Retrograde AAV selectively targets D1-MSNs and rescues parkinsonian symptoms with chemogenetic modulation. [SIAT]

Using gene therapy to alter circuitry in the brain can improve shaking, stiffness, and other symptoms characteristic of Parkinson’s disease, research in animals shows.

Treatment eliminated tremors, restored motor skills, and greatly reduced slowness in movement among primate models with the debilitating neurological disorder.

The gene therapy manipulates circuits deep in the brain involving medium spiny neurons (MSNs) that express the dopamine receptor D1.

It acted more quickly and typically lasted three times longer than treatment based on the dopamine precursor Levodopa (L-Dopa), which is typically used in patients.

Importantly, extended use over several months did not result in the complications seen with long-term treatment based on L-Dopa, such uncontrolled, involuntary movements.

The findings, in the journal Cell, support the feasibility of targeted, circuit-based therapeutic treatments for other brain disorders.

“Importantly, this strategy does not require genetic modification and thus has the potential for clinical applications in humans,” noted the researchers led by Zhonghua Lu, PhD, from the Chinese Academy of Sciences in Shenzhen.

Parkinson’s disease is one of the most common neurodegenerative diseases seen in the elderly and is characterized by the loss of dopaminergic neurons in the midbrain.

Activity of MSNs expressing D1 (D1-MSNs) is chronically suppressed in patients with the condition. They are the only major cell type of the striatum projecting to the substantia nigra pars reticulata, in a direct pathway that promotes movement.

The Chinese researchers engineered an adeno-associated virus (AAV) as a vector for gene therapy in mouse and macaque models of Parkinson’s disease.

The designer retrograde AAV capsid was designed to infect the axons of selected projection neurons. An MSN-enriched promotor and a chemogenetic effector modulated direct pathway neurons and was designed to alleviate symptoms associated with the disease.

The researchers report that promoter elements had strong D1-MSN activity and the chemogenetic effector enabled precise D1-MSN activation after systemic ligand administration.

A single dose alleviated symptoms for longer than 24 hours in primates compared to a typical six-hour therapeutic window for L-Dopa. In addition, there were none of the motor complications such as dyskinesia that occur after L-Dopa treatment following use of the gene therapy for over eight months.

“Our approach, which specifically modulates one of the major dopamine-dependent circuits in the brain, may help differentiate the roles of distinct dopamine systems in emotion modulation and provide an alternative strategy to alleviate parkinsonian mood symptoms,” the researchers reported.

“Overall, the precision gene therapy approach we developed has the potential to transform the landscape of [Parkinson’s disease] treatment and sheds light on the development of targeted, circuit-based therapeutic strategies for other brain disorders.”

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