Current pharmacological and surgical treatments for Parkinson's disease offer symptomatic improvements to those suffering from this incurable degenerative neurological disorder, but none of these has convincingly shown effects on disease progression. Novel approaches based on gene therapy have several potential advantages over conventional treatment modalities. These could be used to provide more consistent dopamine supplementation, potentially providing superior symptomatic relief with fewer side effects. More radically, gene therapy could be used to correct the imbalances in basal ganglia circuitry associated with the symptoms of Parkinson's disease, or to preserve or restore dopaminergic neurons lost during the disease process itself. The latter neuroprotective approach is the most exciting, as it could theoretically be disease modifying rather than simply symptom alleviating. Gene therapy agents using these approaches are currently making the transition from the laboratory to the bedside. This paper summarises the theoretical approaches to gene therapy for Parkinson's disease and the findings of clinical trials in this rapidly changing field. 1. Introduction Parkinson’s disease (PD) is a common neurodegenerative disorder that will assume increasing clinical importance in an ageing society, with an average age of onset between 60 and 65 years, but a peak incidence is found between the ages of 70 and 79 years. The specific incidence is dependent on the age structure of the population studied and is difficult to assess precisely but is around 17 per 100,000 according to a systematic review in this area [1]. PD is classically characterised by the loss of striatal dopaminergic neurons within the basal ganglia; however, the underlying pathophysiology is very complex. Both excitatory glutamatergic and inhibitory γ-aminobutyric acid pathways (GABA) involved in basal ganglia regulation of movement are affected [2]. These changes lead to disinhibition of subthalamic nucleus (STN) output, which in turn increases the activity of excitatory projections to the internal globus pallidus (GPi) and substantia nigra pars reticularis (SNpr). The net result is increased inhibitory outflow from the GPi and SNpr to other basal ganglia nuclei, thalamus, and cortex, leading to the typical motor features of PD [3]. Various therapeutic approaches that target the STN or GPi have been used to improve motor function in PD, including stereotactic lesioning [4, 5], high frequency deep brain stimulation [6, 7] and pharmacological silencing [8]. Dopamine replacement therapies, such
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