‘Patient-on-a-chip’: solving the drug testing dilemma

‘Patient-on-a-chip’: solving the drug testing dilemma

Creating a miniaturised copy of your body on a microfluidic chip followed by disease induction will disrupt the current drug testing dilemma.

The average success rate of drug candidates to pass clinical trials is 17%, once preclinical evaluation has been satisfactory completed. No other industry has to deal with such a poor development efficiency. The main reason for this is the low predictive power of preclinical testing in animals and in human in vitro culture. The former are systemic but not human, and the latter are human but not systemic.

Since 1991 we have been inventing approaches to build and interconnect human organ systems in vitro. TissUse is a privately-owned spin-out of the Technische Universitaet Berlin, Germany, founded in 2010 to commercialise its Multi-Organ-Chip platform, which was the result of these inventions.

Proof of principle has been demonstrated using repeated dose Troglitazone treatment of a 3D on-chip co-culture of human skin and liver equivalents as early as in 2013.1 Dose-dependent drug induced liver injury – the reason for withdrawal of Troglitazone from the markets – could be detected using this human multi-organ assay. This has provided the basis for the establishment of qualified preclinical assays with improved predictive power. Since the inception of its Multi-Organ-Chip Technology in 2013, TissUse has developed an ever-growing portfolio of single human organ equivalents and their relevant combinations (see Fig. 1).

As of today, 19 fit-for-purpose assays have been established. Driven by customers’ demand and specifications, a new assay is added to the pipeline approximately every three months. Once reproducibly has been established, an assay is commercially available globally for each and every user across the industries.

Assays generate scientific data on candidate safety, efficacy and mode of action in the frame of a given context of use and can be applied to the regulatory bodies at IND/IMPD level as supporting best state-of-the-art data.

Prime examples of assays recently adopted by the pharmaceutical industry are:

• A five-day ‘safficacy’ assay combining a healthy human skin equivalent with a human tumor model for evaluation of the therapeutic window of antibody candidates2
• A 14-day human liver-pancreas co-culture model enabling diabetes mellitus type 2 induction for diabetes drug candidate testing3
• An eight week human bone marrow toxicity assay supporting lineage-specific safety evaluation of new biological and chemical entities4

A PBPK-compliant ADMET chip

Based on a four organ chip prototype experiment, specific emphasis has been placed on the development of a PBPK-compliant ADMET chip.5 This new four-organ tissue chip combines intestine, liver and kidney equivalents for absorption, metabolism and excretion respectively. Furthermore, it provides an additional neuronal tissue culture compartment for extended toxicity testing.

We were recently able to establish the respective human organ equivalents from an induced pluripotent stem cell bank of a single donor and co-culture them over a period of 14 days. This, for the first time in history, led to an homeostatic autologous four-organ model.

We finally established a toolbox to create a miniature copy of a healthy human body on our chip platform, starting from just a small donated blood sample. Relevant ethical and legal aspects have been considered to ensure the long term commercial use of resulting tissues. The concept for the creation of a copy of a human body on a chip at a downsizing factor of 1:100.000 has been based on two scientific hypothesis:

• Human organs are built up by multiple, identical, functionally self-reliant structural organoids
• These organoids are evolutionarily conserved and subject to genetically encoded self-assembly

A minimum of ten organs and systems are supposed to be necessary to enable minimal organismal functionality in vitro. We have now established a chip prototype capable of hosting the respective miniaturised organ equivalents at a size of a credit card (see: https://www.youtube.com/watch?v=nkkBu8GrExk). Subsequent induction of a disease will lead to a ‘patient-on-a-chip’ equivalent.

Disruptive potential

These patient-on-a-chip equivalents provide an unprecedented disruptive potential to change the drug development paradigm due to the following elements:

• Patient-on-a-chip trials will eliminate Phase 1 safety testing in healthy volunteers and replace >75% of the preclinical animal testing
• Chip-based trial statistics will be significantly improved compared to today’s clinical trial statistics due to the possibility to run the necessary number of biological repeats per chip-based patient
• The platform enables preselection of a large variety of trial cohorts following any relevant selection criteria such as genotype, gender, predisposition etc.
• Access to interstitial body fluids in the ‘patient-on-a-chip’ equivalents create novel relevant data sets for local disease enrollment not available in current patient trials nor in animal tests today and will significantly boost new target identification
This will lead to an average decrease of the drug development time by factor two and to the reduction of cost by factor five.7 In addition, miniaturised copies of your healthy human body on a chip might well be used for basic research, personalised hazard identification of environmental pollution, and selection of personalised food compositions supporting a healthy life style.

TissUse has a acquired a total of €22.4m using primarily non-dilutive sources. The proven business model has allowed the company to grow at an average CAGR of 50% over the last four years with similar significant growth predicted for the future.

References
1 Wagner et al. ‘A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture.’ Lab Chip 13(18), 3538–3547, (2013)
2 Huebner et al. ‘Simultaneous evaluation of anti-EGFR-induced tumour and adverse skin effects in a microfluidic human 3D co-culture model.’ Scientific Report 8:15010 (2018)
3 Bauer et al. ‘Functional coupling of human pancreatic islets and liver spheroids on-a-chip: Towards a novel human ex vivo type 2 diabetes model.’ Scientific Reports 7, 14620 (2017)
4 Sieber et al. ‘Bone marrow-on-a-chip: Long-term culture of human hematopoietic stem cells in a 3D microfluidic environment.’ J Tissue Eng Regen Med. 12(2):479-489, (2018)
5 Maschmeyer et al. ‘A four-organ-chip for interconnected long-term co-culture of human intestine, liver, skin and kidney equivalents.’ Lab Chip 15, 2688–2699 (2015).
6 Marx et al. ‘Human-on-a-chip developments: a translational cutting-edge alternative to systemic safety assessment and efficiency evaluation of substances in laboratory animals and man?’ Altern. Lab. Anim. 40(5), 235–257, (2012)
7 Marx et al. ‘Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing.’ ALTEX 33(3), 272–321, (2016)

Uwe Marx
CEO & Founder
TissUse GmbH
+49 (0)30 51 30 26 400
uwe.marx@tissuse.com
https://www.tissuse.com/en/

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