Evdokia Anagnostou, MD Clinician Scientist, Holland Bloorview Kids Rehab Hospital Associate Professor, Department of Pediatrics University of Toronto Canada Research Chair in Translational Therapeutics

The challenge > 300,000 children and youth in Ontario with neurodevelopmental disorders (NDs): –Autism Spectrum Disorders (ASD), Attention Deficit Hyperactivity Disorder (ADHD), Obsessive Compulsive Disorders (OCD) and Intellectual Disability (ID). Lifetime cost per individual as high as $2 million in Canada Ability to change long term outcomes remains limited

The challenge Few medications to treat these disorders –Almost none have been discovered by translating the findings from basic sciences such as genomics, animal models, pathology etc. There are many reasons why development of novel treatments for NDs has been limited: e.g. –It is difficult to stratify patients into those most likely to respond to the intervention –Few molecular targets –There are no established networks of excellence to rapidly screen compounds and advance promising compounds

POND An integrated discovery system to expedite –understanding biology –Translation into novel therapeutics Across developmental disorders 4 research sites: HBKRH, SickKids, McMaster, Western >20 investigators, 40 clinicians >15 industry partners and advocacy organizations

The plan Create the first clinical trials network dedicated to neurodevelopmental disorders in Canada –Existing expertise in NDs –Enhancing regulatory expertise –Go where the children are

The plan Embed the OCTN in a large biomarker core –clinical database of children and youth with NDs properly characterize with behavior, cognition Characterize biology –imaging and electrophysiology techniques –Genomics (leveraged) and epigenomics

The plan In parallel: –Develop animal and cellular models better understand disease mechanisms by cross- analyzing data from the human subjects with mouse and cell modelling results enable testing of medications for response and safety before they are used in children.

Database / Biomarker core Currently: >1000 children with ASD, ADHD, OCD,ID –Core technologies used for characterization: Detailed behavioural characterization –Stage 1: demographics –Stage 2 : cross disorder phenotyping –Stage 3: In depth diagnostic phenotyping –Stage 4: Cognitive phenotyping Genomics (leveraged) Imaging ~200 imaged children Electrophysiology (MEG, ERP/EEG, autonomic nervous system markers)

Highlights

Results: Electrodermal activity (EDA)

Results: Effect of anxiety

Future Directions * As of summer 2014: Specific commitment to: Tourette Syndrome Down syndrome Fragile X Rett syndrome NEW RFA for pilot studies, due Summer 2015 New compound for next clinical trial secured: GSK3b inhibitor

Thank you