Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy
Thierry Bordet, … , Axel Kahn, Georg Haase
Thierry Bordet, … , Axel Kahn, Georg Haase
Published October 15, 1999
Citation Information: J Clin Invest. 1999;104(8):1077-1085. https://doi.org/10.1172/JCI6265.
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Article

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

Abstract

Cardiotrophin-1 (CT-1), an IL-6–related cytokine, causes hypertrophy of cardiac myocytes and has pleiotropic effects on various other cell types, including motoneurons. Here, we analyzed systemic CT-1 effects in progressive motor neuronopathy (pmn) mice that suffer from progressive motoneuronal degeneration, muscle paralysis, and premature death. Administration of an adenoviral CT-1 vector to newborn pmn mice leads to sustained CT-1 expression in the injected muscles and bloodstream, prolonged survival of animals, and improved motor functions. CT-1–treated pmn mice showed a significantly reduced degeneration of facial motoneuron cytons and phrenic nerve myelinated axons. The terminal innervation of skeletal muscle, grossly disturbed in untreated pmn mice, was almost completely preserved in CT-1–treated pmn mice. The remarkable neuroprotection conferred by CT-1 might become clinically relevant if CT-1 side effects, including cardiotoxicity, could be circumvented by a more targeted delivery of this cytokine to the nervous system.

Authors

Thierry Bordet, Henning Schmalbruch, Brigitte Pettmann, Albert Hagege, Laetitia Castelnau-Ptakhine, Axel Kahn, Georg Haase

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CT-1 gene expression in pmn mice. (a) Levels of endogenous CT-1 protein ...
CT-1 gene expression in pmn mice. (a) Levels of endogenous CT-1 protein in gastrocnemius muscles of 28-day-old normal (lanes 1–3) and pmn (lanes 4–6) mice analyzed by Western blot. (b, c, d, and e) CT-1 expression after AdCT-1 intramuscular injection in neonatal pmn mice. (b) The right gastrocnemius muscle and the lumbar spinal cord were analyzed in AdCT-1–injected (lanes 1–3) and AdLacZ-injected (lanes 4–5) mice. Adenoviral CT-1 transcripts were detected by RT-PCR in all right gastrocnemius muscles of AdCT-1–injected mice at day 25, whereas only weak RT-PCR signals were detected in the lumbar spinal cords of 15-day-old treated mice. C+: cDNA from AdCT-1-infected 293 cells; C–: without template; –, without RT; +, with RT. (c) CT-1 overexpression was revealed by Western blot analysis in AdCT-1–injected muscles (+) but not in AdLacZ-injected muscle (–). Recombinant CT-1 protein (rCT-1) and conditioned media (CM) from AdCT-1–infected (+) or noninfected (–) fibroblasts were used as controls. The 2 bands of apparent molecular mass 23 and 29 kDa might reflect precursor and mature forms of CT-1 or differently glycosylated isoforms. Note that endogenous CT-1 protein in untreated pmn mice was not detectable under these experimental conditions (50 μg of loaded protein, short exposure time). (d) Sera of AdCT-1– and AdLacZ-injected pmn mice were tested for their neurotrophic activity on motoneurons. The number of motoneurons per field (mean ± SEM) was determined and expressed relative to the number of motoneurons surviving in 50 ng/mL CT-1 (100%) and in neurobasal medium (0%). (e) Sera of 25-day-old pmn mice and rCT-1 (inset) were tested in a ciliary ganglion (CG8) neuron survival assay. Elevated serum CT-1 concentrations (in trophic units [TU]/mL) were detected in all 5 tested AdCT-1–injected pmn mice but in none of the 4 AdLacZ-injected mice. One TU corresponds to the serum dilution that allowed half maximal survival of the neurons.