By introducing a single point mutation into stem cells from the marmoset monkey, researchers are a step closer to developing a primate model for Parkinson’s disease. Researchers at the University of Wisconsin–Madison used CRISPR/Cas9 gene editing to introduce a mutation called G2019S at a single nucleotide within the marmoset cells.  It is the first study to successfully demonstrate introduction of a disease-related monogenic mutation in marmoset derived stem cells using CRISPR/Cas9. Their research was published in a paper in Scientific Reports.

In human cases of Parkinson’s disease, G2019S leads to overexpression of leucine-rich repeat kinase 2 (LRRK2), a kinase enzyme involved in metabolism. Mutations in the LRRK2 G2019S gene are relatively common, associated with 1–3% of Parkinson’s disease cases worldwide. As a result, the LRRK2 gene is also a target for Parkinson’s disease therapeutic intervention.

In this cell-based research, the G2019S-mutated monkey stem cells displayed similar features of faulty metabolism as seen in human Parkinson’s cells — including decreased autophagy and mitochondrial dysfunction. The marmoset stem cells also died more quickly and exhibited higher reactive oxygen species than normal cells. The mutated stem cells also failed to differentiate well into neurons and those that did produced few branches to establish connections with surrounding neurons.

In their experiments, the modified marmoset stem cells were next treated with a genetic approach. By introducing part of a shorted gene to block LRRK2 production, cellular metabolism improved in a manner consistent with normal cells. Both cell types survived similarly and the treated cells could be induced into neurons with more branching.

Several LRRK2 kinase inhibitors that block or eliminate the enzyme’s activity have shown some encouraging results in Parkinson’s disease studies. But they are also associated with inducing lung problems in monkeys. In this study, the use of the truncated LRRK2 therapy via CRISPR/Cas9 did not produce any detrimental effects leading the authors to speculate that this may present a more targeted strategy for reducing LRRK2 activity in Parkinson’s disease.

Developing a primate model for Parkinson’s research has been challenging. By observing how the marmoset mutated stem cells behaved in culture, the researchers hope to build on this technical feat by introducing the mutation into a marmoset for modeling the disease, observing disease progression, and ultimately testing new drug treatments.

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