DNL151, DNL201, and BIIB094: experimental agents for the treatment of Parkinson's disease

IntroductionPathogenic mutations of the abundant leucine-rich repeat kinase 2 gene support the onset of familial and sporadic forms of Parkinson's disease. These genetic variants catalyze kinase activity by substrate phosphorylation. They promote the nigrostriatal neurodegenerative process, i.e. characterized by Lewy body formation.Areas coveredThis narrative review discusses leucine-rich repeat kinase 2 inhibitors as therapeutic concept for beneficial disease modification following a literature search.Expert opinionLeucine-rich repeat kinase 2 gene function contributes to the onset of microglia inflammation, cellular, and mitochondrial dysfunction. Leucine-rich repeat kinase 2 inhibition with oral application of DNL151, respectively DNL201, and intrathecal administration of the antisense oligonucleotide BIIB094 in a single and multiple ascending dose study was safe and well tolerated. Approval of Leucine-rich repeat kinase 2 inhibitors in case of positive clinical study outcomes will introduce personalized medicine for beneficial modification of progression as the most unmet need for treatment of patients with Parkinson's disease. In addition to the currently, preponderantly performed clinical rating with established scales, further clinical trial endpoints, such as dosing of dopamine substitution, may be considered in study designs to demonstrate therapeutic effects on the progression of Parkinson's disease. Certain mutations of the abundant leucine-rich repeat kinase 2 gene contribute to the onset of inherited and sporadic forms of idiopathic Parkinson's disease. These genetic variants enhance the gene related kinase activity and promote nigrostriatal neurodegeneration with features like inflammation of microglia, cellular, and mitochondrial dysfunction. Inhibition of leucine-rich repeat kinase 2 activity was efficacious, safe, and well tolerated in experimental investigations and in the still ongoing clinical study program. Approval of this therapeutic concept after future positive clinical study outcomes is the introduction of personalized medicine based on molecular mechanisms and targets in Parkinson's disease. Beneficial modification of progression is the most unmet need for the therapy of patients with Parkinson's disease.

Automated summary

Certain mutations of the abundant leucine-rich repeat kinase 2 gene contribute to the onset of inherited and sporadic forms of idiopathic Parkinson's disease. Inhibition of leucine-rich repeat kinase 2 activity was efficacious, safe, and well tolerated in experimental investigations and in the still ongoing clinical study program. Approval of this therapeutic concept after future positive clinical study outcomes is the introduction of personalized medicine based on molecular mechanisms and targets in Parkinson's disease. Beneficial modification of progression is the most unmet need for the therapy of patients with Parkinson's disease.