A gene editing approach targeting a specific part of the SNCA gene was able to lower alpha-synuclein levels and protect from Parkinson’s characteristic cellular changes, according to preclinical results.
The study, “Downregulation of SNCA expression by targeted editing of DNA-methylation: A potential strategy for precision therapy in PD,” was published in the journal Molecular Therapy.
Elevated levels of the SNCA gene have been implicated in the development of Parkinson’s disease. This gene provides instructions for making alpha-synuclein protein, which when present at high levels can form toxic aggregates in the brain of a Parkinson’s patient and is the main component of the disorder’s hallmark Lewy bodies.
Methylation — the addition of chemical groups containing one carbon and three hydrogen atoms — to a specific part of the SNCA gene (called intron 1) regulates its conversion to messenger RNA (mRNA) in gene expression.
Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein. Introns are bits of genes that do not contain the information to make proteins and are normally “cut out” during protein production.
Parkinson’s patients have altered methylation levels in their brains when compared to healthy individuals.
Duke University researchers have developed a new epigenetic approach — which changes gene expression rather than the gene itself — targeting intron 1 of the SNCA gene, hoping to fine-tune SNCA expression, and lower alpha-synuclein production.
“This approach would be highly attractive for developing ‘smart drugs’ as disease-modifying interventions for [Parkinson’s], Alzheimer’s disease and other neurological diseases and pathologies associated with dysregulation of gene expression,” Ornit Chiba-Falek, PhD, the study’s senior author, said in a Duke Center for Genomic and Computational Biology news release.
The team developed a system consisting of a modified, harmless viral vector, based on a gene editing approach called CRISPR/dCas9 fused with the catalytic domain (the enzyme’s region where the reaction it is responsible for takes place) of DNA-methyltransferase 3A (DNMT3A).
They then applied this new system to stem cell-derived dopamine-producing neurons — those primarily degenerated in Parkinson’s — from a patient with the SNCA gene triplication, which has been associated with increased production and aggregation of alpha-synuclein in Parkinson’s disease.
By targeting DNA methylation at SNCA’s intron 1, this strategy was able to lower alpha-synuclein mRNA and protein levels. This reduction protected dopamine-producing neurons from characteristic disease-related changes, including the production of reactive oxygen species (ROS) and low cell viability.
When something doesn’t work well in the energy extraction process and cells become full of ROS compounds, oxidative stress occurs. Oxidative stress and dysfunction in mitochondria (the cells’ powerhouses that produce energy) are implicated in Parkinson’s development.
The new gene editing approach “allows an effective and sufficient tight downregulation of SNCA expression levels, suggesting the potential of this target sequence combined with the CRISPR/dCas9 technology as a novel epigenetic-based therapeutic approach for [Parkinson’s],” the authors wrote.
The team is now attempting to validate the system in an animal model. “These studies will further establish, validate and determine the safety of the viral vector tool,” Boris Kantor, PhD, the study’s first author, wrote.
Chiba-Falek said the ongoing studies will provide the foundation for the system’s implementation and later evaluation in clinical trials.
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