AMP-AD Open Data and Tools for Target Discovery. Suzana Petanceska PhD Division of Neuroscience

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1 AMP-AD Open Data and Tools for Target Discovery Suzana Petanceska PhD Division of Neuroscience

2 ALZHEIMER S DISEASE

3 ALZHEIMER S DISEASE - Target Discovery and Preclinical Validation Project Apply a systems biology approach to discover and validate the next generation therapeutic targets using an open science research model: Generate multi-omics human data from postmortem brain tissue and plasma samples (well phenotyped cohorts and brain banks) Build network models of targets/pathways Carry out early target validation in multiple cell-based and animal models. Develop a data portal to enable rapid and broad sharing of data and analytical results*. *Data shared post QC no publication embargo for secondary use of data

4 ALZHEIMER S DISEASE - Target Discovery and Preclinical Validation Project RNAseq Working Group Network Working Group eqtl Working Group Deconvolution Working Group Cross-Species Working Group

5 ALZHEIMER S DISEASE - Target Discovery and Preclinical Validation Project Progress over 5 years Centralized data resource established AMP-AD Knowledge Portal Rich genomic, proteomic, metabolomic human data (raw and processed) made available and being widely used Network models od disease pathways/targets developed Over 100 novel candidate targets identified and being prioritized in collaboration with industry partners Animal models phenotyped/evaluated relative to human networks Web-based interface for sharing target nominations and analytical outputs - AGORA platform - beta version launched Open source research tools for de-risking dark targets - being developed Novel biomarker discovery efforts - initiated Single cell RNAseq profiling (human and mouse) - initiated

6 7043 human samples 15 human studies 15 genomic data types 22 model system studies 60,000 files contributed by 42 investigators across 22 institutions representing samples from 36 research studies Over 1800 users with ~55 new users per month

7 Sci Data Oct 11;3: doi: /sdata Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases. Allen M et al. Sci Data Oct 17;4: doi: /sdata Targeted metabolomics and medication classification data from participants in the ADNI1 cohort. St John-Williams L et al. Sci Data Mar 13;5: doi: /sdata Global quantitative analysis of the human brain proteome in Alzheimer's and Parkinson's Disease. Ping L et al. Sci Data Aug 7;5: doi: /sdata A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research. De Jager PL et al. Sci Data Sep 11;5: doi: /sdata The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease. Wang M et al.

8 ROS/MAP Cohorts

9 An Open Science Knowledge Network PAR Active FOA Drug Repurposing and Combination Therapy Development AMP-AD Target Discovery RFA-AG13-013/RFA-AG RFA-AG18-013/RFA-AG **MICROBIOME AD RFA AG MODEL-AD AMP-AD Knowledge Portal M 2 OVE-AD RFA AG PAR /NOT AG NPS-AD Resilience-AD RFA AG RFA AG

10 Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Redhead et al., Neuron Volume 99, Issue 1, 11 July 2018, Pages e7 Common viral species frequently detected in normal, aging brain Increased HHV-6A and HHV-7 in brains of subjects with AD Findings were replicated in two additional, independent cohorts Multiscale networks reveal viral regulation of AD risk, and APP processing genes

11 ALZHEIMER S DISEASE - Target Discovery and Preclinical Validation Project agora.ampadportal.org Beta Version launched at AAIC over 100 AMP-AD target nominations released

12 View details about each nominated gene, including the rationale for its selection and druggability information. How to Navigate Agora Tutorial 12

13 New Features - Coming Soon Access to detailed methods, data, and analyses that led to target nominations New widgets to incorporate additional lines of evidence: genome explorer (eqtls, GWAS, transcription factor networks) proteomics data metabolomic data integrative ranking across multiple types of evidence single cell RNA-seq druggability widget New widgets to highlight available tools and resources: model systems and other experimental models Enabling users to follow, favorite, and give feedback on gene targets of interest

14 Agora Development Timeline (2018/2019) Now Release Agora 1.0 SfN (Nov 4*) Release Agora 1.5 (April 15) Release Agora 2.0 AAIC 2019 (July 14) Fall 2018 Winter 18/19 Spring 19 Summer 19 Detailed evidence used for nominated targets Druggability widget Improve deployment infrastructure 2-3 additional widgets User interactivity (comment, follow) 2-3 additional widgets

15 Agora 1.0 Launch at SFN 2018, San Diego Nov. 4, 6:30p.m. - 8:00p.m. Hilton Bayfront, Room Indigo 204B RSVP here

16 agora.ampadportal.org - broadcast AMP-AD target predictions - establish confidence in target predictions through unbiased, assessment across multiple types of evaluations - disseminate tools to encourage independent evaluation

17 Current services: - Cloud-based File Sharing - Access restrictions and data governance to support human data sharing - Communication services: user profiles, forums - Beta-version of Agora, the knowledge integration platform Coming in 2019: - Streamlined process for data contribution - Improved query and search for data, people, projects - Active community management: newsletters, customer support - Repository for analytical methods - Cloud-based compute

18 NOT JUST TARGETS

19 AMP-AD: Integrative Proteomics for Novel Target and Biomarker Discovery 4. ~1800 Cases ~3,000 proteins n=1,000 tissues ~11-12,000 proteins n=80 tissues CSF/Plasma QE-Orbitrap Label-free single shot Fusion-Orbitrap Multiplex (TMT)

20 Comprehensive and Integrated Analysis of the Human Brain and CSF Proteome in AD From Brain To CSF Communities of Proteins Relate to biological function and processes Assess Module-phenotype Relationships Module-Based Biomarkers

21 From Brain to Plasma: Proteomic Biomarker Discovery and Validation in the US and UK Allan Levey, Ihab Hajjar & Nick Seyfried Simon Lovestone Rima Kaddurah-Daouk

22 ALZHEIMER S DISEASE - Target Discovery and Preclinical Validation Project RFA AG / RFA AG NIA investment: ~$60M over the next 5 years opportunity to continue and expand the public private partnership

23 - AD ALZHEIMER S DISEASE - Target Discovery and Preclinical Validation Project OPEN DATA OPEN METHODS TARGETS and BIOMARKERS