Leucine-rich repeat kinase 2 (LRRK2) G2019S messenger RNA (LRRK2 G2019S mRNA)

Leucine-rich repeat kinase 2 (LRRK2) G2019S messenger RNA is a therapeutic target for the treatment of Parkinson's disease, particularly in patients carrying the G2019S mutation (Healy et al., 2008). The G2019S mutation, located in the kinase domain, is the most common genetic cause of Parkinson's disease and leads to a gain-of-function characterized by increased kinase activity (West et al., 2005). This pathological activity is linked to impaired vesicular trafficking, lysosomal dysfunction, and the accumulation of alpha-synuclein (Cookson, 2010). Targeting the mRNA transcript with antisense oligonucleotides (ASOs) allows for the reduction of LRRK2 protein levels at the source, rather than just inhibiting the enzyme's activity (Biogen, 2023). The primary therapeutic candidate, BIIB094, utilizes RNase H-mediated degradation to lower LRRK2 mRNA and protein expression in the central nervous system (Ionis Pharmaceuticals, 2023). This approach aims to restore normal cellular function and slow disease progression in both familial and potentially sporadic cases of Parkinson's (Tolosa et al., 2020). Clinical monitoring of this target involves measuring biomarkers such as urinary bis(monoacylglycero)phosphate (BMP) and LRRK2 autophosphorylation (Thaler et al., 2022). Safety concerns associated with LRRK2 reduction include potential effects on lung and kidney tissues, as seen in preclinical knockout models (Baptist et al., 2020). Therapeutic challenges include the need for effective CNS delivery, typically via intrathecal injection, and the long-term impact of reduced LRRK2 levels on systemic health (Fuji et al., 2015).

Other names

LRRK2 G2019S transcriptPARK8 G2019S mRNADardarin G2019S mRNALeucine-rich repeat kinase 2 G2019S mRNA

Antisense oligonucleotide-mediated degradation of mRNA via RNase H recruitment, resulting in reduced expression of the LRRK2 protein (Biogen, 2023).