Gene Therapy for Parkinson Disease


Parkinson disease (PD) presents several features including the relative selective localisation of pathology to the substantia nigra and well‐defined motor symptoms caused by dopaminergic degeneration that make it an ideal target for gene therapy. Parallel progress in viral vector systems has made it possible to deliver therapeutic genes directly into the brain with reasonable safety. To date, gene therapy for PD is mainly based on symptomatic approaches that involve enzyme‐replacement strategies to restore dopamine (DA) levels or correct the functional perturbation of the basal ganglia caused by DA loss and disease‐modifying approaches that depend on delivery of neurotrophic factors and alteration of genetic causes of PD to protect neuronal functions and slow down or even halt disease progression. As supported by the increasing preclinical and clinical evidence, gene therapy may be a promising treatment to relieve the disabling nature of PD.

Key Concepts:

  • Gene therapy for PD focusses on symptomatic approach that involves enzyme‐replacement strategy and disease‐modifying approach that depends on addition of neurotrophic factors.

  • Intrastriatal expression of genes TH, AADC and GCH, the three key enzymes for DA biosynthesis, can compensate for the decreased levels of DA in PD patients.

  • An approach aiming at modulating STN activity is done by delivering gene GAD, the rate‐limiting enzyme for GABA synthesis.

  • Neurotrophic factors including GDNF and NTN have potent trophic activity on dopaminergic neurons and play essential roles in the protection and restoration of neuronal cells.

  • Novel viral vectors are capable of delivering genetic materials to target cells and inducing sustained transgene expression.

  • Four candidates for PD gene therapy including EIAV‐AADC‐TH‐GCH, AAV2‐AADC, AAV2‐GAD and AAV2‐NTN are currently under clinical trial evaluation.

Keywords: gene therapy; Parkinson disease; viral vector; aromatic l‐amino acid decarboxylase; glial cell line‐derived neurotrophic factor; glutamic acid decarboxylase; neurturin; alpha synuclein; parkin

Figure 1.

An overview of changes in basal ganglia function in PD patients (a) before and (b) after gene therapies. In PD state, loss of DA in the striatum results in diminished inhibitory tone in STN. STN becomes hyperactive and leads to excessive stimulation of GPi/SNpr and consequent inhibition of the thalamus causing the reduction in cortical outflow. Gene therapies that involve prevention of dopaminergic neurodegeneration, restoration of DA level in the striatum and provision of GABA in GPi/SNpr are believed to restore normal thalamic tone. Modified from Muramatsu . © Annals of Neurosciences.

Figure 2.

Current progress of gene therapy for PD.



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Further Reading

Coune PG , Schneider BL and Aebischer P (2012) Parkinson's disease: gene therapies. Cold Spring Harbor Perspectives in Medicine 2(4): a009431.

Kordower JH and Bjorklund A (2013) Trophic factor gene therapy for Parkinson's disease. Movement Disorders 28(1): 96–109.

Nakata Y , Yasuda T and Mochizuki H (2012) Recent progress in gene therapy for Parkinson's disease. Current Molecular Medicine 12(10): 1311–1318.

Yasuda T and Mochizuki H (2010) Use of growth factors for the treatment of Parkinson's disease. Expert Review of Neurotherapeutics 10(6): 915–924.

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Choong, Chi‐Jing, and Mochizuki, Hideki(Nov 2013) Gene Therapy for Parkinson Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025023]