome • Pathophysiology and Disease Progression • Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures • Down Syndrome and Aging • Treatment and Management • Research Infrastructure

• Treatment and Management • Co-occurring medical conditions ⁻ Leukemia, CHD, GI problems, childhood diabetes, seizures, obstructive sleep apnea, … • Co-occurring psychiatric or neurobehavior conditions ⁻ Autism spectrum disorder, ADHD, depression, regression • Aging-associated disorders ⁻ Adult CHD, obesity, dementia • Cognition and daily-life functioning

• Treatment and Management • Co-occurring medical conditions ⁻ Leukemia, CHD, GI problems, childhood diabetes, seizures, obstructive sleep apnea, … • Co-occurring psychiatric or neurobehavior Anna Esbensen, PhD conditions Cincinnati Children’s Hospital Medical Center ⁻ Autism spectrum disorder, ADHD, depression, Supporting Parents to Impact Child Outcomes in Down regression Syndrome • Aging-associated disorders Barbara Chini, MD ⁻ Adult CHD, obesity, dementia Cincinnati Children’s Hospital Medical Center • Cognition and daily-life functioning Optimizing Treatment of Persistent Pediatric Obstructive Sleep Apnea

• Treatment and Management • Co-occurring medical conditions ⁻ Leukemia, CHD, GI problems, childhood diabetes, seizures, obstructive sleep apnea, … • Co-occurring psychiatric or neurobehavior conditions ⁻ Autism spectrum disorder, ADHD, depression, regression • Aging-associated disorders ⁻ Adult CHD, obesity, dementia • Cognition and daily-life functioning

Targeting early and life-long cognitive disabilities in DS GABA A receptor GABA B receptor inhibitors*** inhibitors Greater inhibition in hippocampus (excitatory/inhibitory imbalance) GIRK2 blockade Decreased synaptic Improved synaptic plasticity plasticity Suppressed learning Improved learning & & memory memory *** Target of new drugs in Roche & Balance Therapeutics Clinical Trials

• Treatment and Management: Cognition Ernest Pedapati, MD Cincinnati Children’s Hospital Medical Center Brain Stimulation for Cognitive Improvement in Children with Down Syndrome Alberto Costa, MD Case Western Reserve University New Clinical Study on the Effects of Memantine

Understanding the consequences of trisomy 21 Down Syndrome Directions National Institutes of Health Research Plan on Down Syndrome • Pathophysiology and Disease Progression • Down Syndrome-Related Conditions: Screening, Diagnosis, & Functional Measures • Down Syndrome and Aging • Treatment and Management • Research Infrastructure

• Research Infrastructure • Expand research participation • Conduct natural history studies • Build sharable resources Lisa Kaeser, JD ⁻ Model systems NICHD ⁻ Biobanks Overview of why DS-Connect was created and how it can be useful to families • … Stephanie Santoro, MD Nationwide Children’s Hospital Parent Views of the DS-Connect Registry

• Research Infrastructure • Expand research participation • Conduct natural history studies • Build sharable resources ⁻ Model systems ⁻ Biobanks • … Marc Lewis Down Syndrome Achieves DS Biobank

Critical program to identify factors that will help reduce the clinical effects of trisomy 21 Environmental Genetic factors factors Identify affected biological pathways Develop interventions that target imbalance