Accession Number:

ADA504647

Title:

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

Descriptive Note:

Journal article

Corporate Author:

DUBLIN CITY UNIV (IRELAND) INTERNATIONAL CENTRE FOR NEUROTHERAPEUTICS

Report Date:

2008-04-02

Pagination or Media Count:

7.0

Abstract:

Human botulism caused by botulinum neurotoxin BoNT serotype A results in an extraordinarily long duration of neuroparalysis. This toxin blocks acetylcholine release by targeting motor nerve endings, undergoing cytosolic internalisation where its light chain cleaves and inactivates S25, a SNARE protein required for Ca2-dependent exocytosis. Intra-neuronal persistence of the protease activity underlies such sustained muscle weakness, and poses an unmet challenge for designing effective pharmacological treatment. To circumvent this problem, the gene encoding cleavage-resistant S25 S25-R198T was delivered using Adeno-associated virus and expressed in neuro-endocrine cells as well as motor neurons. Initial transfection of chromaffin cells in vitro yielded exocytotically-active S25-R198T that diminished subsequent blockade by BoNTA of evoked catecholamine release. The potential of this gene therapy in vivo was evaluated by stereotaxically administering the recombinant virus into rat spinal cord. Encouragingly, delivery and expression of S25-R198T prior to injecting BoNTA decreased its inhibition of Ach release, as reflected in elevated retention of neuromuscular transmission. A similar, though smaller, protection of synaptic transmission from paralysis by the toxin was seen upon peripherally injecting the therapeutic virus. Another benefit of this therapy was revealed by the observed curtailment of the pattern of nerve sprouting and synapse remodelling induced by BoNTA in rat soleus muscle. This first demonstration of the utility of a DNA-based therapy for one prototype condition, botulism, paves the way for refinement of the technology for application to genetic disorders of motor neurons.

Subject Categories:

  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research
  • Microbiology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE