LRRK2 Kinase Inhibitor
Major advances in understanding how genetics underlies Parkinson's disease (PD) have provided new opportunities for understanding disease pathogenesis and potential new targets for therapeutic intervention. One such target is leucine-rich repeat kinase 2 (LRRK2), an enzyme implicated in both familial and idiopathic PD risk. Six mutations in LRRK2, a large, multi-domain protein, segregate with disease in familial PD. The most common of these mutations, G2019S, accounts for 4% of familial PD and 1-2% of sporadic PD worldwide, with an estimated US prevalent population of 10,000 – 40,000 patients.
Mutations in the gene encoding LRRK2 are autosomal and dominantly inherited, with most patients carrying one mutant and one wild type allele. The risk of developing PD in G2019S carriers is age-dependent: 28% at age 59 years, 51% at 69 years and 74% at 79 years. Elevated activity of the kinase domain is now widely accepted as the unifying etiology of PD-associated mutations in the LRRK2 gene, suggesting that kinase inhibition might have a disease-modifying therapeutic effect for these mutation carriers.