Preclinical models of negative symptoms and their implications for clinical trials. Martien Kas

Size: px

Start display at page:

Download "Preclinical models of negative symptoms and their implications for clinical trials. Martien Kas"

Edward Davis
6 years ago
Views:

1 Preclinical models of negative symptoms and their implications for clinical trials Martien Kas

2 From diagnose to biology ISCTM ~ ECNP Joint Conference 1 September 2017 Paris France

3 The road to restoring neuronal circuits Canter et al., Nature, 2016

4 The puzzle of schizophrenia stahlonline.cambridge.org

5 Integrated experimental approaches Dolmetsch and Geschwind, Cell, 2011

6 How to provide cross-species clinically relevant and quantitative endpoint measures?

7 Behavioural domains across the neuropsychiatric spectrum Kas et al., Molecular Psychiatry, 2007

8 Behavioural domains: negative symptoms Modeling positive versus negative symptoms in animals

9 Social withdrawal is a common (early) symptom across neuropsychiatric disorders Autism Spectrum Disorder Schizophrenia Social withdrawal Alzheimer s Disease Bipolar Depression Major Depression

10 Social withdrawal is influenced by several processes Social perception Social learning Cognitive performance Social information processing Social withdrawal Mentalizing activities Emotionality Reward processing

11 Social withdrawal is influenced by several processes Social perception Social learning Cognitive performance Social information processing Social withdrawal Mentalizing activities Emotionality Reward processing

12 The dopamine hypothesis Brunelin et al., 2013

14 Rodent models to alter dopamine signalling Striatal D 2 R overexpression mouse model Amphetamine model Dopamine transporter knock-out mice Neonatal ventral hippocampal lesion Isolation rearing

15 Recombinant technologies to delete or overexpress the Dopamine-2 receptor in mice Drew et al. J. Neuroscience, 2007

16 Reward processing: testing motivation

17 Performance in the progressive ratio task Drew et al. J. Neuroscience, 2007

18 Evolutionary conserved biological processes?

19 Social withdrawal is influenced by several processes Social perception Social learning Cognitive performance Social information processing Social withdrawal Mentalizing activities Emotionality Reward processing

20 Social information processing

21 duration (s) Social recognition minutes 24 hours

22 Mapping a locus on mouse chromosome 14 for long-term social recognition Mapping a locus on mouse chromosome 14 for social recognition Bruining et al., Biological Psychiatry, 2015

23 Pcdh9: associated to social behavioural deficits in human and dogs

24 Pcdh9-deficient mice: impaired social recognition Bruining et al. Biol. Psychiatry, 2015

25 Sensory processing deficits in Pcdh9 KO mice Touch evoked biting response Sensorimotor performance Prepulse inhibition

26 Cortical thinning of sensory cortex, and local dendritic and spine malformations Bruining et al., Biological Psychiatry, 2015

27 Mouse and human Sensory information processing Genetic variations Cortical integrity

28 From genetic variation to behavioural output Temporal & Spatial Synaptic density

29 Coupling sensory processing to neural biomarkers integrated EEG behavioural analyses

30 Sensory deficits: auditory mismatch negativity

31 Disease diversity

32 Precision medicine Insel and Cuthbert, Science, 2015

33 PRISM: Psychiatric Ratings using Intermediate Stratified Markers Project coordinator: Martien Kas, University of Groningen, the Netherlands Project leader: Hugh Marston, Eli Lilly and Company, United Kingdom The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

PRISM s general concept: Providing quantitative biological measures to facilitate the discovery and development of new treatments for social and cognitive deficits in Alzheimer s disease,

34 PRISM s general concept: Providing quantitative biological measures to facilitate the discovery and development of new treatments for social and cognitive deficits in Alzheimer s disease, schizophrenia and depression The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

23 partners, including major EU Academic Centres, SME s and pharmaceutical industry The project leading to this application has received funding from the Innovative Medicines

35 23 partners, including major EU Academic Centres, SME s and pharmaceutical industry The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

Undertaking under grant agreement No 115916.

36 Human and rodent homologies The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

38 Longitudinal and objective measures of rodent and human social withdrawal The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

BeHapp passive remote behavioural monitoring The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint

39 BeHapp passive remote behavioural monitoring The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

40 Collected Data smartphone app MMS messages GPS location SMS messages Outgoing calls Returned calls Bluetooth signals in the area WiFi signals Incoming calls Application activity, such as: Missed calls Twitter events The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

Initiative 2 Joint Undertaking under grant agreement No 115916.

41 Smartphone passive behavioural monitoring Movement trajectory extraction The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

42 Longitudinal and objective measures of rodent and human social withdrawal The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

Mimicking natural burrowing behaviour The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint

43 Mimicking natural burrowing behaviour The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

Visible Burrow System: studying social interaction in a semi-natural environment The project leading to this application has received funding from the Innovative Medicines

44 Visible Burrow System: studying social interaction in a semi-natural environment The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

45 BTBR: Reduced social interaction and huddling The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

46 Summary Improving treatment efficacy in schizophrenia will benefit from advancing our knowledge on target neural circuitries and representative core readout. Understanding clinical heterogeneity requires the development and application of quantitative biological parameters that can be applied across the diagnostic boundaries. Implementation of homologous clinical and preclinical testing paradigms to assess quantitative biological parameters allow for the development of preclinical model systems to back-translate human findings and further expand our neurobiological knowledge. The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

47 VIDI-grant The project leading to this application has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No This Joint Undertaking receives support from the European Union s Horizon 2020 research and innovation programme and EFPIA.

Innovative Medicines Initiative - the story so far

Innovative Medicines Initiative - the story so far Ruxandra Draghia-Akli MD PhD Director Health, Research & DG Health Research at a Crossroads Are Public-Private Partnerships the Way Forward? European