Targeting α-Synuclein with Antisense Oligonucleotides to Slow Parkinson's Disease
Parkinson's disease is driven by the spread of misfolded α-synuclein through the nervous system and brain. This is one of the few proteins in the body that can become altered in a way that causes other molecules of the same protein to also become altered, leading to solid aggregates and a surrounding biochemistry that is harmful to neurons. As misfolded α-synuclein moves from neuron to neuron, its spread causes disease symptoms. One option for treatment is to suppress the expression of α-synuclein, which slows progression of the altered form. While this seems a worse option in comparison to aiming at selective clearance of altered α-synuclein, there are many established approaches that might be used to downregulate the expression of a specific protein. The easier development path is often chosen, even given that it will lead to inferior therapies.
Antisense oligonucleotides (ASOs) are compounds that can be engineered to induce the target mRNA-specific degradation, which in turn decreases the levels of its corresponding protein. Even though they are not the only drugs that can control the expression of α-synuclein, ASOs have a crucial advantage over other approaches. "Currently, antibody drugs and vaccines targeting α-synuclein are under development, but their effects may not prevent the disease from progressing inside cells. In contrast, nucleic acid drugs like ASOs that specifically control intracellular levels of normal α-synuclein could offer higher safety and efficacy by both retaining the natural physiological functions of the protein while inhibiting the spread of pathogenic α-synuclein."
Considering that Parkinson's disease often emerges and then spreads out from specific regions in the brain, the researchers tested whether administering ASOs locally at diseased sites could be a sound treatment or preventive strategy. To this end, they injected ASOs directly into either the left or right striatum of mice brain and analyzed the spread of α-synuclein pathologies throughout various brain regions using the presence of Lewy body-like and Lewy neurite-like pathologies as indicators.
When ASOs were injected into the left striatum two weeks before inoculation of the mouse brain with disease-causing fibrils at the same site, a significant decrease of over 90% in Lewy pathology-like neuronal inclusion was observed. Compared to the control group, this pre-treatment effectively prevented the spread of abnormal fibrils-induced aggregate towards multiple regions of the brain. Even when ASOs were administered at the same time or even after inoculation with fibrillar α-synuclein, there was a notable inhibitory effect in the left striatum and other areas of the brain.
Link: https://www.tmd.ac.jp/english/press-release/20240607-1/