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Article

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

1
Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
2
Translational Neurodegeneration Section “Albrecht Kossel”, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany
3
Department of Medicine, University of Verona, 37134 Verona, Italy
4
Department of Physiology I, University of Tübingen, 72076 Tübingen, Germany
5
Transfusion Medicine, Medical Faculty, Eberhard Karl University, 72076 Tübingen, Germany
6
Medical Department I, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01069 Dresden, Germany
7
Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, 01307 Dresden, Germany
8
DZNE, German Center for Neurodegenerative Diseases, Research Sites Dresden and Rostock/Greifswald, 18051 Rostock, Germany
9
Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany
*
Authors to whom correspondence should be addressed.
Members of The Network for Translational Research for Neuroacanthocytosis Patients, see Appendix A.
Contributed equally to this work.
J. Pers. Med. 2021, 11(5), 392; https://doi.org/10.3390/jpm11050392
Received: 14 April 2021 / Revised: 4 May 2021 / Accepted: 6 May 2021 / Published: 10 May 2021
(This article belongs to the Special Issue Advances in the Therapeutics of Neurological Diseases)
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. View Full-Text
Keywords: ChAc; neuroacanthocytosis; off-label; dasatinib; TKI ChAc; neuroacanthocytosis; off-label; dasatinib; TKI
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MDPI and ACS Style

Peikert, K.; Glaß, H.; Federti, E.; Matte, A.; Pelzl, L.; Akgün, K.; Ziemssen, T.; Ordemann, R.; Lang, F.; Patients, T.N.f.T.R.f.N.; De Franceschi, L.; Hermann, A. Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease. J. Pers. Med. 2021, 11, 392. https://doi.org/10.3390/jpm11050392

AMA Style

Peikert K, Glaß H, Federti E, Matte A, Pelzl L, Akgün K, Ziemssen T, Ordemann R, Lang F, Patients TNfTRfN, De Franceschi L, Hermann A. Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease. Journal of Personalized Medicine. 2021; 11(5):392. https://doi.org/10.3390/jpm11050392

Chicago/Turabian Style

Peikert, Kevin, Hannes Glaß, Enrica Federti, Alessandro Matte, Lisann Pelzl, Katja Akgün, Tjalf Ziemssen, Rainer Ordemann, Florian Lang, The Network for Translational Research for Neuroacanthocytosis Patients, Lucia De Franceschi, and Andreas Hermann. 2021. "Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease" Journal of Personalized Medicine 11, no. 5: 392. https://doi.org/10.3390/jpm11050392

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