Adeno-Associated Virus Transfer of a Gene Encoding SNAP-25 Resistant to Botulinum Toxin A Attenuates Neuromuscular Paralysis Associated with Botulism
| Autor: | Leonard A. Smith, J. Oliver Dolly, Francesc Pérez-Brangulí, Arvind Raghunath |
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| Rok vydání: | 2008 |
| Předmět: |
Threonine
Synaptosomal-Associated Protein 25 Chromaffin Cells Green Fluorescent Proteins Pseudobulbar Palsy Neuromuscular Junction Neuromuscular transmission Biology Pharmacology medicine.disease_cause Neuromuscular junction Catecholamines Serine Paralysis medicine Animals Botulism Botulinum Toxins Type A Muscle Skeletal Adeno-associated virus Cells Cultured General Neuroscience Gene Transfer Techniques Dependovirus Motor neuron medicine.disease Virology Endocytosis Rats medicine.anatomical_structure Neuromuscular Agents Mutation Clostridium botulinum medicine.symptom Brief Communications Acetylcholine medicine.drug |
| Zdroj: | The Journal of Neuroscience. 28:3683-3688 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | 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 cellsin vitroyielded exocytotically active S25-R198T that diminished subsequent blockade by BoNT/A of evoked catecholamine release. Evaluationin 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. |
| Databáze: | OpenAIRE |
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