ADENOVIRAL GENE-TRANSFER OF CILIARY NEUROTROPHIC FACTOR AND BRAIN-DERIVED NEUROTROPHIC FACTOR LEADS TO LONG-TERM SURVIVAL OF AXOTOMIZED MOTOR-NEURONS

The neurotrophic factors ciliary neurotrophic factor and brain-derived neurotrophic factor can prevent motor neuron cell death during develo pment(1,2) and after nerve lesion in neonatal rodents(3,4). However, l ocal and systemic application of these factors to newborn rats with da maged motor nerves rescues motor neurons only transiently during the f irst two weeks after axotomy(5,6). In order to test the effect of cont inuous delivery of these factors, the effect of localized injection of CNTF- or BDNF-transducing recombinant adenoviruses into the lesioned nerves was investigated. Under such conditions, survival of axotomized motor neurons is maintained for at least 5 weeks. This way of deliver y corresponds to the physiological situation in adult rodents, under w hich endogenous CNTF is present in the cytosol of Schwann cells and BD NF expression is upregulated after nerve lesion, making these factors available to the damaged motor neurons(7,8). Recent results show that overexpression of muscle-derived neurotrophin-3 prevents degeneration of axons and motor endplates, but has only little effect on the number of motor neuron cell bodies in a murine animal model of motor neuron disease(9). Therefore, techniques suitable for tonic exposure to both nerve- and muscle-derived neurotrophic factors may have implications f or the design of future therapeutic strategies against human motor neu ron disease.