Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy.
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.
Bordet
T
T
Institut National de la Santé et de la Recherche Médicale (INSERM) U.129, Institut Cochin de Génétique Moléculaire, 75014 Paris, France.
Schmalbruch
H
H
Pettmann
B
B
Hagege
A
A
Castelnau-Ptakhine
L
L
Kahn
A
A
Haase
G
G
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001369:Axons / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D016472:Motor Neuron Disease / Q000235:genetics / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010525:Peripheral Nerves / Q000187:drug effects
D016207:Cytokines; D018696:Neuroprotective Agents; C092073:cardiotrophin 1