Organs on Chips: The Future of Translational Research

Transcription

1 Organs on Chips: The Future of Translational Research KRISTIN FABRE, PHD SCIENTIFIC PROGRAM MANAGER NIH NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCE (NCATS) 1

2 Advancing regulatory sciences Drug Failure Modes Why drugs fail human trials Human toxicities found in animals Liver Heart Blood Immune Kidney Lost in translation Regulatory decisions about science are outdated 2D cell-culture often does NOT translate to in vivo systems Animal models are not reliable different physiology 2

3 Poor translational research models Seok; PNAS 2013 NCATS Mission To catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions. 3

4 Microphysiological systems (Organs on chips A five-year program (co-operative agreement) involving partnerships of NIH with DARPA and FDA Goal of achieving 10-organ system mimetic that is physiologically relevant ( human on-a-chip ) Useful for drug pre-clinical safety and toxicology drug-screening Representation of human disease and clinical conditions for POC and efficacy studies Sufficient alternative for animal-testing Genetically diverse conceivable for use in clinical trials setting Advancing regulatory science DARPA Microphysiological Systems Program BAA Microphysiological Systems NIH NCATS Microphysiological Systems Program RFA-RM Integrated Microphysiological Systems for Drug Efficacy and Toxicity Testing in Human Health and Disease (UH2/UH3) RFA-RM Stem/Progenitor Cell-Derived Human Microorgans and -tissues (U18) FDA Advice and expertise to NIH and DARPA NIH-FDA collaboration FDA-DARPA sponsored workshops/collaborations NIH-DARPA Partnership Respective programs independently managed and funded by each Agency PI meetings on consecutive days at the same location Performers (awardees) expected to attend both meetings DARPA and NIH have their own processes for evaluating performer/awardee progress DARPA performers asked to provide access to platform/collaborate with NIH awardees 4

5 MPS platforms Characterization of MPS Platforms Tissues supported Platform assembled off the shelf or fabricated in house Platform description scale Connectivity interface between platforms Chemical environment Cell sources used Functional Assays Reference drug and data sets for testing Microphysiological Systems Availability of compound Dosing paradigm Cellular vs organ toxicity Data on human toxicity Toxicity readouts MPS cell sources Can you standardize a set of criteria for each organ system? For each tissue/organ system there is a need to: Define the starting point primary tissue know key information about sex, ethnicity, age, control or disease related phenotypes Develop a standard of functional characteristics (minimum set of) Develop a standard for molecular and cellular characterization (minimum set of) Working Group Leads for tissue/organ standards Donna Stolz Joan Nichols Steve George Rocky Jonathon Himmelfarb Karen Hirschi John Lynch Angela Christiano Liver Lung Cardiac Bone and Cartilage Kidney Vascular Intestine Skin 5

6 Human on a chip Human-on-a-Chip In vivo Correlation Absorption Distribution Metabolism Excretion Conc(t) Effect(t) Toxicity(t) Rare toxicities Read outs Human biology Tissue/organ structure Cell histology Cell viability Mechanical properties Electrical properties Signaling pathways Cell metabolism Protein synthesis Gene expression Enzyme activities Ion channel properties 6

7 BIG Science: it takes a VILLAGE!! 15+ NIH institutes or centers 30+ NIH IC representatives NIH Common Fund FDA DARPA Pharma 25+ universities/medical research centers Program Directors: Danilo Tagle and Marg Sutherland Thank you! Kristin Fabre fabrek@mail.nih.gov 7

8 U18 generated cell resources UH2 generated organ systems 24 months UH3 phase: -Incorporation of differentiated stem- and progenitor-derived cells -Integration of various organ systems Multicellular architecture Vascularization, innervation, hormonal, humoraland immunological signaling Genetic diversity and pharmacogenomic capacity Representation of normal and disease phenotypes 60 months Integration & validation Base period Period 1 Period 2 DARPA bioengineering Platform + 2 systems 4 systems 7 systems 10 systems Cell viability for 4 weeks Integrated system predicts human in vivo efficacy, toxicity, and pharmacokinetics: o safe and effective o safe and ineffective o unsafe, but effective o unsafe and ineffective Period 3 National Center for Advancing Translational Sciences (NCATS) Fundamental science unprecedentedly advanced, but: Poor transition of those advances to interventions that tangibly improve human health Drug/device development system in crisis Clinical trials system in crisis Poor adoption of demonstrably useful interventions 8

9 Catalyzing Collaborations Within NIH NCI NHLBI NIAID OD NIDCR NEI NIA NLM CC NIDDK NIAMS NIDA FIC NHGRI NICHD NCATS NIEHS CIT NIBIB CSR NIAAA NIDCD NINDS NIMH NCCAM NINR NIGMS NIMHD Catalyzing Collaborations Outside NIH Biotech Pharma Academia NCATS FDA/DARPAA Advocacy Groups Non- Profits Complements does not compete with the work of others Revolutionizes the process of translation by promoting innovative research Galvanizes and supports new partnerships Supports and augments regulatory science and its application Expands the precompetitive space 9

10 NIH NCATS/DARPA/FDA partnerships Memorandum of Understanding (MOU) NIH and DARPA will independently manage and fund separate programs that will be highly coordinated across the two agencies FDA provides regulatory and toxicology expertise Program coordination o Sharing of scientific expertise, materials, resources o Jointly held semi-annual meetings o Development of a common set of validation compounds o Facilitation of collaborations Cellular readouts of the Organs on Chips Genomics, proteomics Biochemical and physiological analysis ph, O2, MEA Metabolomics Optogenetics Inflammatory responses Functional analyses 10

11 Poor translational research models Seok; PNAS