Reduced motor symptoms of Parkinson’s disease

Posted: 3 November 2023 | | No comments yet

In rodent and nonhuman primate animals, circuit-specific gene therapy offers promise for Parkinson’s disease and other brain disorders.

A new gene therapy strategy has been developed by researchers from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS) and their collaborators. The strategy selectively manipulates Parkinson’s disease-affected circuitry and reduces the fundamental motor symptoms of Parkinson’s disease in rodent and nonhuman primate animals.

Parkinson’s disease is characterised by midbrain dopaminergic neurons loss and is one of the most common neurodegenerative diseases in the elderly population, affecting over six million people globally.

Dopamine receptor D1-expressing and D2-expressing medium spiny neurons (D1-MSN and D2-MSN, respectively) constitute 90 percent of neurons in the striatum. Both D1-MSN and D2-MSN receive dopaminergic innervation from the substantia nigra pars compacta (SNc) yet have opposing roles in movement control.

D1-MSNs that project to the globus pallidus internal segment (GPi) and substantia nigra pars reticulata (SNr) constitute the direct pathway and promote movement. Contrastingly, D2-MSNs that project to the globus pallidus external segment (GPe) form the indirect pathway and mediate movement inhibition.

Dopamine depletion in Parkinson’s disease causes hypoactivity of the direct pathway and hyperactivity of the indirect pathway, causing various motor symptoms.

The mainstay therapy for Parkison’s disease is Levodopa (L-Dopa)-based treatment. This helps to restore the dopamine system’s function but unfortunately, almost all patients given long-term L-Dopa treatment suffer from motor complications such as motor fluctuations and dyskinesia. Therefore, efficient, precise, and stable treatments are required.

Since the SNr receives dense projection from the D1-MSNs and no projection from the D2-MSNs, the researchers suggested that D1-MSNs could be selectively labelled by injecting highly efficient retrograde adeno-associated virus (AAV) into the SNr. They then can be exclusively manipulated by introducing neuronal activity-regulating elements in the retrograde AAV.

To achieve these aims, the team created a new AAV capsid, called AAV8R12, for efficient retrograde labelling of the D1-MSN in the striatum as well a new promoter G88P2/3/7 with strong D1-MSN activity. With a chemogenetic effector rM3Ds to match systemic administration of the activation drug, this gene therapy strategy was able to specifically activate D1-MSN and thus drive the D1-MSN-mediated direct pathway.

In primate models with Parkinson’s disease, the typical motor symptoms of bradykinesia, rigidity, and tremor were much improved after the circuit-specific approach targeted D1-MSNs was applied. Bradykinesia, for instance, was significantly reduced, tremor was eliminated, and motor skills were restored.

This new approach manipulates the D1-MSN-mediated direct pathway exactly, unlike the L-Dopa treatment which non-specifically activates the dopamine system in both the brain and peripheral organs.

This circuit-manipulating gene therapy not only has therapeutic effectiveness, but also has faster onset and longer duration than L-Dopa treatment. The alleviation of symptoms after a single drug administration lasts longer than 24 hours compared to a typical six-hour therapeutic window for L-Dopa. Motor complications such as dyskinesia shown after L-Dopa treatment were gone after applying the gene therapy over an extended period, such as over eight months.

Circuit-manipulating gene therapy offers promise for Parkinson’s disease treatment and may precede the development of targeted, circuit-based therapeutic strategies for other brain disorders.

This study was published in Cell.

Leave a Reply

Your email address will not be published. Required fields are marked *