Document Detail

A novel morpholino oligomer targeting ISS-N1 improves rescue of severe spinal muscular atrophy transgenic mice.
MedLine Citation:
PMID:  23339722     Owner:  NLM     Status:  MEDLINE    
In the search for the most efficacious antisense oligonucleotides (AOs) aimed at inducing SMN2 exon 7 inclusion, we systematically assessed three AOs, PMO25 (-10, -34), PMO18 (-10, -27), and PMO20 (-10, -29), complementary to the SMN2 intron 7 splicing silencer (ISS-N1). PMO25 was the most efficacious in augmenting exon 7 inclusion in vitro in spinal muscular atrophy (SMA) patient fibroblasts and in vitro splicing assays. PMO25 and PMO18 were compared further in a mouse model of severe SMA. After a single intracerebroventricular (ICV) injection in neonatal mice, PMO25 increased the life span of severe SMA mice up to 30-fold, with average survival greater by 3-fold compared with PMO18 at a dose of 20 μg/g and 2-fold at 40 μg/g. Exon 7 inclusion was increased in the CNS but not in peripheral tissues. Systemic delivery of PMO25 at birth achieved a similar outcome and produced increased exon 7 inclusion both in the CNS and peripherally. Systemic administration of a 10-μg/g concentration of PMO25 conjugated to an octaguanidine dendrimer (VMO25) increased the life span only 2-fold in neonatal type I SMA mice, although it prevented tail necrosis in mild SMA mice. Higher doses and ICV injection of VMO25 were associated with toxicity. We conclude that (1) the 25-mer AO is more efficient than the 18-mer and 20-mer in modifying SMN2 splicing in vitro; (2) it is more efficient in prolonging survival in SMA mice; and (3) naked Morpholino oligomers are more efficient and safer than the Vivo-Morpholino and have potential for future SMA clinical applications.
Haiyan Zhou; Narinder Janghra; Chalermchai Mitrpant; Rachel L Dickinson; Karen Anthony; Loren Price; Ian C Eperon; Stephen D Wilton; Jennifer Morgan; Francesco Muntoni
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-03-06
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-21     Completed Date:  2013-09-06     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  331-42     Citation Subset:  IM    
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MeSH Terms
Alternative Splicing
Base Pairing
Base Sequence
Disease Models, Animal
Gene Order
Mice, Transgenic
Morpholinos / administration & dosage,  chemistry,  metabolism*
Muscular Atrophy, Spinal / genetics*,  metabolism*,  mortality,  therapy
Regulatory Sequences, Nucleic Acid*
Survival of Motor Neuron 2 Protein / genetics*,  metabolism*
Grant Support
097815/Z/11/Z//Wellcome Trust
Reg. No./Substance:
0/Morpholinos; 0/Survival of Motor Neuron 2 Protein

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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