Alternative Approaches to Animal Models

• Alternative approaches are being developed to overcome limitations of traditional animal models in drug development
• These approaches intend to improve accuracy, efficiency, and ethical considerations of preclinical studies.

Organoids

• 3-D structures that mimic the architecture and function of specific organs or tissues
• Organoids derive from human pluripotent stem cells or adult stem cells
• They provide a more physiologically relevant platform for studying disease mechanisms, drug responses, and personalized medicine
• Organoids have been used in cancer research, neurology, and gastrointestinal disorders
• Offer more physiologically relevant models than 2D cell cultures

Organoids in Drug Development

Disease Modeling & Pathophysiology

• Organoids can replicate patient-specific diseases, including cancer, neurodegenerative disorders, and genetic diseases
• Patient-derived tumor organoids (PDTOs) help model drug resistance in cancer therapy

High-Throughput Drug Screening

• Organoids permit rapid testing of thousands of drug candidates and offer more reliable predictions than 2D cultures
• Colorectal cancer organoids have been used to screen chemotherapy responses

Personalized Medicine

• Patient-specific organoids enable tailored treatments based on individual responses
• Cystic fibrosis (CF) organoids help predict which patients will respond to CFTR modulators

Toxicology & Drug Safety Testing

• Organoids improve preclinical toxicology testing by providing human-relevant data
• Liver organoids are used to test drug-induced hepatotoxicity

Regenerative Medicine & Cell Therapy

• Organoids show promise for tissue transplantation of the liver or kidney
• Mini-liver transplants from organoids are explored for liver failure treatment

Microphysiological Systems (MPS)

• Microphysiological Systems (MPS) are also known as "organs-on-chips"
• MPS models can replicate the complexity of human tissues and allow for the study of organ-level responses to drugs, toxicants, and disease
• They have the potential to provide more accurate predictions of drug efficacy, metabolism, and toxicity

Human Tissue Chips

• Human tissue chips are miniature, bioengineered devices that contain human cells cultured in a microfluidic system
• They mimic the structure and function of specific organs and can be used to study drug responses, toxicity, and disease mechanisms in a more human-relevant context
• Human tissue chips have the potential to provide more accurate predictions of drug efficacy and safety

Patient-Derived Biomaterials

• Patient-derived biomaterials, such as tumor samples, organoids, or patient-derived xenografts, can be used to create personalized models for drug testing
• These models better represent the genetic and phenotypic characteristics of individual patients, allowing for tailored therapeutic approaches and precision medicine strategies

In Silico Modeling and Simulation

• Computational modeling and simulation involve using computer algorithms and mathematical models to simulate biological processes, drug interactions, and disease progression
• In silico approaches enable virtual experiments, prediction of drug properties, optimization of dosing regimens, and identification of potential drug targets
• They can reduce the reliance on animal testing and accelerate the drug discovery and development process

High-Throughput Screening (HTS)

• High-Throughput Screening (HTS) involves the rapid screening of a large number of compounds against specific targets or disease models
• Using automated systems and robotic technologies, HTS allows for the efficient identification of potential drug candidates
• HTS approaches often utilize cell-based assays, biochemical assays, or in silico screening methods to prioritize compounds for further development

Bioprinting

• Bioprinting uses specialized printers to fabricate three-dimensional structures using bioinks composed of living cells, biomaterials, and growth factors
• It enables the creation of complex tissues and organs with precise cellular organization and architecture
• These bioprinted models can be used for drug testing, disease modeling, and tissue engineering applications

The Challenge in Drug Development

• 93% of new drugs fail in clinical trials and only 1 out of 20 drugs make it to market
• Developing a new drug costs around 3 billion euros

The Complexity of Biology and Adaptive Responses to Drugs

• Our bodies are complex adaptive systems that maintain conditions for health
• Interconnected biological networks within and between cells
• Bodies adapt to changes, including drugs, and biological systems compensate for alterations
• Adaptive changes can reduce drug effectiveness

The Long-Term Nature of Disease

• Many diseases such as Alzheimer's, cardiovascular disease, and diabetes develop over decades
• Bodies adapt to disease, creating a new "normal"

Current Drug Testing Models and Their Problems

• Include human cells in petri dishes or laboratory animals
• Current models might not accurately represent human diseases
• 2D cell cultures don't mimic real tissues and animal models often don't translate to humans
• Wrong models lead to wrong drugs

The Need for Better Models

• Focus on disease and tissue holistically and create human tissue models capturing disease complexity
• Crucial to improve prediction of drug efficacy and safety

Introducing Organs-on-Chips

• The OrganoPlate is an organs-on-chips device, each containing 96 biological culture chips
• OrganoPlates organize cells to resemble human tissues

The Gut Wall Example

• Natural gut tissue has multiple cell layers with epithelium, fibroblasts, blood vessels, and immune cells
• These have constant cell interactions and signaling

Gut Model in OrganoPlate

• Combines essential cell types in 3D culture, including epithelium, blood vessels, immune cells, and fibroblasts for patient models

Advantages of Organ-on-Chip Models

• Closely resemble natural human tissue and cells interact and move within the model
• Disease processes, for example inflammation, can be observed

Applications Beyond the Gut

• Include liver and kidney disease models
• Vascular damage and immunological disease research
• Tumor modeling

Benefits for Drug Development

• Better mimics human tissue response to drugs
• Incorporates long-term adaptive changes and uses patient-derived cells
• Supports high-throughput testing capabilities

Potential Impact on Drug Success Rates

• Could increase success rate from 5% to 50%
• Supports dramatic reduction in drug development costs
• Results in fewer patients at risk in clinical trials and reduced need for animal testing

Embracing Biological Complexity

• Aims to move beyond single-target drug approaches
• Understand downstream effects in complex systems and capture disease-specific tissue environments

Personalized Medicine Opportunities

• Using patient-specific cells in organ-on-chip models
• Testing drug responses on individual patient tissues
• Provides potential for tailored treatment strategies

Future Directions in Drug Discovery

• Combines multiple organ-on-chip models, integrates artificial intelligence for analysis, and develops more complex disease models

Challenges and Limitations

• Scaling up production of organ-on-chip models
• Ensuring reproducibility across different labs
• Validating models against human clinical data

The Promise of Innovative Treatments

• Potential for treating currently incurable diseases by developing drugs that work with complex biology
• Expect faster translation from lab to clinic

Microfluidics

• Microfluidic channels mimic blood vessels
• Provides continuous flow of nutrients and waste removal
• Allows precise control of fluid dynamics and shear stress

Integrating Mechanical Forces

• Some organs-on-chips incorporate mechanical forces
• Breathing motions for lung models and peristalsis for gut models are examples
• Integration enhances physiological relevance of tissue models

Multi-Organ Systems

• Connecting multiple organ-on-chip models
• Simulates organ interactions and drug metabolism
• Supports potential for whole-body drug response prediction

Organs-on-Chips in Toxicology Studies

• Assesses potential toxic effects of new compounds and enables long-term exposure studies
• It is more sensitive than traditional cell culture methods

The Role of Stem Cells in Organ-on-Chip Technology

• Stem cells generate diverse cell types and create patient-specific organ models
• They are potential for studying developmental biology and congenital diseases