Summary of all the lectures given during the course 'Innovative Cell Biology and Immunology' of the minor 'Topics in Biomedical Sciences' at the Vrije Universiteit van Amsterdam (VU). This is the most extensive summary there is, I put my heart and soul into it. I followed this course during the Cor...
INNOVATIVE CELL BIOLOGY AND
IMMUNOLOGY
LECTURES
1A: INTRODUCTION TO ANIMAL FREE INNOVATIONS
MAIN AIM AND LEARNING GOALS
→ Introduce you to the concept of the international “Transition towards animal free innovations”
• Know the separate phases leading from drug discovery to market approval
• Understand the necessity for improvement and the challenges this involves
• Have insight into the international transition to animal free innovations
TRANSITION TO ANIMAL FREE INNOVATIONS
Clinicians → new drugs, medical devices needed
Clinical problems: no optimal solution = new drugs and medical devices needed
Problems
- Potential drugs not reaching Phase 1 testing
- Only 1 out of 10 drugs entering Phase 1 is finally approved
= Improvement preclinical testing needed
→ challenges scientists for development alternative methods
DRUG DEVELOPMENT PIPELINE
Test throughput: number of tests running in a certain phase
- Animals
- In vitro assays
1. Discovery
o Academic scientists → find mechanism of disease (e.g. melanoma)
= understanding why one patient gets disease, other doesn’t
o Understand pathways = block pathways = stop progression
, o In hundreds of animals
= target found
2. Lead optimization
o Tens of thousands of in vitro assays
o Hundreds of animals
3. Phase I
o Not in animals or in vitro
o Very small group with 10-20 patients
o Testing of safety of drug
4. Phase II
o When Phase I has proven safety
o Expansion of group
o Testing of efficacy – does the drug work?
5. Phase III
o Thousands of patients
6. Submission
o Approval = accepted for use in certain disease in certain patient group
7. Post-marketing approval
o Testing for usefulness in other type of diseases
Where are improvements needed and why?
→ need physiologically relevant human models
1) Prior to entering Phase I clinical study
o Use of hundreds of animals in
discovery phase to find
potential hit
▪ Small rodents mostly
o Optimization
▪ Useful drugs failing
▪ Safety in animals, but
not in humans
= Optimization pre-clinical phase
necessary
→ “Pre-phase 1 in vitro”
o Determine whether substance safe for human exposure
▪ Prediction adverse event
o Identification of mode of action of new drugs – working mechanism of drug
o Identification of target group of patients
▪ Patient variation
▪ Personalized medicine
→ Each clinical trial focuses on specific disease and patient inclusion criteria
→ Different organoid models from different donors = better look into patient
variation
2) Personalized medicine and post-approval extension
→ “Post market approval in vitro”
o Determine whether substance with proven safety and efficacy for certain disease
useful for treatment different disease
▪ Drug for treating hypertrophic scar suitable for treating keloid fibrosis
o Identification target group of patients
▪ Patient variation
▪ Personalized medicine
,TRANSITION TO ANIMAL FREE METHODS
→ Transition to animal free methods
- Anything that comes in contact with humans have to be tested for safety and efficacy →
transition to not using animals
o TPI – Transitie Proefdiervrije Innovatie
- Variation in between all the different topics in which animals are used
o In cosmetics: no animals used; in vitro models available
o Brain models: animal models used extensively; in vitro models hard to create
COLLABORATION
Scientific challenge = collaboration
- Cell biologist - Computational modeling/big data
- Immunologist (correlating in vitro-animal-human
- Technical engineer data)
- Clinician - Patient organizations
- Industry
= working together to solve a problem
SKINLAB
Development different organotypic models by SkinLab: organotypic skin/mucosa models
- Useful in:
1) Barrier function
2) Chronic toxicity
3) Systemic toxicity (acute)
4) Immunotoxicity
5) Allergy vs. tolerance
6) Fibrosis
▪ Scar models used for testing new
therapeutic strategies for burn
wounds
7) Melanoma
▪ Able to recreate melanoma (SK-Mel-
28 cell line-derived tumors) in human
skin equivalent
▪ Future: static culture – try to achieve
metastasis into other tissues, with
organ-on-chip
, 8) Safety and efficacy dental medical devices
▪ Host-microbiome interactions
• Interaction of microbiome with individual
• Multi-species biofilm cultured from healthy human saliva
o Community composition
o Average OTUs > 70
• Reconstructed human Gingiva
o Healthy and suppression of immune response shown
▪ Animal alternative dental implant: Gingiva model
1. Introduction microbiome, saliva and immune cells
2. Investigation biological seal around implants
3. Introduce underlying bone in vitro
o All related to Adverse Outcome Pathways and
- Ideal test requirements
a) Long term, stable culture
▪ >28 days
• Needed to see how drugs affects organ + recovery of organ
b) Tissue complexity
▪ Organotypic – look and feel like real organ
▪ Microenvironment – mini organ in microenvironment that the real organ is in
c) Bio-distribution
▪ Organs linked via vasculature → not stand-alone organs
- Eventually skin-on-chip and mucosa-on-chip lead to multi organ-on-chip
1. Biopsy, blood sample
2. Tissue equivalent, endothelial cells, immune cells
3. Organ-on-chip
4. Visualization circulating immune cells: medium flow through vasculature to different
organs
5. Multi-organ-on-chip
= future perspective
More information:
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