A Pilot Clinical Trial With the Iron Chelator Deferiprone in Parkinson's Disease

BACKGROUND Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects approximately 2% of the population aged over 60 years. The common clinical motor control features are tremor, bradykinesia, postural abnormality and rigidity. However, in many patients non-motor features such as cognitive decline, depression, autonomic disturbances also occur as the disease progresses. The principal pathology is the degeneration of the nigrostriatal dopaminergic system which plays a major role in movement control through the release of dopamine in the striatum. Current therapeutic approach focus on dopamine replacement strategies either through the dopamine precursor L-DOPA or the use of dopamine agonists, and/or the use of monoamine oxidase inhibitors or catecholamine transferase inhibitors which prevent the breakdown of dopamine or facilitate L-DOPA entry into the brain. However, such therapeutic approaches are associated with declining efficacy and long term complications e.g. dyskinesias. Additionally, such therapeutic approaches only treat the clinical symptoms of PD and due not protect the neurons against degeneration hence the disease continues to progress with the patient experiencing increasing disability. Hence there is a chronic need for the development of neuroprotective drugs which prevent further neuronal loss and thus prevent the progression of the disease.

RATIONALE FOR CURRENT STUDY Hypothesis: Increased iron and oxidative stress play a major role in the neurodegenerative process in PD and iron chelation therapy can be effective in removing excess iron from the brain and potentially slowing the neurodegenerative process.

Research question: Can iron chelation therapy with Deferiprone remove excess iron in the substantia nigra in PD patients without toxic side effects. What effect does Deferiprone therapy have on the severity of PD and other brain function e.g. cognition, depression etc.

Increased iron levels have been heavily implicated in the neurodegenerative process in PD. Although many of our cellular processes require iron, when in excessive amounts it can trigger the formation of toxic chemicals called free radicals, of which there is extensive evidence of their increased formation in the PD brain. Hence removal of excess iron by iron chelation (drugs which bind and detoxify iron) represents a potential drug target.

Iron chelators e.g. Deferiprone in doses around 100mg/kg/day, are extensively utilised to treat peripheral iron overload disorders such as beta thalassaemia, where the patients requires regular blood transfusions but iron accumulates in the body when the red blood cells are removed from the circulation. Iron chelation therapy in such patients is associated with minimal side effects with long term use. Recently, in animal models of brain iron overload, we have demonstrated iron chelators can enter the brain removing excess iron. Additionally, we have recently shown that iron chelation therapy protects neurons against toxins in animal models of PD.

In 2007 20 or 30mg/kg/day Deferiprone was used in a pilot clinical trial in Friedreich ataxia (FA)patients, to assess whether the drug was well tolerated, removed excess brain iron and improved the clinical symptoms of FA. FA occurs due to a gene defect leading iron accumulation in the mitochondria in the cerebellum, toxicity of which leads to ataxia or inability to control muscle movements. FA is diagnosed in young individuals (14-26 years of age) and has no clinical treatment. In this 6 months FA study Deferiprone at 20 or 30mg/kg/day was well tolerated by the patients and resulted in a reduction in brain iron, as indicated by MRI brain imaging, and led to a clinical improvement in patient symptoms. Whilst this represents the first clinical use of an iron chelator to treat a neurodegenerative disorder, the FA patients in this study were young (14-23 years old) hence we do not know how aged (average age 60years) individuals commonly affected by PD will respond to iron chelator treatment. Hence the first aim of this study is to conduct the first pilot clinical trial with an iron chelator in newly diagnosed PD patients to assess tolerability along with its ability to reduce iron content in the brain area affected in PD, the substantia nigra, as assessed by MRI.

A number of clinical trials have already been conducted in PD with potential neuroprotective drugs but their ability to slow the disease process has been controversial since these drugs have a direct effects on the symptoms of PD itself. Hence it is difficult to say whether the beneficial effects of the drugs are due the prevention of further neuronal loss thus slowing the disease or whether they improve the patient's ability to move directly. PD progresses in most patients fairly slowly, hence we don't expect to see detectable neuroprotection following 6 months Deferiprone treatment but it will allow us to assess whether Deferiprone therapy has any direct effects on PD symptoms. Hence the second aim of this study will be to examine whether iron chelation therapy has a direct effect on PD symptomology.

If this pilot study clearly demonstrates good tolerability of Deferiprone in PD patients whilst showing good removal of excess SN iron level yet having minimal direct effect on PD symptomology this data will form the basis of large funding application for a multicentre clinical trials to investigate whether long term Deferiprone treatment can slow/halt the progression of PD.