Gene therapy reduces dyskinesia in Parkinson's mouse models

An experimental gene therapy that targets a difficult-to-treat side effect of Parkinson's disease medication has shown promise in preclinical research.

Dyskinesia, a term used to describe uncontrollable and involuntary muscle movements, is a common side effect of long-term use of levodopa, a dopamine replacement drug widely prescribed for people with Parkinson's disease. In a study published in Neuron, researchers significantly reduced and, in some cases, reversed dyskinesia-like symptoms in a mouse model using a targeted gene therapy approach.

'Nearly 80 percent of Parkinson's disease patients will develop dyskinesia. At present, we have a very limited set of tools to help these patients right now. This work points to the possibility of a non-invasive gene therapy that would be transformative,' said Professor D James Surmeier, a neuroscientist and physiologist at Northwestern Feinberg School of Medicine, Chicago, Illinois, and senior author on the paper.

After repeatedly treating mice with levodopa, the researchers found increased signalling through GluN2A-containing NMDA receptors in a subset of neurons known as indirect pathway spiny projection neurons (iSPNs), which help regulate movement. The findings suggest that this abnormal glutamatergic signalling plays a key role in the development of levodopa-induced dyskinesia.

Building on these findings, the team used a targeted gene therapy approach to reduce GluN2A expression specifically in iSPNs. Following treatment, the mice showed a significant reduction in dyskinesia-like behaviours, with some animals showing reversal of established symptoms. The treatment did not appear to reduce the beneficial effects of levodopa.

'What was very exciting was that – in contrast to almost everything else that has been tried in the last 30 years – knocking down this one NMDA receptor subunit in this particular group of cells reversed established dyskinesia,' Professor Surmeier added.

Although the findings are promising, this remains early-stage, proof-of-concept research in animal models. The experimental therapy is aimed at treating a common side effect of Parkinson's medication rather than slowing or stopping the progression of Parkinson's disease itself, and further studies will be needed to establish its safety and effectiveness in humans.