Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the 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. 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). 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. 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.
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http://dx.doi.org/10.3390/jpm11050392 | DOI Listing |
Ann Hematol
December 2024
Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
ETV6::LYN fusion gene is recognized as one of the genetic alterations responsible for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) according to the 2022 WHO classification. However, the clinical features and pathogenesis of MLN-TK with ETV6::LYN are not well defined because of the rarity of the disease. Here, we report an MLN-TK patient with ETV6::LYN that manifested as myeloproliferative neoplasms (MPN) with eosinophilia, myelofibrosis, and T-lymphoblastic lymphoma (T-LBL), which eventually led to acute myeloid leukemia.
View Article and Find Full Text PDFEur J Immunol
December 2024
Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Mast cell (MC)-driven allergic diseases are constantly expanding and require the development of novel pharmacological MC stabilizers. Allergen/antigen (Ag)-triggered activation via crosslinking of the high-affinity receptor for IgE (FcεRI) is fundamentally regulated by SRC family kinases, for example, LYN and FYN, exhibiting positive and negative functions. We report that KIRA6, an inhibitor for the endoplasmic reticulum stress sensor IRE1α, suppresses IgE-mediated MC activation by inhibiting both LYN and FYN.
View Article and Find Full Text PDFBiochem Pharmacol
December 2024
Department of Pharmacology, School of Medicine, Daegu Catholic University, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu 42472, Republic of Korea. Electronic address:
Isobavachin, isolated from Psoralea corylifolia L. exhibits therapeutic potential for osteoporosis or skin disease. Here, we evaluated the pharmacological effects of isobavachin on IgE-dependent inflammatory allergic reactions, as well as the underlying mechanisms, in bone marrow-derived mast cells and a mouse model of passive cutaneous anaphylaxis (PCA).
View Article and Find Full Text PDFClin Cancer Res
December 2024
University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
Purpose: Although the B-cell receptor (BCR) signal plays a critical role in CLL cell survival and a target of current therapies (ibrutinib targets Bruton's tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the "CLL cell-survival signaling network" is largely undefined.
Experimental Design: CLL patients were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism.
Cell Mol Life Sci
December 2024
Institute of Molecular Health Sciences, Department of Biology, ETH Zürich, Otto-Stern-Weg 7, Zürich, 8093, Switzerland.
The development of antiviral strategies is a key task of biomedical research, but broad-spectrum virus inhibitors are scarce. Here we show that fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors reduce infection of several cell types with DNA and RNA viruses by blocking early stages of infection, but not viral cell association. Unexpectedly, their antiviral activity was largely independent of FGFR kinase inhibition.
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