Drugs

Impact Story: Evaluating the Potential of Microengineered Human Cellular Systems to Predict Drug Effects in the Clinic

CDER researchers are developing systems that allow for replication of human physiology and better prediction of drug effects before the initiation of clinical trials. These systems have the potential to reduce costly clinical trial failures resulting from observed toxicities.

Success rate by development stage for new drugs. In a survey of 14 large pharmaceutical companies, it was found that 24 candidate drugs were needed to yield one commercial product.  More than 45% of failures occurred in the three clinical phases of drug development, highlighting the need for better systems for preclinical testing.

Success rate by development stage for new drugs. In a survey of 14 large pharmaceutical companies, it was found that 24 candidate drugs were needed to yield one commercial product. More than 45% of failures occurred in the three clinical phases of drug development, highlighting the need for better systems for preclinical testing.3

Our ability to detect drug toxicity before the clinical phase of drug evaluation is limited by physiological differences between animal models used in preclinical testing and human subjects in clinical trials, as well as differences between drug effects in patients and those observed in laboratory assays.1, 2 These challenges mean that drug developers often conduct costly clinical trials of new drug compounds only to have them fail when toxic effects are observed.3

Developing Systems for Improved Preclinical Prediction of Drug Effects in Humans

Microphysiological systems, organs-on-chip, organoids, and physiological cellular microsystems are different classes of microengineered cellular systems made possible by recent advances in microfabrication, which is the process of fabricating miniature structures at micrometer scales or smaller. In constructing these in vitro experimental platforms, researchers are attempting to replicate human physiology and allow observation of drug effects that may correspond more closely to those that would be seen in patients. In addition to detecting more liabilities before clinical trials are conducted,4 these tools have the potential to replace or supplement clinical trial data when more extensive trials are impractical (e.g., in evaluating drugs to treat rare diseases or developing medical countermeasures to emerging disease threats).5, 6

Through a variety of projects, the Integrated Cellular Systems Laboratory in CDER’s Division of Applied Regulatory Science is studying how to use physiological cellular microsystems to advance drug development. Because hepatic (liver) and cardiac (heart) toxicities account for most of the unanticipated side effects of candidate drugs, CDER researchers are focusing on systems to advance our ability to model drugs’ effects on the liver and heart.

Liver microphysiological systems for measuring drug effects on liver physiology

Liver microphysiological systems enable the culturing of two kinds of primary hepatic cells (Kupffer cells and hepatocytes) in three dimensions and in a medium that is pumped to flow through the resulting microtissue. These conditions prolong liver-specific cellular functions—including enzymatic activities, transport functions, and inflammatory response—and allow for the testing of chronic drug effects, drug–drug interaction effects, and drug-activated mechanisms involving multiple differentiated cell types. CDER researchers have conducted initial evaluations of liver microphysiological systems to support the systems’ utility for the study of drugs with hepatotoxic effects. Cells in these systems show prolonged enzyme activity and more albumin production than cells in traditional culture methods.

Liver microphysiological systems combine different hepatic cell types in three dimensions and under flow conditions for improved modeling of drug effects in the liver.

Liver microphysiological systems combine different hepatic cell types in three dimensions and under flow conditions for improved modeling of drug effects in the liver.

Interconnected on-a-chip systems

A given drug may have toxic effects in multiple organs, but these effects cannot be studied in isolation, because organs interact within the body. CDER scientists are studying how liver microphysiological systems interconnected with other organ-on-a-chip systems can be used to predict drug effects that depend on liver metabolism or cause dual-organ toxicity. By initially studying drugs with known clinical effects in these interconnected systems, researchers will be able to evaluate how different chip-based technologies can be combined for specific uses.

Microengineered single stem cell–derived cardiac myocytes with enhanced maturity

Single cardiac myocytes derived from human induced pluripotent stem cells are microengineered to have the properties of mature cardiac myocytes. The figure shows single cardiomyocytes with α-actinin labeled in green and the nucleus labeled in blue. The stem cell-derived myocyte on the left lacks key properties related to α-actinin organization and expression, while the microengineered stem cell-derived myocyte on the right has physiological organization and expression of α-actinin.

Single cardiac myocytes derived from human induced pluripotent stem cells are microengineered to have the properties of mature cardiac myocytes. The figure shows single cardiomyocytes with α-actinin labeled in green and the nucleus labeled in blue. The stem cell-derived myocyte on the left lacks key properties related to α-actinin organization and expression, while the microengineered stem cell-derived myocyte on the right has physiological organization and expression of α-actinin.

The usefulness of cardiac myocytes (heart muscle cells) derived from pluripotent stem cells for predicting clinical drug effects is limited by characteristics of these cells that fail to replicate physiological settings that define primary mature human tissue. CDER scientists are microengineering stem cell–derived myocytes at the single-cell level so they will become similar to mature cardiomyocytes.7–10 Researchers are measuring critical cardiac functions, including contractility, calcium signaling, and electrical signaling, in these engineered single cells.

Cardiac cellular systems

Microengineered human cellular systems can be used to predict drug effects in the heart. The microengineering of these systems involves using specific microenvironmental cues to induce the cellular alignment that is observed in mature cardiac tissue, tune tissue rigidity, and develop the three-dimensional architecture of heart muscle tissue.11 To enhance the physiological relevance of these systems, microenvironmental cues are combined with other approaches—such as co-culturing of different cell types found in the heart, electrical stimulation of the cells, and genetic editing—to ensure that the cells express key proteins. To advance the use of these cardiac cellular systems as preclinical tools, CDER researchers are comparing how different microenvironmental cues affect cellular responses to drugs that act on the heart.

How does this research improve the drug development process?

CDER researchers are evaluating cellular microsystems platforms that replicate human physiology and can advance drug development and evaluation by detecting drug liabilities early in preclinical drug testing. These platforms will be especially useful in contexts where clinical trials are limited or not feasible, such as efforts to develop medical countermeasures to public health emergencies and to evaluate therapies to treat rare diseases.

References

1. Olson, H, G Betton, D Robinson, K Thomas, A Monro, G Kolaja, et al., 2000, Concordance of the Toxicity of Pharmaceuticals in Humans and in Animals, Regul Toxicol Pharmacol, 32 (1):56-67.

2. Sistare, FD and JJ DeGeorge, 2007, Preclinical Predictors of Clinical Safety: Opportunities for Improvement, Clin Pharmacol Ther, 82 (2):210-214.

3. Ku, MS, 2015, Recent Trends in Specialty Pharma Business Model, J Food Drug Anal, 23 (4):595-608.

4. Wikswo, JP, 2014, The Relevance and Potential Roles of Microphysiological Systems in Biology and Medicine, Exp Biol Med (Maywood), 239 (9):1061-1072.

5. Low, LA and DA Tagle, 2017, Microphysiological Systems (Tissue Chips) and Their Utility for Rare Disease Research. In: M Posada de la Paz, D Taruscio, S Groft, eds. Rare Diseases Epidemiology: Update and Overview. Advances in Experimental Medicine and Biology, vol 1031. Springer, Cham: 405-415.

6. Pamies, D, T Hartung, and HT Hogberg, 2014, Biological and Medical Applications of a Brain-on-a-Chip, Exp Biol Med (Maywood), 239 (9):1096-1107.

7. Ribeiro, AJ, YS Ang, JD Fu, RN Rivas, TM Mohamed, GC Higgs, et al., 2015, Contractility of Single Cardiomyocytes Differentiated from Pluripotent Stem Cells Depends on Physiological Shape and Substrate Stiffness, Proc Natl Acad Sci U S A, 112 (41):12705-12710.

8. Ribeiro, AJS, O Schwab, MA Mandegar, YS Ang, BR Conklin, D Srivastava, et al., 2017, Multi-Imaging Method to Assay the Contractile Mechanical Output of Micropatterned Human iPSC-Derived Cardiac Myocytes, Circ Res, 120 (10):1572-1583.

9. Ribeiro, MC, LG Tertoolen, JA Guadix, M Bellin, G Kosmidis, C D’Aniello, et al., 2015, Functional Maturation of Human Pluripotent Stem Cell Derived Cardiomyocytes in Vitro—Correlation Between Contraction Force and Electrophysiology, Biomaterials, 51:138-150.

10. Kijlstra, JD, D Hu, N Mittal, E Kausel, P van der Meer, A Garakani, et al., 2015, Integrated Analysis of Contractile Kinetics, Force Generation, and Electrical Activity in Single Human Stem Cell-Derived Cardiomyocytes, Stem Cell Reports, 5 (6):1226-1238.

11. Ronaldson-Bouchard, K, SP Ma, K Yeager, T Chen, L Song, D Sirabella, et al., 2018, Advanced Maturation of Human Cardiac Tissue Grown from Pluripotent Stem Cells, Nature, 556 (7700):239-243.

 
 

 

Page Last Updated: 10/05/2018
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