Developing the Next Generation of Parkinson’s Disease Therapies
Posted in Special Feature on 13th Mar 2013
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder associated primarily with the death of the dopaminergic neurones in the substantia nigra. All of the treatments currently available for the treatment of PD address the primary motor symptoms. In addition, the management of non-motor symptoms requires a multi-drug therapeutic approach. However, none of the therapies currently available influence the progression of the condition and some can have significant deleterious side effects.
In the longer term, strategies need to be developed that will actually target the disease itself rather than the symptoms – agents that will slow down or halt the progression of the neurodegenerative process or even the development of a pre-symptomatic preventative strategy. If disease-modifying treatment is provided at a sufficiently early stage prior to the onset of the primary motor symptoms, this could essentially be considered as being a cure.
This review will outline some of the potential strategies that may target the neurodegenerative process and target the disease rather than the symptom.
Genetic studies to identify drug targets
If clinically effective disease modifying strategies are to be developed, a detailed understanding of the cellular and molecular basis of the neurodegenerative process is required.
Genome-wide association studies (GWAS), in addition to the identification of specific family cohorts, have allowed us to identify genes that are associated with PD.1 This has led to the identification of a number of potential drug targets. Due to its potential as a genetic risk factor for the development of PD (1-3% of sporadic cases), the LRRK2 gene has been studied extensively.2 While the exact protein function remains unknown, it is likely to be a serine/threonine kinase and may play a role in neurite outgrowth, protein translation and vesicular storage and mobilisation. The majority of LRRK2 mutations are associated with an increased kinase activity. Therefore, enzyme inhibitors may provide a potential therapeutic target.2 Studies of other genes associated with inherited forms of PD suggest that mitochondrial dysfunction and abnormal protein processing are also associated with PD.3 A greater understanding of the roles of the biochemical pathways associated with PD-associated gene mutations will help in the identification of targets that will form the basis of the next generation of disease-modifying therapeutic agents.
Alpha synuclein (α-Syn) is the primary component of Lewy bodies which are the pathological hallmarks of the disease. Additionally, the gene has been identified in GWAS studies as being associated with inherited forms of PD.1 The protein is present in Lewy bodies as an insoluble misfolded form of the protein and this is probably due to a dysregulation of the lysosomal and proteosomal protein processing pathways within the cell. There is an increasing body of evidence to suggest that the misfolded form of α-Syn, which is the basis of Lewy body pathology, can then spread between cells from affected to unaffected regions of the brain. Post mortem studies of foetal tissue grafted into the brain of a PD patient identified Lewy body-like lesions in the transplanted tissue although, due to the age of the tissue in the graft, this is unlikely to have occurred spontaneously.4 Furthermore, a single intracerebral inoculation of misfolded α-Syn into the brains of animal models has been reported to induce neurodegeneration. This is accelerated in transgenic mice over-expressing α-Syn.
Collectively, these findings support the hypothesis that α-Syn can exist as a prion-like protein that can adopt a self-propagating conformation that contributes towards the neurodegenerative process.5 This is likely to play an important role in the development of PD and agents that could prevent protein misfolding, aggregation or transmission may form the basis of future neuroprotective therapies.6
Another therapeutic target that may be influenced by PD-associated gene mutations is the mammalian target of rapamycin (mTOR). This protein serine/threonine kinase plays a role in cellular differentiation, development, regeneration and repair.7 The blockade of mTOR activity in cell culture models during oxidative stress can lead to dopaminergic neuronal cell death as a result of autophagy activation. It also plays a role in many aspects of homeostasis that are critical for cellular health. Recent studies have also reported that rapamycin can rescue cellular mitochondrial dysfunction associated with certain PD genes.8 However, mTOR activation as a therapeutic target may require a fine level of modulation because other studies suggest that inactivation of mTOR and an increase in autophagy may actually preserve dopaminergic neurons in PD, possibly through an α-Syn associated pathway.
The repurposing of existing drugs to treat PD
The development of new drugs is a lengthy and costly process, so there has been an increasing interest in the repurposing of existing drugs.9 These agents are already in use in humans so could go straight into phase II trials to assess their clinical effectiveness and particularly their potential to modify the rate of disease progression.
One class of drugs that has gained considerable interest for the treatment of PD is the GLP-1 antagonist class which is used to treat diabetes. Indeed, based on epidemiological studies, patients with diabetes mellitus have been reported to have a 36% increased risk of developing PD.10 Initial studies in animal models have suggested that one of these drugs, exenatide, may have neuroprotective properties.11 Furthermore, the thiazolidinedione class of anti-diabetic drugs have been reported to have a neuroprotective effect in PD and it has been proposed that this is achieved at least in part through anti-inflammatory and anti-oxidant activities. However, the thiazolidinediones have been reported to demonstrate the adverse cardiovascular effects in a small number of subjects.
Calcium channel blockers have been proposed as a suitable class of drugs due to their potential neuroprotective properties. Based on studies on the tolerability of the drug for people with PD,12 a phase II study of isradipine is currently underway. Other drugs that may be suitable for repurposing based on preclinical studies include statins13, iron chelating agents14 and cannabinoids.15
In order to rigorously assess the potential effectiveness of new drugs to influence the progression of PD, reliable animal models that mimic the key components of the condition such as cell death and the development of PD pathology are essential. While the current gold standard models are based on the degeneration of dopaminergic neurons following the administration of the toxins MPTP or 6-OHDA, these toxins act acutely with the rapid and irreversible death of dopaminergic neurons at the site of toxin injection. They are useful for assessing symptomatic drugs but have limited use in screening neuro-restorative therapies. Even when administered slowly and at low doses, they neither replicate the pathology nor the changes in other neurotransmitter systems that are observed in the latter stages of the disease.
The next generation of models that can be used to assess disease-modifying therapies are therefore being developed based on an understanding of the genetics of the condition in addition to the environmental factors that have been associated with the onset of PD such as pesticides.16 While none of these models recapitulate exactly all of the behavioural and pathological changes that are characteristic of PD, when combined they may provide us with a useful library with which to assess potential new therapeutic compounds which could influence the development and progression of the disease.17 An illustration of the complexity of disease modelling is the role of LRRK2 mutations in the generation of animal models. Transgenic mice constitutively expressing an LRRK2 mutation do not show any specific degeneration of dopaminergic neurons, although there is an impairment of dopamine release with parallel behavioural problems. However, transient expression of a mutant form of the gene using specific viral vectors induces degeneration of dopaminergic neurons. Furthermore, neuronal degeneration has been observed in C. elegans and Drosophila which constitutively express the mutant gene.2 The reason for this remains obscure although the role of gene dosage and duration of expression may play a key role.
While initial clinical studies on the glial-derived neurotrophic factor (GDNF) in humans demonstrated clinical efficacy, there was a lack of neuroprotective effect against the toxicity of human wild-type α-Syn in an animal model of PD.18 Again, this highlights the potential differences between animal models and the clinical setting and the importance of using a number of animal model systems in the early stages of drug screening.
Ultimately, the use of animal models to screen prospective drug compounds should be fit for purpose and recapitulate the events that occur in humans corresponding to the time at which the drugs are prescribed in the clinic.19
Biomarkers and clinical trials
If drugs that act to influence the course of PD progression are to be effective, a reliable and early diagnosis is required, ideally in the pre-motor stage of the disease. A number of early symptoms have been identified including the loss of olfaction, REM sleep behavioural disorder and constipation. However, the development of a specific and sensitive blood biomarker is the ultimate goal if the rate of disease progression is to be monitored accurately.20
Most importantly, if potential disease modifying agents are to be confirmed as being clinically effective, the drug trial should be designed appropriately. This includes specific patient inclusion and exclusion criteria and it is important that negative trial results should not be associated with bad clinical trial design. Furthermore, care must be taken to assess appropriate outcome measures. Not all clinical rating scales represent a meaningful change for the trial participants.
Finally, it is vital to be able to distinguish between true disease modification and a symptomatic effect of the therapy. A long-lasting placebo effect can be common in PD and most treatments that have been shown to exhibit potential disease modifying properties are also likely to exhibit pro-dopaminergic symptomatic effects. This underlines the fact that an objective and reproducible biomarker is ultimately required to assess the disease state and whether this is being modified by the therapy.
This is an exciting time for the development of the next generation of PD drugs which will target the disease rather than the symptoms. However, we must ensure that all of the studies are carried out using the most appropriate models and effective clinical outcome parameters. It is only then that we can say that we are really moving closer towards our ultimate goal – a cure for PD.
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