Parkinson's disease is the fastest-growing neurodegenerative disease in the world and affects more than 10 million people. It is characterized by the progressive loss of dopamine-producing neurons, which leads to both motor and non-motor symptoms.

While several therapies are available to help manage symptoms, Parkinson's disease remains a significant unmet medical need. No approved treatment has been shown to stop or slow the underlying neurodegenerative processes that drive disease progression.

At this year's AD/PD conference in Copenhagen, Neumirna's Director of Preclinical Development, Lluís Riera-Ponsati, presented new scientific data from Neumirna's Parkinson's disease program, highlighting the therapeutic potential of targeting microRNA 27b.

Targeting a regulator of multiple disease pathways
‍Parkinson's disease is not driven by a single biological mechanism. The accumulation of α-synuclein, mitochondrial dysfunction, oxidative stress, and neuroinflammation are all believed to contribute to the progressive loss of dopaminergic neurons that characterizes the disease.

Neumirna's Parkinson's disease program focuses on miR-27b, a microRNA that is upregulated early in the disease and modulates several of these disease-related pathways. MicroRNAs are small, non-coding RNA molecules that regulate networks of genes and biological pathways. By selectively inhibiting miR-27b with an antisense oligonucleotide (ASO), Neumirna’s approach aims to influence multiple disease-relevant processes simultaneously.

This multimodal strategy may be particularly relevant in a disease as complex as Parkinson's, where several pathological processes contribute to neuronal dysfunction and degeneration.

The data presented at AD/PD show that inhibition of miR-27b was associated with effects across several hallmarks of Parkinson's disease pathology in a preclinical model, including sustained target engagement, reduced α-synuclein accumulation, preservation of the nigrostriatal pathway and attenuated neuroinflammatory responses.

The study evaluated a single administration of antimiR-27b, with effects assessed eight weeks later. Researchers observed evidence of miR-27b inhibition alongside changes in several disease-relevant markers.

Sustained target engagement
A single administration produced potent miR-27b inhibition that was sustained at the eight-week study endpoint, demonstrating long-lasting target engagement in the model. In addition, treated animals showed improvements in motor activity. This suggests that the biological effects of miR-27b inhibition were accompanied by measurable functional improvements in the model.

Reduced α-synuclein burden
The accumulation of α-synuclein is widely considered a hallmark of Parkinson's disease and is thought to contribute to neuronal dysfunction and degeneration.

Animals treated with antimiR-27b showed a reduced α-synuclein signal in the substantia nigra compared with animals in the control group, suggesting that miR-27b inhibition may promote processes involved in α-synuclein clearance.

Protection of the nigrostriatal pathway
The progressive loss of dopaminergic neurons is one of the defining features of Parkinson's disease. Treatment was associated with higher counts of TH-positive neurons in the substantia nigra and TH-positive projections in the striatum, findings consistent with protection of the nigrostriatal pathway in this model.

Reduced neuroinflammatory responses
Neuroinflammation is increasingly recognized as an important contributor to disease progression. The data presented demonstrated effects on microglia, the brain's resident immune cells. AntimiR-27b treatment reduced microglial activation and shifted microglial morphology toward that observed in the control group, supporting an anti-inflammatory effect in the model.

Effects across multiple hallmarks of Parkinson's disease
Viewed individually, each of these findings contributes to a different piece of the puzzle. Together, they suggest that inhibition of miR-27b may influence several biological processes that are implicated in Parkinson's disease.

While these findings are preclinical and do not predict clinical outcomes, they support continued development of miR-27b inhibition as a potential disease-modifying approach for Parkinson's disease.

The article is based on the poster presentation "miRNA Targeting for Disease Modification in Parkinson’s Disease", authored by Lluís Riera-Ponsati, Malthe B. Scharf, Clara Mayer, Jorge Santiago Bajo, Elsa Pioli, Erwan Bezard, Sakari Kauppinen, Henrik Klitgaard, Janine T. Erler, and Ellen K. Donnelly, with contributing institutions including Neumirna Therapeutics, the Center for RNA Medicine at Aalborg University, MOTAC Neuroscience, and the Biotech Research and Innovation Centre.