AMP-AD Open Data and Tools for Target Discovery

Suzana Petanceska PhDDivision of Neuroscience

ALZHEIMER’S DISEASE

ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project

Apply a systems biology approach to discover andvalidate the next generation therapeutic targets using an open science research model:

Generate multi-omics human data from postmortem brain tissue and plasma samples (well phenotypedcohorts and brain banks)

Build network models of targets/pathways

Carry out early target validation in multiple cell-basedand animal models.

Develop a data portal to enable rapid and broad sharingof data and analytical results*.

*Data shared post QC – no publication embargo for secondary use of data

Network Working GroupRNAseq Working Group eQTL Working Group

Deconvolution Working Group Cross-Species Working Group

ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project

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

ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project

Progress over 5 years

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

www.synapse.org/ampad

22 model system studies15 genomic data types7043 human samples 15 human studies

Sci Data. 2018 Sep 11;5:180185. doi: 10.1038/sdata.2018.185.

The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease. Wang M et al.

Sci Data. 2018 Aug 7;5:180142. doi: 10.1038/sdata.2018.142.A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research.De Jager PL et al.

Sci Data. 2018 Mar 13;5:180036. doi: 10.1038/sdata.2018.36.Global quantitative analysis of the human brain proteome in Alzheimer's and Parkinson's Disease. Ping L et al.

Sci Data. 2017 Oct 17;4:170140. doi: 10.1038/sdata.2017.140.Targeted metabolomics and medication classification data from participants in the ADNI1 cohort.St John-Williams L et al.

Sci Data. 2016 Oct 11;3:160089. doi: 10.1038/sdata.2016.89.Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases.Allen M et al.

ROS/MAP Cohorts

AMP-AD Target

Discovery

AMP-ADKnowledge

Portal M2OVE-AD

NPS-AD

**MICROBIOMEAD

Drug Repurposingand

Combination Therapy Development

Resilience-AD

MODEL-AD

RFA-AG13-013/RFA-AG17-054RFA-AG18-013/RFA-AG18-014

RFA AG15-010RFA AG16-014

RFA AG17-061RFA AG-18-029

PAR 17-032Active FOA

PAR-18-596/NOT AG-18-001

An Open Science Knowledge Network

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

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 64-82.e7

ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project

agora.ampadportal.org

Beta Version launched at AAIC 2018 - over 100 AMP-AD target nominations released

12

View details about each nominated gene, including the rationale for its selection and druggability information.

http://agora.ampadportal.org/helpHow to Navigate Agora Tutorial

• 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

New Features - Coming Soon

Agora Development Timeline (2018/2019)

Fall 2018 Winter 18/19 Spring 19 Summer 19

Now

• Detailed evidence used for nominated targets

• Druggability widget• Improve deployment

infrastructure

Release Agora 1.0 SfN (Nov 4*)

Release Agora 1.5(April 15)

• 2-3 additional widgets

Release Agora 2.0 AAIC 2019 (July 14)

• User interactivity (comment, follow)• 2-3 additional widgets

Agora 1.0 Launch at SFN 2018, San Diego Nov. 4, 6:30p.m. - 8:00p.m.

Hilton Bayfront, Room Indigo 204B

RSVP here

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

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

NOT JUST TARGETS

AMP-AD: Integrative Proteomics for Novel Target and Biomarker Discovery

4.

Fusion-OrbitrapMultiplex (TMT)

QE-OrbitrapLabel-free

“single shot”

~11-12,000 proteinsn=80 tissues

~3,000 proteinsn=1,000 tissues CSF/Plasma

~1800 Cases

Comprehensive and Integrated Analysis of the Human Brain and CSF Proteome in AD

Relate to biological functionand processes

Assess Module-phenotypeRelationships

To CSF

Communitiesof Proteins

Module-BasedBiomarkers

From Brain

From Brain to Plasma: Proteomic Biomarker Discovery and Validation in the US and UK

Simon Lovestone

Allan Levey, Ihab Hajjar& Nick Seyfried

Rima Kaddurah-Daouk

RFA AG18-013 / RFA AG18-014NIA investment: ~$60M over the next 5 years

opportunity to continue and expand the public private partnership

ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project

TARGETSand

BIOMARKERS

OPEN METHODS

OPEN DATA

- AD

ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project