Molecular Therapy
NWI-BM078
6 EC
Year 1
Quarter 1
Medical Biology: Human Biology – Master
,Contents
L1 Personalized healthcare.………………………………………………………………………………..…………3
L2 Drug Transporters & Metabolism……………………………………………………………………………..5
Tutorial Pharmacology and Drug Disposition……………………………………………………………….11
Research highlight: Mitochondrial Carrier Proteins……………………………………………………..15
L3 + L4 Drug targeting and delivery I and II………………………………………………………………….17
Research highlight: Nanoparticle delivery in mice……………………………………………………….25
L5 Drug targeting and delivery III…………………………………………………………………………………27
L6 Overview Drug Development Pipeline………………………………………………………………..…..36
L7 General Introduction to Retinal Diseases………………………………………………………………..41
L8 Gene Augmentation Therapy………………………………………………………………………..………..44
L9 Splicing Modulation………………………………………………………………………………………………..46
L10 Genome Editing……..…………………………………………………………………………………………….49
L11 Renal Physiology…………………………………………………………………………………………………..51
L12 Current Therapy of Renal Tubulopathies………………………………………………………………55
Research highlight: Renal Replacement Therapies………………………………………………………59
L13 Drug-induced Renal Pathologies…………………………………………………………………………..62
L14 Kinase Receptor Signaling…………………………………………………………………………………….65
Summary Chapter 16 Lodish……………………………………………………………………….………………71
L15 Fundamental knowledge about cancer therapeutics……………………………………………72
L16 Clinical aspects therapeutics………………………………………………………………………………..79
L17 G-protein coupled receptor signaling + general signaling…………………………………….80
L18 Fundamental knowledge about pain therapeutics……………………………………………….88
L19 Clinical aspects therapeutics………………………………………………………………………………..94
2
,L1 – Personalized healthcare
Principle of personalized medicine:
- The right therapy for right patient at right intensity at right time
- Molecular biomarkers as key drivers of patient selection
- = Personalized healthcare, precision medicine
Personalized medicine in melanoma → Focused on BRAF mutation
- BRAFV600E cells always grow and become cancer cells
- RAF inhibitors will block pathway, block cell growth and inhibit cancers (in mice) that have a
BRAFV600E mutation
- 60% of melanoma patients have BRAFV600E mutation → receptor does not need two
phosphorylation sites anymore, making it constitutively active
- Basis for a personalized medicine! → develop drug that works on oncogenic cells and have a
less high affinity on normal cells
1. Inhibit growth of cells by targeting the signaling transduction pathway of the cell
2. Cells stop growing (proven with IHC)
3. Tumors disappeared (proven with FDG-PET)
4. Patients live longer
Biomarkers = a characteristic that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
- Molecular biomarkers provide a molecular impression of a biological system (cell, animal,
human)
- Biomarkers can be various sorts of data, or combinations thereof
Application of biomarkers in pharmaceutical companies:
- Exposure: does the compound get to the site of action?
- Mechanism: does the compound cause its intended pharmacological/functional effects?
- Efficacy: does the compound have beneficial effects on disease or clinical pathophysiology?
- Safety: what is the therapeutic window (how safe is the drug)?
- Responders: how do sources of variability in drug response in target population affect
efficacy and safety?
Pharma strategy based on personalized medicine → The 5R’s assessment:
- Right Target
- Right Tissue
- Right Safety
- Right Patients
- Right Commercial Potential
In diseased patients it is more efficient to analyze proteins (proteomics) than the genome.
The power of omics in diagnostics:
1. Increase diagnostic yield (use more than one patient)
2. Put biomarker change in context (look at the change of that biomarker (metabolite, protein
etc.) compared to the other biomarkers in the body)
Technology innovation is driving impact in personalized healthcare
3
, Crucial to combine different molecular views to understand human health and disease (X-omics)
Fast translational of biomarker research to implement was needed
Personalized diagnosis: metabolic screening adds strongly to genetic screening in identifying
mechanism of disease
3 translational innovation gaps:
- Research to research
1. You cannot read all the articles published on the topic of interest (here: biomarkers)
2. Half of published data cannot be reproduced
- Research to diagnostics
- Research to society
High expectations of big data, but not all data is useful data
Big data:
- Findable
- Accessible
- Interoperable
- Reusable
Outlook in personalized health(care): always look on the end user → the patient/citizen you want to
help
4
NWI-BM078
6 EC
Year 1
Quarter 1
Medical Biology: Human Biology – Master
,Contents
L1 Personalized healthcare.………………………………………………………………………………..…………3
L2 Drug Transporters & Metabolism……………………………………………………………………………..5
Tutorial Pharmacology and Drug Disposition……………………………………………………………….11
Research highlight: Mitochondrial Carrier Proteins……………………………………………………..15
L3 + L4 Drug targeting and delivery I and II………………………………………………………………….17
Research highlight: Nanoparticle delivery in mice……………………………………………………….25
L5 Drug targeting and delivery III…………………………………………………………………………………27
L6 Overview Drug Development Pipeline………………………………………………………………..…..36
L7 General Introduction to Retinal Diseases………………………………………………………………..41
L8 Gene Augmentation Therapy………………………………………………………………………..………..44
L9 Splicing Modulation………………………………………………………………………………………………..46
L10 Genome Editing……..…………………………………………………………………………………………….49
L11 Renal Physiology…………………………………………………………………………………………………..51
L12 Current Therapy of Renal Tubulopathies………………………………………………………………55
Research highlight: Renal Replacement Therapies………………………………………………………59
L13 Drug-induced Renal Pathologies…………………………………………………………………………..62
L14 Kinase Receptor Signaling…………………………………………………………………………………….65
Summary Chapter 16 Lodish……………………………………………………………………….………………71
L15 Fundamental knowledge about cancer therapeutics……………………………………………72
L16 Clinical aspects therapeutics………………………………………………………………………………..79
L17 G-protein coupled receptor signaling + general signaling…………………………………….80
L18 Fundamental knowledge about pain therapeutics……………………………………………….88
L19 Clinical aspects therapeutics………………………………………………………………………………..94
2
,L1 – Personalized healthcare
Principle of personalized medicine:
- The right therapy for right patient at right intensity at right time
- Molecular biomarkers as key drivers of patient selection
- = Personalized healthcare, precision medicine
Personalized medicine in melanoma → Focused on BRAF mutation
- BRAFV600E cells always grow and become cancer cells
- RAF inhibitors will block pathway, block cell growth and inhibit cancers (in mice) that have a
BRAFV600E mutation
- 60% of melanoma patients have BRAFV600E mutation → receptor does not need two
phosphorylation sites anymore, making it constitutively active
- Basis for a personalized medicine! → develop drug that works on oncogenic cells and have a
less high affinity on normal cells
1. Inhibit growth of cells by targeting the signaling transduction pathway of the cell
2. Cells stop growing (proven with IHC)
3. Tumors disappeared (proven with FDG-PET)
4. Patients live longer
Biomarkers = a characteristic that is objectively measured and evaluated as an indicator of normal
biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
- Molecular biomarkers provide a molecular impression of a biological system (cell, animal,
human)
- Biomarkers can be various sorts of data, or combinations thereof
Application of biomarkers in pharmaceutical companies:
- Exposure: does the compound get to the site of action?
- Mechanism: does the compound cause its intended pharmacological/functional effects?
- Efficacy: does the compound have beneficial effects on disease or clinical pathophysiology?
- Safety: what is the therapeutic window (how safe is the drug)?
- Responders: how do sources of variability in drug response in target population affect
efficacy and safety?
Pharma strategy based on personalized medicine → The 5R’s assessment:
- Right Target
- Right Tissue
- Right Safety
- Right Patients
- Right Commercial Potential
In diseased patients it is more efficient to analyze proteins (proteomics) than the genome.
The power of omics in diagnostics:
1. Increase diagnostic yield (use more than one patient)
2. Put biomarker change in context (look at the change of that biomarker (metabolite, protein
etc.) compared to the other biomarkers in the body)
Technology innovation is driving impact in personalized healthcare
3
, Crucial to combine different molecular views to understand human health and disease (X-omics)
Fast translational of biomarker research to implement was needed
Personalized diagnosis: metabolic screening adds strongly to genetic screening in identifying
mechanism of disease
3 translational innovation gaps:
- Research to research
1. You cannot read all the articles published on the topic of interest (here: biomarkers)
2. Half of published data cannot be reproduced
- Research to diagnostics
- Research to society
High expectations of big data, but not all data is useful data
Big data:
- Findable
- Accessible
- Interoperable
- Reusable
Outlook in personalized health(care): always look on the end user → the patient/citizen you want to
help
4
