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

Abstract

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 in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside 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, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: 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”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

Changes in blood cell deformability in Chorea-Acanthocytosis and effects of treatment with dasatinib or lithium

“…The acanthocyte count over the treatment is given in figure 2E and shows that the fraction of acanthocytes remains constant within a certain range of fluctuation without a systematic trend for both treatments, which is in line with the clinical data (19).…”

“…While we observed bigger RBCs in ChAc patients, values for the mean corpuscular volume (MCV) reported in Peikert et al, 2021 (19) did not show an increased RBC volume for patients P1-P3. Sizes reported in RT-FDC measurements are based on the projected cross-sectional area of the deformed cells.…”

“…The sharp drop in deformation for the RBCs occurred at different timepoints for P3 than for P1 and P2. A possible correlation to this can be found in the levels of Lyn kinase and the autophagy marker p62 for the patients reported in Peikert et al, 2021 (19). Lyn kinase levels for P3 dropped directly after treatment start and stayed on this level during the treatment while the levels for P1 and P2 had a sudden rise after 10 weeks of treatment.…”

“…Data from Peikert et al, 2021 indicated that with 12asatinib treatment, F-actin became more localized at the cortex (19). These modifications in the actin network likely contribute to changes in RBC deformability (41) that we observed here.…”

“…We included 5 ChAc patients in this study for whom diagnosis was confirmed by Western blot (absence of chorein/VPS13A protein) and genetic testing (31). The clinical parameters of the patients are listed in Table S1 and for P1-P3 further information can be found in Peikert et al, 2021 (19). Patients and healthy control blood donors were enrolled in ongoing studies on the pathogenesis and natural history of neurodegenerative diseases approved by the institutional review board of the Technische Universität Dresden, Germany (EK 45022009, EK 78022015).…”