Generation and Characterization of a genetic @entity3392 model of @entity2057 carrying the @entity1 XXXX gene.

@entity1 @entity23247 @entity19 @entity409 @entity11280 @entity2057 @entity3392 @entity19972
BACKGROUND: Animal models of @entity1 diseases are essential as they allow analysis of the disease process at the cellular level and can advance therapeutics by serving as a tool for drug screening and target validation. Here we report the development of a complete genetic model of @entity2057 ( @entity2057 ) in the vertebrate @entity3392 to complement existing @entity3392 , @entity19 , and invertebrate models and show its utility for testing compounds that alter @entity23247 splicing. RESULTS: The @entity1 motoneuron disease @entity2057 is caused by low levels, as opposed to a complete absence, of the @entity11280 ( @entity11280 ). To generate a true model of @entity2057 in @entity3392 , we have generated a transgenic @entity3392 expressing the @entity1 @entity23247 gene ( @entity23247 ), which produces only a low amount of full-length @entity11280 , and crossed this onto the @entity11280 -/- background. We show that @entity1 @entity23247 is spliced in @entity3392 as it is in @entity1 and makes low levels of @entity11280 protein. Moreover, we show that an antisense oligonucleotide that enhances correct @entity23247 splicing increases full-length hSMN RNA in this model. When we placed this transgene on the @entity11280 mutant background it rescued the neuromuscular presynaptic @entity19972 defect that occurs in @entity11280 mutants and increased their survival. CONCLUSIONS: We have generated a transgenic fish carrying the @entity1 @entity23247 gene. This gene is spliced in fish as it is in @entity1 and @entity19 suggesting a conserved splicing mechanism in these vertebrates. Moreover, antisense targeting of an intronic splicing silencer site increased the amount of full length @entity11280 generated from this transgene. Having this transgene on the @entity11280 mutant fish rescued the presynaptic defect and increased survival. This model of @entity3392 @entity2057 has all of the components of @entity1 @entity2057 and can thus be used to understand @entity409 in @entity2057 , can be used as an vivo test for drugs or antisense approaches that increase full-length @entity11280 , and can be developed for drug screening.
