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The Journal of Neuroscience, April 2, 2008, 28(14):3683-3688; doi:10.1523/JNEUROSCI.5690-07.2008

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Brief Communications
Adeno-Associated Virus Transfer of a Gene Encoding SNAP-25 Resistant to Botulinum Toxin A Attenuates Neuromuscular Paralysis Associated with Botulism

Arvind Raghunath,¹ Francesc Perez-Branguli,¹ Leonard Smith,² and J. Oliver Dolly¹

¹International Centre for Neurotherapeutics, Dublin City University, Dublin 9, Ireland, and ²Integrated Toxicology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland 21702-5011

Correspondence should be addressed to Prof. J. Oliver Dolly, X230, International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland. Email: oliver.dolly{at}dcu.ie

Advances in viral gene therapy have opened new possibilities for treating a range of motor neuron diseases, but these have not yet been translated into clinically applicable therapies because of difficulties in delivery to susceptible/damaged neurons, ambiguities in the identity of gene(s) implicated, and a paucity of means to quantify any physiological improvement. Most of these hurdles can be overcome by using the neuromuscular paralysis induced by botulinum neurotoxin type A (BoNT/A) as a prototype disease. Furthermore, because human botulism, occasionally fatal, causes prolonged muscle disablement as a result of the intraneuronal persistence of the toxin's SNAP-25 (S25)-cleaving protease, development of a genetic approach could lead to a potential treatment for this debilitating disease. Adeno-associated viral delivery of a cleavage-resistant S25 gene (S25-R198T) to chromaffin cells in vitro yielded exocytotically active S25-R198T that diminished subsequent blockade by BoNT/A of evoked catecholamine release. Evaluation in vivo, by administering this virus into rat spinal cord before injecting BoNT/A, showed a decreased inhibition of acetylcholine release as reflected in elevated retention of neuromuscular transmission. A similar, although smaller, protection of synaptic transmission from the toxin was seen after peripherally injecting the therapeutic virus. Such therapy also curtailed nerve sprouting normally induced by BoNT/A. This first demonstration of the utility of a DNA-based therapy for botulism paves the way for further advances in its treatment and for application to genetic disorders of motor neurons.

Key words: botulinum; gene transfer; neuromuscular junction; motor neuron; SNARE proteins; sprouting

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Received Nov. 15, 2007; revised Feb. 7, 2008; accepted Feb. 8, 2008.

Correspondence should be addressed to Prof. J. Oliver Dolly, X230, International Centre for Neurotherapeutics, Dublin City University, Glasnevin, Dublin 9, Ireland. Email: oliver.dolly{at}dcu.ie

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