Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in an Ultra-Rare Disease

ABSTRACT Background Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms and therefore represents a promising drug target. Methods We evaluated an individual off-label treatment with the FDA-approved tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8-50.4 weeks) of three ChAc patients. Alongside with a thorough safety monitoring, we assessed motor and non-motor scales (e.g. MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g. serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels and acanthocyte count did not reveal consistent effects. However, reduction of initially elevated Lyn kinase activity and accumulated autophagy markers as well as partial restoration of actin cytoskeleton was found in red blood cells. Discussion We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. Here, we suggest a panel of outcome parameters for future clinical trials in ChAc.