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

1986

Trisomy 21: increased dosage of chromosome 21 genes

2016 1959

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

Models systems are critical for understanding pathophysiology and disease progression

Research Tools

Mouse chr16 Mouse chr10 Mouse chr17

Human chr21

https://www.nih.gov/news-events/nih-research-matters/comparing-mouse-human-genomes

Human chr21

Ts65Dn Research Tools: Mouse models

Human chr21

Mouse models

+ + + (ND)

• + -
• CHD

Research Tools: Mouse models

Research Tools: Induced pluripotent stem cells (IPSC)

Body cell

Pathophysiology Effect of genetic variants Disease progression Effect of chr21 gene dosage Treatment targets Drug screening Treatment effects

Reaching our goals through an iterative process

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

Understanding the consequences of trisomy 21

• Pathophysiology and Disease Progression

Use model systems to characterize:

• Synaptic function
• Vesicular trafficking
• Mitochondrial function
• Neuronal spine development
• APP processing and signaling pathways

• 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
• ur 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

Dierssen, 2012

DS mouse

Inhibitory neurons Excitatory neurons

Wild type mouse

Memory and learning systems impaired in Down syndrome: Hippocampal defect

Understand the genes involved in alteration

• f brain formation: e.g., DYRK1A

Dierssen, 2012

Gardiner, 2008

Alzheimer disease and aging

Birth defects Survival to term

Cognition and behavior

• Pathophysiology and Disease Progression

Identify factors that explain variation in outcomes

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

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

Understand the factors that lead to variation in cognition and behavior

250 participants

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

Genetic factors Develop interventions that target imbalance Identify affected biological pathways

• Birth defects
• Days in NICU
• Hospitalization
• …

Tarek Alsaeid, MD Cincinnati Children’s Hospital Medical Center Does congenital heart disease affect neurodevelopmental

• utcomes in children with Down syndrome?

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

Understanding the consequences of trisomy 21

• 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

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

Understanding the consequences of trisomy 21

• Down Syndrome and Aging

Experience of an adult clinic for DS in Madrid, Spain

(Real de Asua et al., 2015)

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?

Clinical Findings

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?

• Down Syndrome and Aging

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

Understanding the consequences of trisomy 21

• 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

conditions

⁻ Autism spectrum disorder, ADHD, depression, regression

• Aging-associated disorders

⁻ Adult CHD, obesity, dementia

• Cognition and daily-life functioning

Anna Esbensen, PhD Cincinnati Children’s Hospital Medical Center Supporting Parents to Impact Child Outcomes in Down Syndrome Barbara Chini, MD Cincinnati Children’s Hospital Medical Center 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

Greater inhibition in hippocampus (excitatory/inhibitory imbalance) Decreased synaptic plasticity Suppressed learning & memory Improved learning & memory Improved synaptic plasticity

GABA A receptor inhibitors*** GABA B receptor inhibitors GIRK2 blockade

*** 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

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

Understanding the consequences of trisomy 21

• Research Infrastructure
• Expand research participation
• Conduct natural history studies
• Build sharable resources

⁻ Model systems ⁻ Biobanks

• …

Lisa Kaeser, JD NICHD 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 factors Genetic factors Develop interventions that target imbalance Identify affected biological pathways

Recruitment Network Clinical Assessment Biological Samples Genetic Assessment DS-Connect

LonDownS

1000 participants 1000 genomes

Recruitment Network Clinical Assessment Biological Samples Genetic Assessment DS-Connect

LonDownS

Trisomy 21 Research Society

1000 participants 1000 genomes

Recruitment Network Clinical Assessment Biological Samples Genetic Assessment

International Down syndrome Genomic Consortium

1000 participants 1000 genomes

Biobank

Recruitment Network Clinical Assessment Biological Samples Genetic Assessment DS-Connect

LonDownS

International Down syndrome Genomic Consortium Trisomy 21 Research Society

1000 participants 1000 genomes

Biobank

What is our common goal?

• Increase quality of life of those with

Down syndrome

• Decrease health effects of extra

chromosome 21