Designing Human In Vitro Models for Drug Development

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

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Human iPSC-Derived Glia as a Tool for Neuropsychiatric Research and Drug Development

International Journal of Molecular Sciences ◽

10.3390/ijms221910254 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10254

Author(s):

Johanna Heider ◽

Sabrina Vogel ◽

Hansjürgen Volkmer ◽

Ricarda Breitmeyer

Keyword(s):

Drug Development ◽

Neuropsychiatric Disorders ◽

Autism Spectrum ◽

In Vitro Models ◽

Neuropsychiatric Diseases ◽

Culture Models ◽

Target Screening ◽

Induced Pluripotent ◽

The Impact

Neuropsychiatric disorders such as schizophrenia or autism spectrum disorder represent a leading and growing burden on worldwide mental health. Fundamental lack in understanding the underlying pathobiology compromises efficient drug development despite the immense medical need. So far, antipsychotic drugs reduce symptom severity and enhance quality of life, but there is no cure available. On the molecular level, schizophrenia and autism spectrum disorders correlate with compromised neuronal phenotypes. There is increasing evidence that aberrant neuroinflammatory responses of glial cells account for synaptic pathologies through deregulated communication and reciprocal modulation. Consequently, microglia and astrocytes emerge as central targets for anti-inflammatory treatment to preserve organization and homeostasis of the central nervous system. Studying the impact of neuroinflammation in the context of neuropsychiatric disorders is, however, limited by the lack of relevant human cellular test systems that are able to represent the dynamic cellular processes and molecular changes observed in human tissue. Today, patient-derived induced pluripotent stem cells offer the opportunity to study neuroinflammatory mechanisms in vitro that comprise the genetic background of affected patients. In this review, we summarize the major findings of iPSC-based microglia and astrocyte research in the context of neuropsychiatric diseases and highlight the benefit of 2D and 3D co-culture models for the generation of efficient in vitro models for target screening and drug development.

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Integration of the Immune System into Complex In Vitro Models for Preclinical Drug Development

Biomimetic Microengineering ◽

10.1201/9780367814809-18 ◽

2020 ◽

pp. 341-370

Author(s):

Jason Ekert ◽

Sunish Mohanan ◽

Julianna Deakyne ◽

Philippa Pribul Allen ◽

Nikki Marshall ◽

...

Keyword(s):

Immune System ◽

Drug Development ◽

In Vitro Models ◽

Preclinical Drug Development

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Development and Application of In Vitro Models of Hematopoiesis to Drug Development

Toxicologic Pathology ◽

10.1177/019262339302100216 ◽

1993 ◽

Vol 21 (2) ◽

pp. 231-240 ◽

Cited By ~ 21

Author(s):

Ahmed Deldar ◽

Charles E. Stevens

Keyword(s):

Drug Development ◽

In Vitro Models

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Use of In Vitro Models in Drug Development and Issue Resolution

Advanced Issue Resolution in Safety Pharmacology ◽

10.1016/b978-0-12-812206-8.00014-5 ◽

2019 ◽

pp. 287-302

Author(s):

David O. Calligaro

Keyword(s):

Drug Development ◽

In Vitro Models

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Chemoresistance of Cancer Cells: Requirements of Tumor Microenvironment-mimicking In Vitro Models in Anti-Cancer Drug Development

Theranostics ◽

10.7150/thno.29098 ◽

2018 ◽

Vol 8 (19) ◽

pp. 5259-5275 ◽

Cited By ~ 37

Author(s):

Yeonho Jo ◽

Nakwon Choi ◽

Kyobum Kim ◽

Hyung-Jun Koo ◽

Jonghoon Choi ◽

...

Keyword(s):

Tumor Microenvironment ◽

Drug Development ◽

Cancer Cells ◽

In Vitro Models ◽

Cancer Drug ◽

Anti Cancer

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In Vitro Models of the Blood–Brain Barrier and Their Use in Drug Development

The Blood-Brain Barrier and Drug Delivery to the CNS ◽

10.1201/9780824741990.ch4 ◽

2000 ◽

Author(s):

C Duhem ◽

V Buee-Scherrer ◽

B Dehouck ◽

R Cecchelli ◽

M Dehouck ◽

...

Keyword(s):

Drug Development ◽

Blood Brain Barrier ◽

In Vitro Models ◽

Brain Barrier ◽

Blood Brain

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The Combination of Cell Cultured Technology and In Silico Model to Inform the Drug Development

Pharmaceutics ◽

10.3390/pharmaceutics13050704 ◽

2021 ◽

Vol 13 (5) ◽

pp. 704

Author(s):

Zhengying Zhou ◽

Jinwei Zhu ◽

Muhan Jiang ◽

Lan Sang ◽

Kun Hao ◽

...

Keyword(s):

Drug Development ◽

In Silico ◽

In Vitro Models ◽

Clinical Settings ◽

Culture Methods ◽

Physiologically Based Pharmacokinetic ◽

Induced Pluripotent ◽

In Silico Models

Human-derived in vitro models can provide high-throughput efficacy and toxicity data without a species gap in drug development. Challenges are still encountered regarding the full utilisation of massive data in clinical settings. The lack of translated methods hinders the reliable prediction of clinical outcomes. Therefore, in this study, in silico models were proposed to tackle these obstacles from in vitro to in vivo translation, and the current major cell culture methods were introduced, such as human-induced pluripotent stem cells (hiPSCs), 3D cells, organoids, and microphysiological systems (MPS). Furthermore, the role and applications of several in silico models were summarised, including the physiologically based pharmacokinetic model (PBPK), pharmacokinetic/pharmacodynamic model (PK/PD), quantitative systems pharmacology model (QSP), and virtual clinical trials. These credible translation cases will provide templates for subsequent in vitro to in vivo translation. We believe that synergising high-quality in vitro data with existing models can better guide drug development and clinical use.

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