Disease modification in PD Flashcards
Define disease modifying strategy
Disease modifying strategies alter the progression of the disease. This could be through:
‘Neuroprotection’ – intervention that affects the pathogenesis of the disease to preserve neurones or slow down / halt ongoing degeneration.
‘Neurorepair’ – provide cell replacement, regeneration or repair.
What are the main challenges (6) to developing a disease modifying strategy within parkinson’s disease.
Besides Parkinson’s being a multifaceted complex neurodegenerative disorder with both dopaminergic and non-dopaminergic features there is:
- Poorly understood mechanisms of pathogenesis
- A lack of reliable animal models
- A lack of biomarkers
- The progressive nature
- Target engagement
- Confounding effects of potent symptomatic treatment
Why would a disease modifying therapy be useful in PD?
Current therapies are dopaminergic enhancements, which is initally effective in treating dopaminergic symptoms. However, there are several limitations:
- Neurodegenaration continues to progress, and these treatments can only potentiate existing dopaminergic activity.
- L-DOPA has serious motor side-effects that emerge with increased dosages required over time due to progressive neurodegenaration
- Non-dopaminergic motor and nonmotor features emerge or worsen and dominate the late stages of the illness
Slowing the degenaration or promoting repair mechanisms may therefore prolong L-DOPA free years, reduce the dose and prolong the amount of time that it is effective for.
Key mechanisms in Parkinson’s pathogenesis
- Neuroinflammation. Activated microglia release inflammatory cytokines.
- NMDA receptor mediated excitotoxicity. Leading to increases in intracellular calcium and excitotoxic pathways leading to neuroa dysfunction and cell death
- Altered Ca++ homeostasis. Cav1.3 becomes upregulated
- Michondrial dysfunction. Caused by JNK pathway activation, high Ca++. Leads to reduced ATP, OS and cytochrome C release activating capsases - all converge onto cell death.
- Loss of neurotrophic support. GDNF receptor becomes blocked due to alpha synuclein, which reduces the expression of RET, which is the tyrosine kinase mediating GDNF signalling. Reduced activation of pro-survival pathways.This would normally activate pro-survival pathways
- alpha synuclein misfolding. Accumulation into toxic oligomers and prion-like transmission.
- Increased leucine-rich repeat kinase 2 activity. Causes neuronal dsyfunction and cell death.
Selegiline for P.D.
Selegiline is an irreversible MAO-B inhibitor.
It appears to be disease modifying, slowing down the progression of PD. Two clinical trials show selegiline extends time period until L-DOPA is required. It’s proposed mechanisms are:
- Enhancing striatal dopamine by reducing its breakdown.
- Reducing oxidative stress (DA metabolism produces ROS).
- Anti-apoptotic effects.
However, studies have not been able to verify the extend to which selegiline is disease modifying, as it may also have symtomatic benefits. It has a long wash out period, and results have been inconclusive (e.g., unified parksinson’s disease rating scale was improved at 48wk but not 60wk)
Another drug which has the same anti-apoptotic moiety has selegeline without the MAO-B inhibition has been shown to be ineffective, but this may be due to dosing issues. However, it could indicate the selegeline acts through dopaminergic enhancement.
Vitamin E for P.D
Vitamin E is a powerful lipid-soluble antioxidant. It failed clinical trials whose primary measure was reduced need for symptomatic treatment.
Define biomarker
An obectively measured characteristic relating to an underlying biological process, which may be related to pathogenesis in a disease
Mitochondrial enhancers
Despite the role of oxidative stress and mitochondrial dysfunction in PD, mitochondrial enhancers have not yet shown clinical efficacy.
Mitochondrial dysfunction and oxidative stress are implicated in Parkinson’s Disease, with familial mutations parkin and PINK-1 both being linked to mitochondrial abnormalities, and sporadic PD patients showing reduce complex I activity in the SNc.
- *Co-Q10** is an electron carrier for complex I-II and a free radical scavenger. It failed clinical trials due to efficacy, despite showing significant reduction of deterioration in earlier studies.
- *Mitoquinone** is a powerful antioxidant. It failed to slow progression over a 12 month period.
- *Creatine** acts a short term energy source for tissues with high energy requirement (i.e., the brain). It showed neuroprotective features in animal and cellular models of PD. However, it showed futility in a blind placebo-controlled composite endpoint clinical trial of duration 5-7yrs.
Translational issues in PD: Animal models.
Many preclinical studies rely on toxin animal models of PD (6-OHDA mouse model and MPTP primate model). Both of these models show rapid irreversible degeneration of dopaminergic nigral neurons leading to Parkinsonism. There are two limitations:
- PD is a gradual progressive disease that develops over decades
- PD does not only consist of dopaminergic features.
Two approaches that may show benefit in the future are transgenic models based on a-synuclein, parkin and LRRK2 mutations and induction of cell-cell transmission of a-synuclein through inoculation with fibrils.
No animal model mimicks all features of PD pathogenesis, and selection of the most clinically relevant models should form a key step in experimental design to enhance translation between preclinical and clinical trials
Translational issues in PD: Clinical trials
Clinical trials for neuroprotective drugs must determine whether the effect is symptomatic or disease altering.
Washout period. If a drug is neuroprotective, then there will be a difference between the placebo group and the drug group after the washout period even if the drug also shows some symptomatic benefit, due to the slower progression of the disease in the drug group. However, drugs like Selegeline (irreversible) can have a washout period of months. Washout periods could pose ethical dilemmas as patients may not be able to take any treatment during this long phase.
Delayed start. Placing some patients on the drug therapy several months before others could be used to assess neuroprotective effects. if the effects are only symptomatic, then the drug group and control group would be the same at the end, as no disease modification has occcured. However, delayed starts may contain higher droupouts, especially for those in placebo group.
Primary end points. The relevance of the primary end point should be considered. Parkinson’s consists of dopaminergic and non-dopaminergic and motor or non-motor features. The end-point should be carefully considered against the drug mechanisms. For example, the UPDRS is weighted towards motor dysfunction, particularly tremor - and could therefore miss several other disease features that the drug is improving.
Assessing neuroprotection in PD clinical trials
This can (and should be done) through clinical measures such as the UPDRS, however biomarkers are a potential technique through which neuroprotection could be distinguished from symptomatic relief - and could be used alongside other clinical measures to validate results.
CSF markers for a-synuclein along with 6 others has been used to separate PD from controls and other diseases such as AD, and shown to correlate with disease progression.
Biomarkers could also be used to measure the amount of drug reaching the relevant brain areas - as plasma levels are not necessarily reflective. Some failed clinical trials coud be attributed to incorrect dosages, as the drug has a narrow effective range and not enough of the compound reaches the brain.
PET and SPECT as PD biomarkers
These have been used by default to measure dopaminergic cell count. However, there are a number of limitations and concerns:
- The radioactive tracers might be affected by the pharmacological interventions, causing changes to not be reflective of changes in dopaminergic cell count.
- Some features of advanced PD do not have a major dopaminergic basis.
- They are not yet validated as measures of neuroprotection as their correlation with neuropathology and clinical symptoms has not been clearly defined.
Consideration with using biomarkers
Biomarkers may not necessarily be well associated with the desired clinical end point and therefore using them as a surrogate end point may throw up false negatives/positives.
For example, the drug could affect the biomarker but not the disease - or it could affect the disease and not the biomarker, or it may alter another imporant disease process not associated with that biomarker.
Novel targets for neuroprotection in PD under current investigation?
- adenosine system
- inflammatory pathways
- calcium channels
- a-synuclein aggregation
- LRRK2 kinase activity
Futher studies into antioxidants and trophic factors are continuing.
Failed neuroprotective strategies in PD.
Mitoprotective/Bioenergetic enhancers. Co-Q10, mitoquinone, creatine
Anti-apoptotic. TCH346 has the same moeity as MAO-Bi that is hypothesised to be anti-apoptotic but has no MAO-B inhibition. it was ineffective but this could be due to narrow dose range.
Trophic factors. So far these have failed (5 including GDNF) but continue to be investigated.
Antioxidants. Vitamin E failed but several others are in ongoing investigation.
Glutamate antagonists. Riluzole.
