Forum - 8 juin Partenariats novateurs en recherche biopharmaceutique. Michel Maziade, M.D., FRCPC. Marc Hébert, PhD

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1 Translational platform utilizing electroretinography (ERG) profiles for stratifying patients and pharmacological response in major psychiatric disorders Forum - 8 juin Partenariats novateurs en recherche biopharmaceutique Michel Maziade, M.D., FRCPC Directeur scientifique Centre de recherche Université Laval Robert-Giffard Titulaire, Chaire de recherche du Canada en génétique des maladies neuropsychiatriques Professeur titulaire de Psychiatrie, U. Laval Marc Hébert, PhD Professeur agrégé, ophtalmologie Faculté de Médecine, Université Laval Centre de recherche Université Laval Robert-Giffard

2 Translational platform utilizing electroretinography (ERG) profiles for stratifying patients and pharmacological response in major psychiatric disorders We thank the CQDM partners for their support

3 Prevalence 5 millions persons : North America 200,000 persons : Canada persons : Québec 16 % of Québec health care costs

4 Challenges to overcome in psychiatric disorders 3 main obstacles to rapid progress: 1. No direct access to central nervous system in humans; 2. Lack of physiological endophenotypes to stratify patients and treatment response 3. Rarity of longitudinal access to intelligent multiphenotype biobanks.

5 A problem to be solved: Need to stratify patients into etiologically homogeneous subgroups a costly problem in psychiatric research- academia and industry Heterogeneity of psychiatric diagnosis DSM nosology is a consensual categorisation (schizophrenia; depression) Diagnosis has little neurobiological or etiological basis No existing scientific means to stratify the patients within a diagnosis Consequence Diminishes the power of pharmacological/clinical trials and neurobiological studies. Diminishes also the comparability among different samples or studies

6 Porous boundaries of DSM diagnoses Depression Schizophrenia Mood disorder Psychosis

7 Proposed solution to CQDM Use a novel biomarker that offers a direct access to the CNS --- the retina Our goal is to develop a pharmacodiagnostic technology that can be used to accurately stratify patients and predict treatment response. this technology will play a role in assisting clinicians and pharmaceutical companies To maximize therapeutic benefits both in clinical research and in treatment setting.

8 Management of risk: available databank of patients and controls Our databank: - Diminish risk in data collection - Accelerate data collection Origin of patients and controls - From the Eastern Quebec multigenerational families, gathered over a period of 20 years into a sample of 48 multigenerational kindred totalizing 1500 members. - A collection of several hundred SZ patients and unrelated controls that NDEI Inc. has assembled.

9 Advantages of the retina in psychiatric disorders The retina is part of the central nervous system Allows for the assessment of the full dynamic response originating from cones and rods photoreceptors. Changes in ERG response observed in these disorders reflect A disturbance in monoamines such as dopamine and serotonin. A powerful site of investigation for understanding brain disorders such as SZ, BP and MDD (Hébert et al, 2010).

10 Electroretinogram (ERG) = mirror of the brain Similar to EKG or EEG but at the level of the eye. Bio-potentiel generated by the retina in response to standardized light stimulation. Non invasive technique. Allows the assessment of cones (used for day vision) and rods (used for night vision), separately. Recording electrode Very tiny almost impercitible fiber impregnated with silver

11 b-wave Flash intensities (log cd.s.m -2 Vmax b-wave amplitude (µv) ½ Vmax Log K Low Intensities (log) High

12 Three strong bodies of data from our team To support our CQDM application: 1. Pilot findings in seasonal affective disorder patients 2. Pilot findings in young non-affected offspring of a parent affected by schizophrenia or bipolar disorder 3. ERG Animal models

13 Reduced rod b-wave observed in both HR offspring (panel A) and D1- KO (panel B) mice, when compared to their respective controls. A) B) 600 WT n=17 HO n=15 Amplitude (µv) Flash Intensity (log unit) Right shift of the rod luminance response function observed in SAD patients (panel C) and the DAT-KO mice (panel D). This indicates a reduction in rod sensitivity (log K parameter). C) D) 600 WT n=19 HO n=11 Amplitude (µv) Flash Intensity (log unit)

14 Overall conclusions stemming from our data ERG profiles: Good candidates as trait and state markers of the disease Shows inter-individual variability Not an artifact of pharmacological agents or neurobiological secondary effects of the disease Modulated by dopaminergic genes in animals that mimic the human ERG dysfunctions Moreover: pharmacological agents may influence ERG profiles ERG is an additional tool or biomarker of response to treatment.

15 The concept: Breaking down the diagnosis in its physiological and cognitive components Level 1 Diagnosis Schizophrenia Depression Mood disorder Anxiety disorder ERG anomalies [Shared or specific] Level 2 ERG ERG Profile 1 ERG Profile 2 ERG Profile 3 Level 3 Etiology Genes Environment

16 Hypotheses and objectives Hypothesis: within SZ, subjects will divide into strata of ERG profiles Objectives: 1. To measure ERG in 100 patients with schizophrenia and 100 controls. 2. To stratify patients based on specific ERG profiles 3. To assess the relationship between the patients ERG strata and response to treatment, type and dose of medication. Deliverable after one year Identification of biomarkers to stratify/profile SZ patients and treatment response

17 Impact on the Drug Discovery and Development Process The identified biomarkers (ERG profiles) will be used to: Enrich patient populations based upon the response hypothesis; Obtain biomarkers to stratify patients before inclusion in clinical trials; Enhance study power through identification of good and poor responders to treatments; Conduct high-speed and affordable clinical trials due to smaller studies composed of more homogeneous samples; Increase the period of patent protected sales thanks to an accelerated drug development; Reduce the overall risk of drug development.

18 Contributions of CQDM to our research group Funding and partnership Great improvement of research, accelerate the rate of discoveries Opportunity to adjust to mutual goals after LOI acceptation phase Opportunity to readjust to mutual goals after funding decision Liaison with pharmaceuticals

19 Novel Inter-technology Approach An interdisciplinary approach integrating Electroretinography (Hébert), Clinical and genetic epidemiology (Roy; Maziade), Statistical modelization and biostatistics (Mérette), Clinical neuropharmacology (Bouchard; Roy; Filteau) Project coordinator (Fortier) basic and clinical scientists used to work together. Michel Maziade M.D., FRCPC Marc Hébert Ph. D. Caroline Fortier Chantal Mérette, Ph. D. Roch-Hugo Bouchard, M.D., FRCPC Marie-Josée Filteau, M.D. FRCPC Marc-André Roy, M.D., FRCPC

20 Translational platform utilizing electroretinography (ERG) profiles for stratifying patients and pharmacological response in major psychiatric disorders We thank the CQDM partners for their support