Gene therapy for Parkinson’s disease: a way forward?

By Elisa Botting

Parkinson’s disease is a neurodegenerative disorder with no current cure. The disease results in the loss of neurons responsible for the release of dopamine (termed dopaminergic neurons) in the substantia nigra – a region of the brain’s basal ganglia which is important for movement¹ . Its progressive nature means that symptoms like a tremor and muscular rigidity worsen as the patient ages¹. The production of reactive oxygen species when dopamine is oxidised is believed to be the cause of the neuron cell apoptosis that presents as Parkinson’s disease². This sequential process which leads to cell apoptosis presents exciting opportunities for using gene therapy to treat Parkinson’s disease.

Today, gene therapeutic approaches are largely divided into two categories, namely, therapies that are delivered via local administration and systemic administration³. The former has been the preferred choice of clinicians in treating Parkinson’s disease³. This is because the brain contains a protective layer, known as the brain blood barrier, which makes the use of systemic delivery particularly challenging⁴. Whilst some systemic gene therapeutic deliveries using AAV-9 as their vector have been shown to cross the blood barrier to an extent, their transduction patterns do not target structures affected by Parkinson’s disease, thus rendering such delivery methods ineffective for treating this particular disease⁴. So, where does this leave gene therapy for Parkinson’s disease?

There are two main considerations for gene therapy approaches in treating Parkinson’s disease: ensuring that the gene therapy transduction patterns are targeting the substantia nigra nerve cells that are lost due to Parkinson’s, and that the brain blood barrier is by- passed. To address both these considerations, clinicians have suggested three types of gene therapy using local administration delivery methods.

The first of these is the use of a lentivirus with enhanced retrograde characteristics as a vector³. The vector has the ability to alter the envelope of the recombinant virus and thus carry a signal to the neurons³. The promising results of this therapy in animal tests later led to human phase I/II trials of lentiviral vector gene therapy being conducted⁵. This technique, in combination with introducing genes that encode dopamine producing enzymes (such as tyrosine hydroxylase, GTP- cyclohydrolase-1 and aromatic amino acid decarboxylase) into the basal ganglia, has the ability to provide symptomatic relief for Parkinson’s patients⁵.

The second type of gene therapy focuses on the GABAergic pathway that is disrupted in individuals with Parkinson’s due to damage inflicted to the substantia nigra³. This disruption is caused by the increase in activity of the subthalamic nucleus – a part of the brain that is involved in the basal ganglia and pallidus, which play a crucial role in movement and coordination⁵. To treat this, clinicians can increase the levels of the GABA protein to prevent the interruption of the pathway⁵. Like the previously explored type of gene therapy, this also aids in the alleviation of symptoms for patients.

The third type of gene therapy has the potential to both relieve the symptoms of Parkinson’s and target the disease progression itself. This therapy uses direct injections into the region of the brain affected by Parkinson’s, with the aim of reaching the affected nerve cells. This is achieved through the medium of neurotrophic factors like GDNF, BDNF and neuturin, which prevent the death of substantia nigra nerve cells – and thus preventing progression of Parkinson’s disease⁵. These protein factors reach the nerve cells by causing a transduction in the putamen – the structure which makes up one of the nuclei of the basal ganglia (where the nerve cells are located) and is responsible for body movements⁵.

Whilst this article has explored three types of gene therapy, to date only the lentivirus and AAV-2 method of gene therapy have been used as potential vectors in gene therapy for treating Parkinson’s disease³. Nevertheless, the involvement of gene therapy in treating this disease is not restricted to these methods or the techniques explored in this article. It has been suggested that certain techniques could be used to correct the entire imbalance in the basal ganglia circuitry or to even restore dopaminergic neurons killed off by the disease – illustrating the great potential of gene therapy in treating human diseases and improving life quality for patients⁵.


  1. NHS. Parkinson’s disease. Available from: [Accessed Oct 29, 2021].
  2. Naoi, M. & Maruyama, W. Cell death of dopamine neurons in aging and Parkinson’s disease. Mechanisms of Ageing and Development. 1999111 (2-3), 175-188. Available from: doi: 10.1016/s0047-6374(99)00064-0.
  3. Blits, B. & Petry, H. Perspective on the Road toward Gene Therapy for Parkinson’s Disease. Frontiers in Neuroanatomy. 2017Available from: doi: 10.3389/fnana.2016.00128
  4. Foust K, Nurre E, Montgomery C, Hernandez A, Chan C, Kaspar B. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2009. 27(1):59-65. Available from: doi: 10.1038/nbt.1515
  5. Denyer, R. & Douglas, M. R. Gene Therapy for Parkinson’s Disease. Parkinson’s Disease. 2012 Available from: doi: 10.1155/2012/757305.

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