Extracellular RNA Communication

1

December 9, 2006: Congress unanimously passes a reauthorization bill affirming importance of NIH and its vital role in advancing biomedical research to improve the health of the Nation

Origins of the Common Fund

Establishes the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) within Office of the Director and the NIH Common Fund to provide a dedicated source of funding to enable trans-NIH research

Establishes the Division of Program Coordination, Planning, and Strategic Initiatives (DPCPSI) within Office of the Director and the NIH Common Fund to provide a dedicated source of funding to enable trans-NIH research

2004: NIH Roadmap is launched

Criteria for Common Fund Programs

• Transformative: Must have high potential to dramatically affect biomedical and/or behavioral research over the next decade

• Catalytic: Must achieve a defined set of high impact goals within 5-10 years

• Synergistic: Outcomes must synergistically promote and advance individual missions of NIH Institutes and Centers to benefit health

• Cross-cutting: Program areas must cut across missions of multiple NIH Institutes and Centers, be relevant to multiple diseases or conditions, and be sufficiently complex to require a coordinated, trans-NIH approach

• Unique: Must be something no other entity is likely or able to do

InterdisciplinaryInterdisciplinaryResearchResearchConsortiaConsortia

PROMIS:PROMIS:Clinical Clinical

OutcomesOutcomesAssessmentAssessment

NIHNIHCenter forCenter for

RegenerativeRegenerativeMedicineMedicine

RegulatoryRegulatoryScienceScience

MolecularMolecular LibrariesLibraries

and Imagingand Imaging

Human Human MicrobiomeMicrobiome

Protein Protein CaptureCapture

Pioneer AwardsPioneer AwardsNew Innovator AwardsNew Innovator AwardsTransformative Transformative Research AwardsResearch AwardsEarly Independence AwardsEarly Independence Awards

StructuralStructuralBiologyBiology

Bioinformatics andBioinformatics and Computational BiologyComputational Biology

Building Blocks,Building Blocks,Biological PathwaysBiological Pathways

And NetworksAnd Networks

Genotype-Genotype-TissueTissue

ExpressionExpression

Current Common Fund Programs

Library of Library of Integrated Network-Integrated Network-

Based Cellular Based Cellular Signatures Signatures

(LINCS)(LINCS)

NanomedicineNanomedicine

Science ofScience ofBehaviorBehaviorChangeChange

Gulf Oil SpillGulf Oil SpillLong TermLong TermFollow UpFollow Up

Global Global HealthHealth

Knockout Knockout Mouse Mouse

PhenotypingPhenotyping

NIH Medical NIH Medical ResearchResearchScholarsScholars

Bridging Bridging Interventional Interventional Development Development Gaps (BrIDGs)Gaps (BrIDGs)

Clinical ScienceClinical Scienceand Translationand TranslationAwards (CTSAs)Awards (CTSAs)

HCS ResearchHCS ResearchCCollaboratoryollaboratory

High-RiskHigh-RiskResearchResearch

NIHCommon Fund

Health Health EconomicsEconomics

EpigenomicsEpigenomics

MetabolomicsMetabolomics

SingleSingleCellCell

AnalysisAnalysis

Undiagnosed Undiagnosed Diseases Diseases ProgramProgram

Extracellular RNAExtracellular RNACommunicationCommunication

http://commonfund.nih.gov/

Common Fund Strategic Planning Process

Phase 1: Identification of broad topic areas that address the biggest challenges and greatest opportunities in biomedical research

Phase 2: Refinement of broad areas into well-defined programs and initiatives

*These are projects originating at a grass-roots level with scientists across all fields and/or from the institute/center directors at the NIH*

Timeline of Common Fund Programs

PHASE 1 PHASE 2Strategic Planning Implementation Transition

18 months 5-10 years > 10 years

NEW PROGRAM

■ Enabling Infrastructure■ Bridging Interventional Development Gaps (BrIDGs)

■ Molecular Libraries and Imaging

Common Fund programs catalyze research across a broad spectrum of diseases/conditions

■ New Tools, Technologies, Data, Approaches ■ Human Microbiome Project

■ Library of Integrated Network-Based Cellular Signatures (LINCS)

■ Patient Reported Outcomes Measurement Information System (PROMIS)

■ Epigenomics

What makes a program Common Fund’able?

New FY 2013 program: Extracellular RNA CommunicationOpportunity to explore new paradigms of intracellular and inter-species communication

based on the release, transport, uptake, and regulatory role of exRNAs

Refs: Molec Cancer 2011, 10:117; Cell Res. Sept 2011, 1; Nat Biotech. 2011, 29(4):341.

What is the effect of Extracellular RNAs on human health and disease?

New FY 2013 program: Extracellular RNA Communication

RFA-RM-12-010: Establishment of a central repository for exRNA standards, protocols, and data

RFA-RM-12-011: Development of reference profiles for healthy human exRNAs in a variety of body fluids

RFA-RM-12-012: Support of coordinated analyses to define fundamental biological principles of exRNA generation, distribution, uptake, and effector function

RFA-RM-12-013, RFA-RM-12-014: Investigation of the possible clinical utility of exRNAs as biomarkers and therapeutic delivery vehicles

RNAs can be exported from cells in extracellular vesicles, or bound to lipids or proteins, to circulate through the body and affect distant cells

Opportunity to explore new paradigms of intercellular and inter-species communication based on the release, transport, uptake, and regulatory role of exRNAs

Current Funding Opportunity Announcements:

Common elements shared by all exRNA RFAs:•Applications should involve multidisciplinary teams

Multi-PI leadership plans may be required Web collaboration tool

•Milestones-driven awards•Awardees from all 5 initiatives will form a consortium

Determine fundamental principles associated with exRNAs Provide ready access of newly developed tools and

resources to consortium members Facilitate dissemination of data and technologies to the

general research community Data release/sharing

•Applications from foreign institutions are acceptable Note that RFA RM-12-010 can have a foreign component

Extracellular RNA Communication Program

10

11

Extracellular RNA Communication Program

Common elements shared by all exRNA RFAs:•Important dates:

Letter of Intent Due Date: October 12, 2012Application Receipt: November 13, 2012Scientific Merit Review: February – March 2013Advisory Council Review: May 2013Earliest Start Date: July 2013Kick-Off Meeting: September 26-27,

2013

RFA RM-12-012

Extracellular RNA Biogenesis, Biodistribution, Uptake, and

Effector Function (U19)

12

Goals: • Encourage multidisciplinary teams of investigators to submit applications

to determine the principles that guide the selection of regulatory RNA molecules for extracellular transport and to determine the function of these extracellular RNAs (exRNAs).

• The main scientific areas of interest include:(1) exRNA biogenesis, (2) biodistribution, (3) uptake of exRNA by target cells, and (4) the physiological impact of delivered exRNA in target cells/tissues.

• It is expected that enabling tools, technologies, bioreagents, and analytical approaches that elucidate pathways by which exRNAs are packaged, secreted, transported, and taken up by recipient cells will be developed.

Budget:• The U19 funding mechanism allows for multi-project applications. Total

funds = 7.2 million total costs/yr to fund 4-6 projects.

13

RFA RM-12-012Extracellular RNA Biogenesis, Biodistribution,

Uptake, and Effector Function (U19)

RFA RM-12-012

14

Select Review Criteria:• Are the exRNAs to be studied (if model systems are utilized) likely to be

relevant to human biology?• How appropriate are the expertise and experience of the investigative team in

the context of exRNA?• ……do the project PD(s)/PI(s) have the necessary skills and experience to

contribute to the success of this consortium? • Will the complementary perspectives of the research team enable innovative

approaches that would not be likely without a coordinated team effort? • Are the plans sufficiently flexible to exploit emerging research opportunities? • Are appropriate and quantifiable milestones and timelines clearly defined? • If the aims of the application are achieved, will the findings significantly

increase our understanding of the biosynthetic pathways by which RNAs are directed for extracellular transport and of the mechanisms that regulate their secretion, biodistribution, uptake, and of their biological functions?

RFA RM-12-011

Reference Profiles of Human Extracellular RNA

(U01)

15

RFA RM-12-011Reference Profiles of Human

Extracellular RNA (U01)Goals:• Develop reference profiles for non-coding extracellular RNAs from healthy

human blood and other body fluid samples. Generate a comprehensive catalog that is inclusive of exRNAs secreted in

extracellular vesicles or bound to carriers.

• Development of reference profiling methods that facilitate identification of both endogenously derived and exogenously obtained exRNA species.

Capture of trans-kingdom exRNAs such as those derived from diet or microbiome.

• Development of tools, supporting methodologies and techniques. Distinguishing endogenous and exogenously derived/trans-kingdom species.

Budget:• 4.0 million total cost/year to fund 3-5 U01 applications.

16

RFA RM-12-011

• RFA solely focused on human samples.• Projects should be based on existing samples.• Limited prospective collection for validation purposes.• Informed consents for use and sharing of sample and

data should be in place.• A multidisciplinary team structure encouraged.• A fee for service type arrangement not responsive. • Animal or other non-human models not within scope.

17

RFA RM-12-013

Clinical Utility of Extracellular RNA for Biomarker Development

(UH2/UH3)

18

RFA RM-12-013Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3)

• GOAL: To identify and quantify exRNA-based biomarkers derived from human body fluids

• Utilizes UH2/UH3 Phased Cooperative Agreement mechanism

• Applicants must submit a single application with the research strategy section divided into a 12-page UH2 exploratory phase and a 12-page UH3 phase for biomarker qualification and validation studies.

• The maximum period of support for the combined UH2 and UH3 phases is 5 years. The UH2 phase can be for 1-2 years of support. The second UH3 phase can be for 3-4 years of support.

19

RFA RM-12-013Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3)

• UH2 Exploratory phase should address the following:– plans to identify leads for potentially useful biomarkers;– plans to prioritize identified leads; – computer modeling or simulations and/or statistical justification for the

number of subjects/samples proposed; clear scientific rationale for the range and types of subjects/samples to be used and involvement of key personnel with statistical expertise;

– attention paid to variability in patient demographics, histology, prognosis, stage, and mode of detection;

– matching of control subjects with case subjects; – outcome measures or primary data items for analysis reflecting sensitivity and

specificity metrics; – sampling variability; – plans for confirmatory or cross validation studies with a new set of bio-

specimens. • $500,000 total cost per year• Use of pre-existing biospecimen collection

20

RFA RM-12-013Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3)

• UH3 biomarker validation/qualification phase may include the following:– Studies that correlates a biomarker with pathogenesis, disease processes,

progression or regression of disease, response to therapy, accepted clinical endpoints, symptom management, etc

– studies to design or improve the biomarker assay system to be robust, quantitative, reliable, and translatable to many laboratories, or to fall within costs that are appropriate for clinical use

– studies to establish sampling or biomarker monitoring strategies that are non-invasive

– studies to determine the relationship between biomarker measurements made from biofluids compared to those measurements obtained from tissues

– studies to assess factors, such as sex, age, smoking behavior, etc., that are associated with biomarker status or level in control subjects

– studies to assess factors associated with biomarker status or level in case subjects—in particular, disease characteristics such as stage, histology, grade, and prognosis

– studies to assess the impact of covariates on the discriminatory abilities of the biomarker before clinical diagnosis, including demographics, disease-related characteristics, and other clinical information about the subject

• $1,000,000 total cost per year• Prospective collection of biospecimens may be proposed in order to perform

confirmatory or validation studies.

21

RFA RM-12-014

Clinical Utility of Extracellular RNA for Therapy Development

(UH2/UH3)

22

RFA RM-12-014Clinical Utility of Extracellular RNA for

Therapy Development (UH2/UH3)• GOAL: To develop and advance the therapeutic utility of

exRNAs, RNA-containing extracellular vesicles (EVs) or exosomes, and/or exRNA-bound to other carrier molecules, such as lipoproteins and RNA-binding complexes.

• Utilizes UH2/UH3 Phased Cooperative Agreement mechanism.

• Applicants must submit a single application with the research strategy section divided into a 12-page UH2 phase consisting of proof of concept studies and another 12-page UH3 phase for the pre-clinical optimization, safety and toxicology studies.

• The maximum period of support for the combined UH2 and UH3 phases is 5 years. The UH2 phase can be for 3 years of support. The second UH3 phase can be up to 3 years of support.

23

RFA RM-12-014Clinical Utility of Extracellular RNA for

Therapy Development (UH2/UH3)• UH2 proof of concept studies may include:

– Feasibility studies in cell and animal models of disease– Targeting organ systems recalcitrant to therapeutic delivery– Crossing the blood-brain barrier and other physiological barriers– Delivering exRNA (miRNA, long non-coding RNA, mRNA, siRNA, etc.)

to modulate gene expression and mitigate disease pathogenesis– Identification of surface markers for cell-specific targeting and fusion– Technologies for efficient loading of EVs and/or exRNA-binding

complexes to serve as carriers for targeted delivery– Specific disruption of pathways in cases where intercellular-signaling

mediated by exRNAs can lead to onset and progression of disease– Induction of immune response upon delivery of exRNA

• $500,000 total cost per year

24

RFA RM-12-014Clinical Utility of Extracellular RNA for

Therapy Development (UH2/UH3)• UH3 phase may include:

– preclinical efficacy testing; – predictive ADME (absorption, distribution, metabolism, and

excretion) and toxicology testing;– optimization of candidate therapeutics; – formulation and stability studies, process development and

manufacturing of candidate therapeutics; – development of SOPs and assays to support the production of

cGMP materials for exRNA. This FOA supports only preclinical development, so production of clinical grade materials for clinical trial use is outside the scope;

– pre-clinical pharmacology and toxicology studies.• $1,000,000 total cost per year

25

RFA RM-12-010

Data Management and Resource Repository (DMRR) on

Extracellular RNA

26

RFA RM-12-010Data Management and

Resource Repository (DMRR) on Extracellular RNA (U54)

Goal: • Support a Data Management Resource/Repository (DMRR) for the

ExRNA Program. DMRR will integrate the efforts of all of the funded components of the program and serve as a community-wide resource for ExRNA standards, protocols, and data through the development of an ExRNA Atlas.

• Applications must be from US institution, but foreign components OK.

Budget:• Set aside: $2.5M/year total costs maximum to fund 1 grant.

DMRR U54 DMRR components/cores and activities include:

Responsiveness: • Make sure your application has the three required components and the

administrative core:1. Scientific Outreach Component

• ExRNA Atlas website (e.g. data, protocols ) • Support meetings, workshops, etc

2. Data Coordination Component • metadata standards • exRNA-seq data• other data types (e.g. genotype, phenotype) and data from outside

program• Data deposition (e.g. GEO, dbGAP)

3. Data Integration and Analysis Component • Analysis tools and strategies (e.g. exogenous vs endogenous

exRNAs)• exRNA catalogs• Software, tool, and “app” development• Help analyze data for integrative consortium papers• Help PIs funded by other RFAs analyze their data

4. Administrative Core• Facilitating interaction between three U54 components and rest of

ExRNA consortium• ExRNA program teleconferences and workshops, steering committee

meetings• Yearly consortium-wide meeting (50-100 attendees)

DMRR U54 DMRR components/cores and activities include:

DMRR Review Criteria Highlights

SIGNIFICANCE INVESTIGATORS

– ExRNA or RNA biology expertise?– RNA-seq data expertise? – Experience managing a project of this magnitude?

INNOVATION APPROACH

– Are plans aligned with the anticipated DMRR activities?– Do plans support achievement of the proposed goals/milestones? – Is the proposed DMRR data release plan appropriate for a community resource project? – How well will the DMRR components integrate the efforts of all of the funded components

of the ExRNA program and serve as a community-wide resource via an ExRNA Atlas? – Data transportability and data interoperability in the future? (Flexibility)

ENVIRONMENT– Letters of collaboration and institutional support show strong commitment to the project?

• FAQs on the Extracellular RNA program http://commonfund.nih.gov/Exrna/faq.aspx

• Web Collaboration Portalhttp://commonfund.nih.gov/Exrna/cwcp/

index.aspx

FAQ and Web Collaboration Tool

31

Questions for Working Group?

Working Group Members• Alexandra Ainsztein, Ph.D., Program Director, National

Institute of General Medical Sciences (NIGMS)• Maureen Beanan, Ph.D., Program Director, National Institute

of Allergy and Infectious Diseases (NIAID)• Philip J. Brooks, Ph.D., Program Director, National Center for

Advancing Translational Sciences (NCATS)• Michelle Freund, Ph.D., Program Director, National Institute

of Mental Health (NIMH)• Christine Gatlin, Ph.D., Program Director, National Human

Genome Research Institute (NHGRI)• Max Guo, Ph.D., Chief, Genetics and Cell Biology Branch ,

National Institute on Aging (NIA)• George A. McKie, D.V.M., Ph.D., Program Director, National

Eye Institute (NEI)• Matthew Reilly, Ph.D. , Program Director, Genetics &

Proteomics , National Institute on Alcohol Abuse and Alcoholism (NIAAA)

• John Satterlee, Ph.D., Program Director, National Institute on Drug Abuse (NIDA)

• Pothur R. Srinivas, Ph.D., M.P.H., Program Director, National Heart, Lung, and Blood Institute (NHLBI)

• Robert Star, M.D., Director, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

• Xenia Tigno, Ph.D., M.S., Program Director, National Institute of Nursing Research (NINR)

• Sundar Venkatachalam, Ph.D., Program Director, National Institute of Dental and Craniofacial Research (NIDCR)

• Steven Zullo, Ph.D., Program Director, National Institute of Biomedical Imaging and Bioengineering (NIBIB)

Working Group Coordinators:• T. Kevin Howcroft, Ph.D., Program Director , National

Cancer Institute (NCI)• Suresh Mohla, Ph.D. , Chief (TBMB) and Division Associate

Director , National Cancer Institute (NCI)• Danilo A. Tagle, Ph.D., Associate Director for Special

Initiatives, National Center for Advancing Translational Sciences (NCATS)

Scientific Review Officer:• Richard Panniers, Ph.D., Chief , Center for Scientific Review

(CSR)

Grants Management Specialists:• Cheryl Nathaniel, National Institute on Drug Abuse (NIDA)• Tracee S. Gilchrist, National Heart Lung and Blood Institute

(NHLBI)• Crystal Wolfrey, National Cancer Institute (NCI)• Christina Fleming, National Center for Advancing

Translational Sciences (NCATS)• Judy Musgrave, National Center for Advancing Translational

Sciences (NCATS)

NIH Common Fund• Patricia (Trish) Labosky, Ph.D., Program Leader, National

Institutes of Health (NIH)

32