Lecture 23 - Therapeutics for Alzheimer's Disease Flashcards
Abeta load
Abeta synthesis - Abeta clearance
Potential enzyme targets for AD therapy
1)
2)
1) Beta secretase
2) Gamma secretase
Name of gamma secretase inhibitor
Semagacestat
What is semagacestat?
A gamma secretase inhibitor
What is gamma secretase?
A multi-subunit protein complex.
A protease.
Cleaves amyloid progenitor protein
Effect of semagacestat
1)
2)
1) Dose-dependently lowers plasma, CSF and brain Abeta in animals, and lowered plasma and CDF Abeta in humans
2) In stage III clinical trail, did not slow Alzheimer’s.
Lead to worsening of measures of cognition
Problem with gamma-secretase inhibitors
Many off-target effects, as they are quite non-selective
Example of a non-gamma secretase target of semagacestat
NOTCH.
If NOTCH is cleaved, can lead to cancer development
Beta-secretase inhibitor development
1)
2)
1) In early stages of development
2) Merck drug MK-8931 is undergoing stage 2 and 3 clinical trials
Type of protease that beta secretase is
Aspartyl protease
Another way to approach Alzheimer’s therapy by targeting proteases
Promote alpha secretase function.
Results in a truncated Abeta
Basic idea of Alzheimer’s vaccine
Immunise with Abeta antigen
Testing of Alzheimer’s vaccine idea
APP transgenic mice inoculated with Abeta vaccine
Name of a putative Alzheimer’s vaccine
AN1792
AN1792
Aggregated Abeta42 peptide antigen
AN1792 trail outcome
1)
2)
3)
1) Stage II, mild to moderate AD patients immunised
2) No significant differences in cognitive tests between antibody responder and placebo groups
3) Had to stop trail because of 6% of patients developing meningoencephalitis
AN1792 effects
Reduced number of Abeta plaques five years after immunisation, but this didn’t slow progression of neurodegeneration
6% rate of meningoencephalitis development
Monoclonal antibody treatment for AD
Bapineuzumab
Humanised MAb against epitope Abeta1-5
Binds both soluble and fibrillar Abeta
Bapineuzumab clinical trial results
1)
2)
1) Unpromising stage I and II
2) Failed in stage III trails. No difference between AD patients with or without ApoE4 allele
ApoE4 gene
Greatest risk-factor gene for AD
Why might it be dangerous to elicit an immune response against Abeta?
Abeta is a self protein.
Attempted MAb therapies for AD
1) Bapineuzumab
2) Solanezumab
Solanezumab
MAb therapy that binds to Abeta16-24
Preferentially binds to soluble Abeta
Solanezumab clinical trial outcomes
1)
2)
3)
1) In AD mouse model, reversed memory effects without affecting Abeta load
2) Phase II trials, increased plasma and CSF levels of Abeta40 and 42, indicating that plaque load in brain was
decreased
3) In phase II and III trials, cognitive endpoints were not met
MAb therapy that targets Abeta16-24
Solanezumab
MAb therapy that targets Abeta1-5
Bapineuzumab
AD vaccine targeting Tau
12aa sequence from human tau
Comprised phosphorylated serine 396 and serine 404 epitope
Reduced number of neurofibrillary tangles
Tramiprosate 1) 2) 3) 4)
1) Oligomerisation inhibitor
2) Sulphated glycosaminoglycan mimetic
3) Maintains Abeta42 in non-fibrillar form
4) Reduces Abeta42-induced cell death
Oligomerisation inhibition therapy
Tramiprosate
Tramiprosate clinical trial outcomes
Failed to improve cognitive performance in definitive stage III trial
What kind of drug is clioquinol?
Metal-protein attenuating compound
Example of a metal-protein attenuating compound
Clioquinol
Clioquinol mechanism of action
Chelates Cu and Zn
This prevents Cu being able to form dityrosine crosslinks between Abeta monomers
Crosses blood brain barrier
Modulates amyloid pathology in transgenic mice
Clioquinol clinical trial outcomes
Efficacious in a small-phase II human clinical trial
Name of a modified version of Clioqunol
PBT2
What is PBT2?
A modified version of Clioquinol
Clinical trial outcome of PBT2
GFC hit when PBT2 was to go to trial, so only a small, underpowered trial could take place
MCI
Mild cognitive impairment
Peak age of AD onset
80
When does prodromal AD (amnestic MCI) normally begin?
~10 years before onset of AD
A way to test for AD
1)
2)
3)
1) Inject thioflavin T (radioactive marker)
2) PET scan patient
3) Thioflavin T relative fluorescence in area of brain with Abeta aggregation. This correlates with Braak staging of AD progression
Possible AD treatments 1) 2) 3) 4) 5)
1) Secretase inhibitors
2) Vaccine (Abeta vaccine, tau vaccine)
3) Oligomerisation inhibitors
4) Metal-protein attenuating compounds
5) Antioxidants
