Journal Article

DZNE-2025-00546

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Therapeutic sphingosine-1-phosphate receptor modulation by repurposing fingolimod (FTY720) leads to mitigated neuropathy and improved clinical outcome in a mouse model for Charcot-Marie-Tooth 1X disease.

Yuan, X. (First author)DZNE* ; Klein, D. ; Maier, A.-M. ; Martini, R.

2025
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.nmd.2025.105345

Abstract: Previous studies have shown that both the innate and adaptive immune systems foster progression of neuropathy and clinical symptoms in a mouse model for Charcot-Marie-Tooth 1X disease. Here we demonstrate a possible therapeutic translation of these findings using the clinically approved sphingosine-1-phosphate receptor modulator fingolimod (FTY720) in connexin32-deficient mice mimicking Charcot-Marie-Tooth 1X disease. Treatment with FTY720 prevented an increase of CD8+ and CD4+ T-lymphocyte numbers in both femoral quadriceps nerve as well as in ventral spinal roots. While macrophages of ventral spinal roots show a similar, albeit non-significant trend, macrophages from quadriceps nerve are not reduced upon treatment. On the histopathological level, axonopathic changes were reduced in ventral spinal roots, but not in quadriceps nerves upon treatment. Electrophysiological recordings displayed improved nerve conduction parameters upon FTY720 treatment, while clinically, FTY720 treatment ameliorated distinct parameters of motor performance and grip strength. We suggest that targeting the adaptive immune system might be a pharmacological treatment option for mitigating disease burden particularly in severe cases of Charcot-Marie-Tooth 1X.

Keyword(s): Axon damage ; FTY720 ; Fingolimod ; Inherited peripheral neuropathy ; Macrophages ; Myelin ; Neuroinflammation ; T-lymphocytes

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Contributing Institute(s):

1. Neuroimmunology and Neurodegenerative Disease (AG Neher (München))

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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