Lecture 24 - Neurodegeneration Therapeutics Flashcards
What are some possible targets?
- BACE
- gamma secretase
- Cu
- Aβ aggregation
- APP
- Oligomerisation
- Degradation
Describe how secretases are targeted
Give an example
Drug developed that blocks the active sites
eg.
Semagacestat
Merck trial
Why did gamma secretase inhibitors not work?
Side effects due to non-selectivity:
• gamma secretrase also cleaves other proteins in the body such as NOTCH protein
• NOTCH is important in development
• Interference with NOTCH → malignancy
Discuss β secretase inhibitors
Discuss:
• Human trials
- Active site has two Aspartates
- Active site is large → difficult to make a compound that fits in here
Merck Drug:
• Currently in phase 2/3 trials
• Seems to have good safety profiles
Discuss gamma secretase inhibitors
Discuss results in:
• Animals
• Humans
Semagacestat
• Gamma secretase inhibitor
In animals
• Lowered levels of Aβ in plasma, CSF and brain
In humans:
• Lowered levels of Aβ in plasma in humans
• Phase III trials shown not to slow AD progression
• Caused worsening of clinical measures of cognition etc.
Discuss active vaccination as treatment for AD
Discuss results in:
• Mice
• Humans
Shenck came up with a vaccine against Aβ
Transgenic mouse model • Overexpression of APP • Aβ as antigen in vaccine • Immunised mice had no Aβ deposition • Control mice had Aβ deposition
Result:
• Reduction in Aβ plaque aggregation
How would this work:
• Ab need to cross the BBB
• This is possible (went against the accepted dogma)
Vaccination trials:
• Aβ as the antigen in the vaccine
• Mild to moderate AD patients immunised
Results:
• No significant difference between vaccine group and control groups
• Trial stopped due to encephalitis is some subjects
• In the people who were immunised, the Aβ load was lower than the control group post mortem
• This reduction in Aβ load did not seem to have affected the disease progression
Discuss passive immunisation for AD
Discuss results in:
• Mice
• Humans
- Bapineuzumab
• Humanised mAbs against soluble and fibrillar Aβ injected into patients
Results in mice:
• Reduced Aβ load in transgenic mice
In humans:
• Phase I and II: less promising results than in mice
• Phase III trials: failed, no difference between control and vaccine groups
- Solanezumab:
• Humanised mAb against soluble Aβ
Results in mice:
• Reversed memory deficits
• Didn’t affect brain Aβ load, but soluble Aβ is not significant in the brain
Results in humans:
• Phase II: increase plasma and CSF levels of Aβ → due to decreased brain load
• No effect on behavioural outcomes
• Phase III: cognition endpoints were not met
Describe Tau immunisation
Discuss results in:
• Mice
NB Tau is intracellular → Ab needs to get into the cell. This has been possible
Immunogen: Human Tau peptide sequence
Mice model study: • Tau transgenic mice (have tau pathology) • Three groups: I = before onset II = moderate III = advanced tau pathology • Measurement of NFTs: → Reduction in all three groups
Discuss oligomerisation inhibitors Results in: • in vitro • Mice • Humans
Tramisprosate
Sulfated glucosaminoglycan mimetic
Results in vitro:
• Keeps Aβ from aggregating
• Reduced Aβ-induced cell death
In transgenic mice:
• Reduced Aβ plaque load in brain
Clinical trials:
• Failure to reduce load and improve cognitive performance
Discuss Cu as a target
PBT-2, MPACs
Clioquinol based compound, with similar properties
• Chelates Zn and Cu ions
• Crosses the BBB
In transgenic mice:
• Reduced Aβ aggregation
In human trials:
• Efficacious in small phase II trial
• Good safety profile
• Affected Aβ and tau
→ Global financial crisis made it impossible to do a big phase III trial
• Another small phase II trial was done instead
• Failed, but they think that the trial was too small (only 27 people received the drug)
• This doesn’t mean that the drug doesn’t work, it just means the trial wasn’t done properly
How is copper involved in AD?
- Induces di-tyrosine cross linking Aβ, which is toxic
* Production of reactive oxygen species that lead to neuronal dysfunction and death
What are some other proposed treatments for AD?
Anti-oxidants Neuroprotectants Anti-infammatories Alpha secretase activator Tau aggregation inhibitors
When should AD be treated?
Discuss the phases of the disease progression
- Pre-symptomatic phase:
• no clinical symptoms
• 50 years of age
• Aβ is aggregating and causing cell death - Prodomal
- Dementia:
• Cognition declines
Since Aβ deposition is accumulating very early on, we need to treat people very early on, i.e. when they are still cognitively normal
Up until now, therapies have only been treating people who are symptomatic. This is probably too late, and the damage from Aβ has already occurred, and downstream effects have been triggered
At this point, the down stream effects need to be targeted in treatment
• Inflammation
• Oxidative stress
etc.
Discuss diagnostic tests for Aβ deposition in the pre-symptomatic phase, now and in the future
- PET scanning
• Radioactively marked ThT (which binds to Aβ) administered
• Isotope picked up by PET scanning
• Aβ deposition can be detected at pre-AD stage - Blood test
• Still looking for a blood based predictor of Aβ burden
• Still being studied
Compare the following: • Bapineuzumab • Semagacestat • Solanezumab • Tramiprosate
Bapineuzumab:
• mAb against fibrillar Aβ
Semagacestat:
• Gamma secretase inhibitor
Solanezumab:
• mAb against soluble Aβ
Tramiprosate:
• Oligomerisation inhibitor
