Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice

Abstract

Amyotrophic lateral sclerosis (ALS) is mainly a sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS cases (FALS) have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Transgenic mice overexpressing a mutated form of human SOD1 with a Gly93Ala substitution develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months. We investigated the effects of neurotrophic factor gene delivery in this FALS model. Intramuscular injection of an adenoviral vector encoding cardiotrophin-1 (CT-1) in SOD1G93A newborn mice resulted in systemic delivery of CT-1, supplying motoneurons with a continuous source of trophic factor. CT-1 delayed the onset of motor impairment as assessed in the rotarod test. Axonal degeneration was slowed and skeletal muscle atrophy was largely reduced by CT-1 treatment. By monitoring the amplitude of the evoked motor response, we showed that the time-course of motor impairment was significantly decreased by CT-1 treatment. Thus, adenovirus-mediated gene transfer of neurotrophic factors might delay neurogenic muscular atrophy and progressive neuromuscular deficiency in ALS patients.

Cardiotrophin-1 Review

“…Axonal degeneration was slowed and skeletal muscle atrophy was largely reduced by CT-1 treatment. Thus, adenovirus-mediated gene transfer of neurotrophic factors might delay neurogenic muscular atrophy and progressive neuromuscular defi ciency in ALS patients 56,70 . Administration of an adenoviral CT-1 vector to newborn progressive motor neuropathy mice leads to sustained CT-1 expression in the injected muscles and bloodstream, prolonged survival of animals, and improved motor functions.…”

Intraparenchymal spinal cord delivery of adeno-associated virus IGF-1 is protective in the SOD1G93A model of ALS

“…Previous studies in animal models of motor neuron disease (SOD1, wobbler, progressive motor neuronopathy, spinal muscle atrophy) have shown that therapeutic benefits can be achieved via adenovirus-, lentivirus-, herpes simplex virus-and adeno-associated virus (AAV)-based delivery of genes such as mutant SOD1-targeted RNAi [48,49], VEGF [6], NT-3 [28], CNTF [2], GDNF [1,58], IGF-1 [34], Bcl-2 [5] and cardiotrophin-1 [13]. Clinical translation with some of these proteins has not yielded similar efficacy in human ALS patients [12,25,26,36]; however, trials have mostly involved systemic injection of protein, not viral vector-based gene delivery.…”

Glycinergic and GABAergic Synaptic Activity Differentially Regulate Motoneuron Survival and Skeletal Muscle Innervation

“…During embryonic development, approximately half of the motoneurons generated undergo programmed cell death (PCD) (Oppenheim, 1991). Motoneuron survival and differentiation depend on trophic factors secreted from target muscle fibers and Schwann cells surrounding motor axons (Bordet et al, 2001;Acsadi et al, 2002;Wang et al, 2002;Lu et al, 2003). Reductions in skeletal muscle activity improve the access of a motoneuron to target-derived trophic factors by increasing the extent to which motor axons branch and form neuromuscular synapses (Oppenheim et al, 2000b;Millecamps et al, 2001Millecamps et al, , 2002.…”