Lecture 7- Translational applications Flashcards
drug development phases
phase 1- healthy volunteers, safety and dosage
phase 2- small no. patients, effectiveness, side effects
phase 3- more patients, effectiveness, adverse reactions
phase 4-additional post-marketing testing
biomarkers
can help diagnose pre-symptomatic cases
tau CSF- biomarker
CSF tau- increased (dying neurons release extracellularly)
- higher concentration= greater cognitive impairment in normal-MCI-AD spectrum
- increased CSF tau not specific for AD
- similar increase not seen in pure tauopathies, indicate role of Abeta
CSF Abeta- biomarker
CSF abeta- decreases over time
- Abeta42 aggregated, retained within brain, not released in soluble form into CSF
- low concentrations would match clinical diagnosis of AD
molecular neuroimaging- biomarker
study normal brain function, early disease states, longitudinal studies, treatment response
PET (positron emission tomography)
inject chemical ligand labelled with radio isotope, detects gamma rays
PiB
PET ligand for amyloid; cross BBB, bind to amyloid, detect amyloid
PET signal and braak staging
correlation- Abeta deposition/plaque location progressed
Abeta burden in dementia in AD, HC, MCI
AD- SUVR above cutoff, PiB positive–>Abeta burden
HC- SUVR below cutoff, PiB positive; pre clinical cases?
MCI- PiB positive (non memory MCI), PiB negative (amnestic MCI)
SUVR
standardised uptake value ratio
ApoE4 and PiB signal
higher PiB signal
-higher SUVR score, E4 is a risk factor for AD, greater amyloid deposition
neurogenetic testing
identify gene mutations, must be done with genetic counselling
genetic stratification
very important if you know who to treat, easier during drug trials
Parkinsons disease treating dopaminergic pathway
L-dopa
MAO-B inhibitors
dopamine agonists
anti-cholinergic drugs- interfere with production/uptake of ACh–>reduces tremors and muscle stiffness
cholinergic pathway
project to thalamus
important role in working memory, conscious awareness and attention
AChesterase inhibitors (Aricept)
enhances cholinergic activity (since inhibiting breakdown of ACh)
5 drug targets
alpha secretase activator anti-oxidant neuroprotectants anti inflammatory tau aggregation inhibitor
tramiprosate (homotaurine)
sulfated glycosaminoglycan mimetic
- oligomerisation inhibitor
- maintain Abeta in non-fibrillar form
- reduces Abeta42 induced cell death
- transgenic mice- reduced amyloid plaque and soluble/insoluble Abeta 40/42 levels
- clinical trials- failed to improve cognitive performance
MPACs
metal protein attentuating compounds- targets metals bound to Abeta
- e.g. Clioquinol, PBT2
Abeta, metals and async
Abeta interacts with metals, drive async toxicity
clioquinol
- chelates Zn and Cu, disaggregation of amyloid into smaller pieces of Abeta
- crosses the BBB
- small phase 2 human trial -reduction in amyloid load
PBT2
follow up MPAC to clioquinol
- oxygen and nitrogen groups provide chelating properties
- phase 2a trial- positive outcomes
- global financial crisis- not even funds, trial design wrong
semagacestat (eli lilly)
gamma secretase inhibitor
gamma secretase inhibitor
semagacestat (eli lilly)
- lowered plasma, CSF and brain Abeta in animals
- lower CSF and plasma Abeta in humans
- changed both Abeta40/42 levels
- phase 3 trials- NO slow AD progression, caused worsening of clinical measures of cognition
- side effects- increased incidence of skin cancers, infections
problem with gamma secretase inhibitors
non selective
- cleaver other proteins as well e.g. NOTCH0- important protein
anti-Abeta vaccines for AD
- only seen as theoretical before someone did it
Approach - immunize AD mouse model with Abeta antigen
Result - reduction in amyloid plaques, and Abeta levels
-Abs also crossed BBB
vaccine in active immunisation against AD
AN1792- aggregated Abeta42 peptide antigen
-phase 2a trial- patients immunized
-no significant differences between Ab responder and placebo groups
-trials stopped- meningoencephalitis in 6% patients-T cell activation
- some patients long term followup
-Mean Abeta load 5 years later decreased
-NO evidence for improved survival or improvement in time to severe dementia
Ie- reduced amyloid plaque but no effect on progression of neurodegeneration
3 vaccines for passive immunisation for AD
preformed purified Abs
1- Bapineuzumab
2- Solanezumab
3- Aducanumab
Bapineuzumab
binds both soluble and fibrillary Abeta
- reduced amyloid burden in transgenic mice
- trials not promising results
- phase 3 trials- failed in AD patients with or without ApoE4 allele
Solanezumab
preferentially binds soluble Abeta
- mouse model- reversed memory deficits without affecting brain Abeta load
- phase 2 trials- increased plasma and CSF levels of Abeta40/42- GOOD- plaque load decreasing
- no effect on behavioural outcomes (cognition)
- phase 3 trials- primary endpoints (congitive, functional) NOT met
- secondary analysis - modest slowing in cognitive decline
Aducanumab
binds soluble oligomers and insoluble fibrils
- included PET imaging of amyloid
- phase 1b trial- reduced amyloid levels, slowed down cognitive decline
- but not powered enough to determine effect on cognition
- did bigger trials- no robust change
anti async Ab
Antibody- Syn303
- wire hang test- motor performance
- did better with Syn303
- decreases number of async aggregates
- increases survival of TH positive neurons (dopaminergic)
Syn303
anti asynuclein Ab
Syn506
Ab that recognises misfolded async found in LBs
anti tau Ab
Ab- HJ8.5
- P301S transgenic mice
- increases in plasma tau levels, decrease in phospho-tau (hitting its target)
- improves motor function
3 mechanisms of Ab mediated therapeutics
1- microglial phagocytosis
2- catalytic disaggregation
3- peripheral sink mechanism
microglial phagocytosis
microglial recruitment to opsonised Abeta
- Fc receptor mediated phagocytosis `
catalytic disaggregation
Abs binds to fibrillar Abeta
- solubilisation of Abeta fibrils, neutralise/disaggregate
peripheral sink mechanism
Ab sequestering to circulating Abeta in periphery
-increased efflux from parenchyma to blood system
failure of major clinical trials
- actual mouse models not true representation
- drug target no longer critical for pathogenic/clinical phenotype
- treating subjects too advanced in the disease pathway
