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Therapeutic benefit of ciliary neurotrophic factor in progressive motor neuronopathy depends on the route of delivery
Author(s) -
Haase Georg,
Pettmann Brigitte,
Bordet Thierry,
Villa Pascal,
Vigne Emmanuelle,
Schmalbruch Henning,
Kahn Axel
Publication year - 1999
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/1531-8249(199903)45:3<296::aid-ana4>3.0.co;2-8
Subject(s) - ciliary neurotrophic factor , motor neuron , amyotrophic lateral sclerosis , neurotrophic factors , biology , brainstem , neuroscience , viral vector , medicine , spinal cord , pathology , recombinant dna , disease , gene , biochemistry , receptor
Ciliary neurotrophic factor (CNTF) has demonstrated therapeutic effects in several mouse mutants with motoneuronal degeneration. However, the poor bioavailability and toxic side effects of recombinant CNTF protein have complicated its use in patients with amyotrophic lateral sclerosis. CNTF gene transfer strategies were developed but faced the question of whether CNTF should be delivered to motoneuron cell bodies or to their axons or muscle targets. To address this issue, we have used an adenoviral vector (AdCNTF) coding for a secretable form of CNTF and compared different routes of its administration in the mouse mutant progressive motor neuronopathy ( pmn ). Intramuscular, intravenous, and intracerebroventricular injections of AdCNTF or the control vector AdlacZ resulted in transgene expression in skeletal muscle fibers, hepatocytes, and ependymal cells, respectively, as determined by histochemistry and reverse transcription–polymerase chain reaction. AdCNTF intramuscularly treated and intravenously treated pmn mice showed a 25% increase in mean life span and a reduced degeneration of phrenic myelinated nerve fibers, which correlated with elevated CNTF serum bioactivities. In contrast, intracerebroventricular AdCNTF administration did not affect the mean life span or motor axonal degeneration of pmn mice. The differential efficacy of peripheral and central CNTF vector administrations might be of interest for future studies in human motor neuron diseases. Ann Neurol 1999;45:296–304