An experimental small molecule treatment for Parkinson’s disease can correct hallmarks of the condition in cells and animals. The study, published in Science Translational Medicine, shows that a small-molecule inhibitor of leucine-rich repeat kinase 2 (LRRK2) corrects features of Parkinson’s disease in cell models, and was safe in patients and volunteers.
Parkinson’s is a brain disorder that affects more than 10 million people worldwide. It affects as many as 2% of adults age 65 or older globally, and the condition’s prevalence will only grow as the world’s population ages.
“Despite this burden, there are no therapies that can modify the core trajectory of the condition,” note the authors. Currently, most treatments are aimed at reducing the main symptoms and maintaining a quality of life for the patient.
However, studies have suggested that targeting mutations in the LRRK2 gene could aid in Parkinson’s disease treatments.
LRRK2 is an emerging target for disease-modifying therapies for Parkinson’s disease. Mutations in LRRK2, which encodes for a multidomain protein kinase, are the most common genetic risk factors for Parkinson’s disease. Kinase are a type of enzyme that add phosphates to other molecules, such as sugars or proteins. Multidomain kinases are involved in diverse cellular functions, including cell growth, muscle contraction and immune response. They have also been shown to influence lysosomes, the terminal catabolic stations that rid cells of waste products.
Increased LRRK2 kinase activity impairs the function of lysosomes, leading to a build-up of cellular waste that contributes to neurodegeneration and other pathologies of Parkinson’s disease.
DNL201 in animal and cell models
DNL201, developed by Denali Therapeutics, is a central nervous system (CNS) penetrating LRRK2 kinase inhibitor. In the study, DNL201 reduced LRRK2 activity and restored lysosomal function in cell models. In addition, DNL201 improved lysosomal function in mouse astrocytes and fibroblasts from patients with lysosomal storage disease.
The compound did not cause adverse events when it was given to macaques at pharmacologically relevant doses.
DNL201 in humans
In phase I clinical trials, DNL201 was studied in healthy volunteers and patients with Parkinson’s disease. Here, DNL201 inhibited LRRK2 kinase activity and altered downstream lysosomal biomarkers at doses that were generally well tolerated.
Together, the findings from this study support the hypothesis that LRRK2 inhibition can correct lysosomal dysfunction in patients with Parkinson’s disease, and indicate that larger-scale clinical trials are warranted.
Neuroscience researcher Patrick Lewis said in a related Focus, “The new work opens the door to testing the implications of almost 20 years of accumulated research into LRRK2 and [Parkinson’s disease], as well as sustaining a promising avenue of drug discovery […] into the next phase of development.”
Written by Charlotte Harrison, Science Writer
Image Credit: Canva