State of research

Chorea-acanthocytosis (ChAc) is an incurable neurodegenerative disease of young adulthood characterized by deformed erythrocytes (acanthocytes) caused by mutations in the VPS13A gene. A key pathophysiological mechanism is an increased activity of the tyrosine kinase Lyn. Tyrosine kinase inhibitors (TKIs) such as dasatinib or nilotinib are approved for the treatment of leukemia and are therefore immediately available for translation into neurology. In addition, TKIs have already been tested in the context of neurodegenerative diseases in phase II/III studies and show good safety data (e.g. Pagan et al., JAMA Neurol, 2019; Turner et al., Ann Neurol, 2020; Simuni et al., JAMA Neurol , 2020).

Results of preclinical research

An international consortium led by our working group (EMINA-2) has succeeded in demonstrating the connection between increased Lyn kinase activity and pathological phenotype in both erythrocyte and neuron models (derived from patient-specific iPSC). Among other things, Lyn inhibition led to a reduction in neuronal hyperexcitability and the restoration of disrupted autophagy processes in the cell model (Lupo et al., Blood, 2016; Stanslowsy et al., J Neurosci., 2016).

Results of clinical translation

An early clinical translation took place in the context of individual treatment attempts of individual ChAc patients with dasatinib. The treatment proved safe. Experimental read-outs such as Lyn kinase activity, autophagy-associated proteins and the actin cytoskeleton indicated a positive "target engagement" in the erythrocytes, while predefined clinical outcome parameters could not show a positive response regarding the central nervous system (Peikert et al., J Pers Med, 2021). At the same time, in cooperation with our cooperation partners, the TKIs dasatinib and nilotinib were tested comparatively in the mouse model - in the sense of a "reverse translation". With both, analogous to the clinical data, an improvement in the peripheral blood phenotype could be shown, but only nilotinib sufficiently into the basal ganglia penetrated and there positive effects on autophagy processes and secondary neuroinflammation were detectable (Peikert/Federti et al., Acta Neuropathol Commun, 2021). Thus, nilotinib emerges as the most promising candidate for further studies. Insufficient knowledge of the natural course of the disease and a lack of biomarkers turned out to be significant limitations for immediate clinical trial readiness in this context. This project succeeded in identifying promising biomarker candidates, including neurofilament in serum (Peikert et al., Parkinsonism Relat Disord, 2020) and ESR (Darras/Peikert et al., Cells, 2021; Rabe et al., Biomolecules, 2021).

Perspectives

The successor substance nilotinib is currently being used and examined in individual patients as part of individual healing trials. However, a general recommendation for the use of this drug in ChAc cannot be derived from the results obtained so far. As part of the individual treatment attempts, protocols for the longitudinal recording of the course of the disease were established for the first time, which can be used in future studies in combination with the established biomarkers. Current projects will also contribute to a better understanding of the natural course of the disease and thus to "clinical trial readiness".

Financial support

The work on rare diseases on the one hand and the rapid clinical transfer of basic sciences to the patient on the other is the central point of the newly created Schilling professorship to which Prof. Hermann has been appointed. The Hermann and Lilly Schilling Foundation for Medical Research in the Stifterverband promotes university neurology by creating new professorships and working groups in such. The project was also funded by the "Rostock Academy for Clinician Scientists" (RACS), the "Centre for Regenerative Therapies Dresden" (CRTD) and the Else Kröner Clinician Scientist Program at the TU Dresden.

Therapeutic targeting of Lyn kinase to treat chorea-acanthocytosis
Peikert K*, Federti E*, Matte A, Constantin G, Pietronigro EC, Fabene PF, Defilippi P, Turco E, Del Gallo F, Pucci P, Amoresano A, Illiano A, Cozzolino F, Monti M, Garello F, Terreno E, Alper SL, Glaß H, Pelzl L, Akgün K, Ziemssen T, Ordemann R, Lang F, Brunati AM, Tibaldi E, Andolfo I, Iolascon A, Bertini G, Buffelli M, Zancanaro C, Lorenzetto E, Siciliano A, Bonifacio M, Danek A, Walker RH, Hermann A*, De Franceschi L*. May 2021. Acta Neuropathol Commun 9:81. doi:10.1186/s40478-021-01181-y. *contributed equally.

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

The Erythrocyte Sedimentation Rate and Its Relation to Cell Shape and Rigidity of Red Blood Cells from Chorea-Acanthocytosis Patients in an Off-Label Treatment with Dasatinib
Rabe A*, Kihm A*, Darras A*, Peikert K*, Simionato G*, Dasanna AK*, Glaß H, Geisel J, Quint S, Danek A, Wagner C, Fedosov DA, Hermann A, Kaestner L. May 2021. Biomolecules 11(5):727. doi.org/10.3390/biom11050727. *contributed equally.

Acanthocyte Sedimentation Rate as a Diagnostic Biomarker for Neuroacanthocytosis Syndromes: Experimental Evidence and Physical Justification
Darras A*, Peikert K*, Rabe A, Yaya F, Simionato G, John T, Dasanna AK, Buvalyy S, Geisel J, Hermann A, Fedosov DA, Danek A, Wagner C, Kaestner L. April 2021. Cells 10(4):788. doi.org/10.3390/cells10040788. *contributed equally.

Neurofilament light chain in serum is significantly increased in chorea-acanthocytosis
Peikert K, Akgün K, Beste C, Ziemssen T, Buhmann C, Danek A, Hermann A. November 2020. Parkinsonism Relat Disord 80:28-31. doi: 10.1016/j.parkreldis.2020.09.004.