Non-Animal Approaches - The Way Forward Multi-Organ-Chip developments: Towards a paradigm shift in drug development

Transcription

1 Non-Animal Approaches - The Way Forward Multi-Organ-Chip developments: Towards a paradigm shift in drug development

2 Transatlantic Think Tank on Toxicology Berlin June 2015 Biology-inspired microphysiological system approaches to solve the prediction dilemma of drug testing (Adrian Roth and Uwe Marx) Microphysiological systems (MPS) are microfluidic cell culture devices capable of emulating human biology at the smallest biologically acceptable scale. Evaluation for Drugs National Center for Safety Leading MPS experts from academia and SMEs JaCVAM MPS status report Marx et al., ALTEX 33 (3) (36 authors)

3 Types of MPS and key players Olivier Frey, Zürich, Switzerland Leiden, The Netherlands Linda Griffith, Cambridge, USA Seattle, USA Michael Shuler, Ithaka, USA James Hickman, Orlando, USA Donald Ingber, at Harvard Medical School, Boston, USA Emulate Inc. Marx et al. (2016) ALTEX 33 (3) Uwe Marx. Berlin, Germany

4 The Multi-Organ-Chip (MOC) Technology Access Point On-Chip Pump Features: Chip format of a standard microscopic slide Microfluidic Channel Organoid Culture Units On-chip micro-pump and natural tissue to fluid ratio Variable physiological shear stresses applicable Tissue cultures 100,000-fold smaller than original organs Rapid prototyping of any relevant chip design Compatible with life tissue imaging

5 The Multi-Organ-Chip Platform

6 Historical sketch of our Multi-Organ-Chip platform Organ-Chip 4-Organ-Chip Human-on-a-Chip Liver Skin Liver - prime metabolic organ - blood protein supplier Intestine - target for food additives - oral administration Skin - target for cosmetics - dermal administration Kidney - urine removal - toxicity target 2018

7 Our organoid engineering pipeline tissue explants primary cells de novo assembly commercial models cell lines ipsc-derived cells Liver 1. Intestine 2. Kidney* 3. Brain 4. Pancreas 5. islets Skeletal muscles 6. Adipose tissue 7. Skin 8. Hair* 9. Lung 10. Bone marrow* 11. subcutaneous explants punch biopsies follicular unit extraction precision cut tissue slices punch biopsies Lymph node 12. Vasculature * in collaboration with the TU Berlin, Germany

8 Human 2-Organ-Chip Assays 8-40 circuits / exp. (n = 3-5) In-process controls Viability, e.g. LDH metabolism, e.g. glucose cell morphology others de novo assembly of organ equivalents 1-8 weeks 1-4 weeks at homeostasis (preclinical and clinical safety testing) tissue explants Endpoint readouts histology qpcr metabolites microarrays -omics others exposure regimen Human MoA/AOP data-based informed decision, prior to any use in man (or animals)!

9 Preparing for ADMET: 28d 4-Organ-Chip feasibility intestinal lumen: surrogate blood circuit: excretory circuit: 250 µl 830 µl 600 µl 2 g/l Gluc 10 % HS 2.5 g/l Gluc 10 % HS 1 g/l Gluc Increased systemic complexity

10 The 4-Organ-Chip: Intestine Liver Skin - Kidney Skin CK µm CK15 Liver Cytokeratin 8/18 Vimentin Intestine Cytokeratin 19 Adsorption SmI 24w format Metabolism Distribution Kidney Excretion ADMET-Chip Maschmeyer et al., Lab Chip. 2015, 15(12): NaK-ATPase NaK ATPase human RPTEC/TERT cell line

11 The 4-Organ-Chip as part of H2020-PHC-2015-single-stage_RTD (PHC , RIA) Systemic toxicity testing in vitro Chemical space, Start: , ~ 30m, 5 years, 41 partners PBPK modeling + O 2 food & drugs feces bile 4OC prototype PBPKcompliant food & drugs urine feces bile urine

12 Next Generation Human-on-a-Chip Marx et al., Altern Lab Anim Oct;40(5): Marx et al., ALTEX 2016 May 15. doi: /altex

13 A roadmap towards MPS-based decision-making Regulatory acceptance none (MPS-based regulatory science) validated safety assays validated hazard identification, systemic efficacy assay Industrial adoption none (initial MPS evaluation) MoA assessment, toxicity testing systemic safety testing, disease modeling, on-chip clinical trials Innovative solutions single- and multi-organ MPS tools human Body-ona-chip models Marx et al. (2016) ALTEX 33 (3)

14 Thank you for your attention