Molecular Therapy
MOLECULAR THERAPY
KW1 Radboud Universiteit
2024/2025
0
,Molecular Therapy
1
,Molecular Therapy
TABLE OF CONTENTS
BLOC I: DRUG DELIVERY AND DEVELOPMENT ................................................................ 3
UNIT 1: Drug delivery .................................................................................................. 3
UNIT 2: Drug development ........................................................................................ 18
BLOC II: PHARMACODYNAMICS AND -KINETICS........................................................... 23
UNIT 3: Pharmacology and drug disposition .............................................................. 23
UNIT 4: Biotransformation ........................................................................................ 29
UNIT 5: Transporters ................................................................................................. 34
BLOC III: GENETIC THERAPY FOR RETINAL DISEASE ..................................................... 39
UNIT 6: Genetic therapy for inherited retinal diseases ................................................ 39
UNIT 7: Gene augmentation therapy (adding DNA) ..................................................... 42
UNIT 8: Splicing modulation therapy (fixing RNA) ....................................................... 46
UNIT 9: Genome editing therapy (fixing DNA) ............................................................. 52
BLOC IV: THERAPY FOR RENAL TUBULOPATHIES .......................................................... 57
UNIT 10: Renal physiology ........................................................................................ 57
UNIT 11: Current studies and therapy of renal tubulopathies ...................................... 62
UNIT 12: Drug-induced renal pathologies .................................................................. 68
BLOC V: MODERN CANCER THERAPIES ....................................................................... 71
UNIT 13: Basic knowledge RTK and cytokine signalling ............................................... 71
UNIT 14: Targeted cancer therapies ........................................................................... 81
BLOC VI: MODERN PAIN MANAGEMENT ....................................................................... 88
UNIT 15: GPCR-mediated signalling .......................................................................... 88
UNIT 16: Pain management (focus on GPCRs) ........................................................... 97
UNIT 17: Clinical aspects of pain management ........................................................ 104
2
, Molecular Therapy
BLOC I: DRUG DELIVERY AND DEVELOPMENT
UNIT 1: Drug delivery
1. General concepts in drug delivery
Drug delivery aims at achieving a high concentration of a drug molecule at the site of action
(absorption of the drug across a biological membrane). In this way, side effects, as for
example for toxic chemotherapeutics, can be reduced and the activity increased. Drug
delivery frequently is combined with targeting approaches.
- Characteristics of classical drugs:
o Small organic molecules.
o Lipophilic: to cross membranes (stomach, intestine...).
o Distribute freely through the body.
o Act by inhibiting enzymes/ receptors.
- Limitations of classical drugs:
o Chemical diversity limited: due to size and lipophilicity.
o Risk of side effects:
▪ Insufficient specificity: cross reactivity with other targets that are
more than one part of the body.
▪ Inhibition of important metabolic routes in non-target organs
(cancer).
o Poor inhibitors of protein-protein interactions are flat surfaces, so it is not as
easy to attach like deep pockets for binding.
o Oligonucleotides offer a very straight-forward way to inhibit or change
protein expression in a highly specific manner.
2. Drug targeting
Enhance the concentration of a drug at its site of action (target).
- Avoid side effects.
- Use expensive drugs more effectively:
o Less total dose.
o Higher concentration for longer period: protect from degradation and
excretion.
- For an established drug molecule.
Dual challenge
- Remain undetected until the target.
- Find and and hit your target.
3. The main components of a nanomedicine
- Surface modification: prevents rapid clearance.
- Targeting ligand: antibody, HER2 (breast cancer cells), growth factors (EGF-A), …
- Drug.
- Matrix: encapsulates and releases the drug. The ratio drug/matrix should be as hig
as possible.
o Liposome.
3
MOLECULAR THERAPY
KW1 Radboud Universiteit
2024/2025
0
,Molecular Therapy
1
,Molecular Therapy
TABLE OF CONTENTS
BLOC I: DRUG DELIVERY AND DEVELOPMENT ................................................................ 3
UNIT 1: Drug delivery .................................................................................................. 3
UNIT 2: Drug development ........................................................................................ 18
BLOC II: PHARMACODYNAMICS AND -KINETICS........................................................... 23
UNIT 3: Pharmacology and drug disposition .............................................................. 23
UNIT 4: Biotransformation ........................................................................................ 29
UNIT 5: Transporters ................................................................................................. 34
BLOC III: GENETIC THERAPY FOR RETINAL DISEASE ..................................................... 39
UNIT 6: Genetic therapy for inherited retinal diseases ................................................ 39
UNIT 7: Gene augmentation therapy (adding DNA) ..................................................... 42
UNIT 8: Splicing modulation therapy (fixing RNA) ....................................................... 46
UNIT 9: Genome editing therapy (fixing DNA) ............................................................. 52
BLOC IV: THERAPY FOR RENAL TUBULOPATHIES .......................................................... 57
UNIT 10: Renal physiology ........................................................................................ 57
UNIT 11: Current studies and therapy of renal tubulopathies ...................................... 62
UNIT 12: Drug-induced renal pathologies .................................................................. 68
BLOC V: MODERN CANCER THERAPIES ....................................................................... 71
UNIT 13: Basic knowledge RTK and cytokine signalling ............................................... 71
UNIT 14: Targeted cancer therapies ........................................................................... 81
BLOC VI: MODERN PAIN MANAGEMENT ....................................................................... 88
UNIT 15: GPCR-mediated signalling .......................................................................... 88
UNIT 16: Pain management (focus on GPCRs) ........................................................... 97
UNIT 17: Clinical aspects of pain management ........................................................ 104
2
, Molecular Therapy
BLOC I: DRUG DELIVERY AND DEVELOPMENT
UNIT 1: Drug delivery
1. General concepts in drug delivery
Drug delivery aims at achieving a high concentration of a drug molecule at the site of action
(absorption of the drug across a biological membrane). In this way, side effects, as for
example for toxic chemotherapeutics, can be reduced and the activity increased. Drug
delivery frequently is combined with targeting approaches.
- Characteristics of classical drugs:
o Small organic molecules.
o Lipophilic: to cross membranes (stomach, intestine...).
o Distribute freely through the body.
o Act by inhibiting enzymes/ receptors.
- Limitations of classical drugs:
o Chemical diversity limited: due to size and lipophilicity.
o Risk of side effects:
▪ Insufficient specificity: cross reactivity with other targets that are
more than one part of the body.
▪ Inhibition of important metabolic routes in non-target organs
(cancer).
o Poor inhibitors of protein-protein interactions are flat surfaces, so it is not as
easy to attach like deep pockets for binding.
o Oligonucleotides offer a very straight-forward way to inhibit or change
protein expression in a highly specific manner.
2. Drug targeting
Enhance the concentration of a drug at its site of action (target).
- Avoid side effects.
- Use expensive drugs more effectively:
o Less total dose.
o Higher concentration for longer period: protect from degradation and
excretion.
- For an established drug molecule.
Dual challenge
- Remain undetected until the target.
- Find and and hit your target.
3. The main components of a nanomedicine
- Surface modification: prevents rapid clearance.
- Targeting ligand: antibody, HER2 (breast cancer cells), growth factors (EGF-A), …
- Drug.
- Matrix: encapsulates and releases the drug. The ratio drug/matrix should be as hig
as possible.
o Liposome.
3
