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J Neurol (2011) 258:179–188 DOI 10.1007/s00415-010-5796-9


Gene therapy: a viable therapeutic strategy for Parkinson’s disease?
Alexander L. Berry • Thomas Foltynie

Received: 21 July 2010 / Revised: 21 September 2010 / Accepted: 7 October 2010 / Published online: 21 October 2010 Ó Springer-Verlag 2010

Abstract Gene therapy represents a potentially useful additional technique toameliorate the motor symptoms of Parkinson’s disease (PD), and the motor complications of its treatment. The neurodegenerative process itself, as well as the non-motor symptoms of PD, both remain less amenable to most of the current gene therapy approaches. This review presents an overview of the four gene therapies in phase I/II clinical trials, outlines some of the challenges they face, andproposes additional alternative strategies that might improve the clinical prospects of gene therapy for PD. In so doing, we hope to highlight the issue of the current absence of effective treatment for non-motor symptoms of PD and the potential of further candidate targets for gene therapy intervention that might improve upon this, for both specific individuals with genetic forms of PD as well as‘‘sporadic’’ PD patients. Keywords Parkinson’s disease Á Gene therapy Á Basal ganglia Á Non-motor

Introduction Effective treatment of the motor symptoms of Parkinson’s disease (PD) involves compensating the striatum and output nuclei of the basal ganglia for the loss of the degenerating nigrostriatal dopaminergic input. Compensatory
A. L. Berry Department of Molecular Neuroscience, UCL Institute ofNeurology, Queen Square, London WC1N 3BG, UK T. Foltynie (&) Sobell Department of Motor Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK e-mail:

strategies can be initially achieved with oral medications (dopamine receptor agonists and/or levodopa) that can maintain functional independence in most patients for the first years after diagnosis.Despite the proven efficacy of the dopamine precursor levodopa, the combination of longterm L-dopa treatment together with advancing neurodegeneration almost invariably results in the development of ‘‘ON/OFF fluctuations’’ in motor disability and L-dopa induced dyskinesia [1, 2]. In later PD, oral medications may be supplemented by drug delivery via alternative routes (e.g. transdermal patches,subcutaneous injections, or intra-jejunal gels) or by continuous electrical stimulation of basal ganglia structures (DBS). These strategies do not influence the underlying neurodegenerative process and therefore have a limited duration of effectiveness and have limited effects on the non-motor symptoms (NMS) of PD (see Table 1). Superior innovative treatments for these aspects of PD are even morepressing than the need to develop novel motor therapies. In this review, we discuss how the technology of gene therapy has been, or is currently being evaluated in trials of PD patients as well as discussing the current challenges for existing approaches, and future possible alternative gene therapy options for PD (see Table 2).

Major gene therapy programs in PD Substantial improvements in genetherapy technology (development of viral vectors with high transduction efficiency and little or no risks of mutagenesis, toxicity, expression of viral proteins, or provocation of immune response) have precipitated gene therapy research programs in multiple diseases, including PD. Targeting specific neuronal circuitry in PD patients offers an important


180 Table 1 Common PD nonmotor symptomsand their responses to dopamine therapy

J Neurol (2011) 258:179–188

Symptom Neuropsychiatric symptoms Depression, apathy, anxiety Anhedonia Hallucinations Dementia Sleep disorders Restless legs REM behavior disorder/REM loss of atonia Non-REM sleep disorder Somnolence Vivid dreaming Insomnia Autonomic symptoms Urinary urgency Urinary frequency Nocturia Orthostatic hypotension Sexual...
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