Document Detail


Antisense oligonucleotides for the treatment of spinal muscular atrophy.
MedLine Citation:
PMID:  23544870     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Spinal muscular atrophy (SMA) is an autosomal recessive disease affecting ∼1 in 10,000 live births. The most striking component is the loss of α-motor neurons in the ventral horn of the spinal cord, resulting in progressive paralysis and eventually premature death. There is no current treatment paradigm other than supportive care, though the past 15 years has seen a striking advancement in understanding of both SMA genetics and molecular mechanisms. A variety of disease-modifying interventions are rapidly bridging the translational gap from the laboratory to clinical trials, including the application of antisense oligonucleotide (ASO) therapy for the correction of aberrant RNA splicing characteristic of SMA. Survival motor neuron (SMN) is a ubiquitously expressed 38-kD protein. Humans have two genes that produce SMN, SMN1 and SMN2, the former of which is deleted or nonfunctional in the majority of patients with SMA. These two genes are nearly identical with one exception, a C to T transition (C6T) within exon 7 of SMN2. C6T disrupts a modulator of splicing, leading to the exclusion of exon 7 from ∼90% of the mRNA transcript. The resultant truncated Δ7SMN protein does not oligomerize efficiently and is rapidly degraded. SMA can therefore be considered a disease of too little SMN protein. A number of cis-acting splice modifiers have been identified in the region of exon 7, the steric block of which enhances the retention of the exon and a resultant full-length mRNA sequence. ASOs targeted to these splice motifs have shown impressive phenotype rescue in multiple SMA mouse models.
Authors:
Paul N Porensky; Arthur H M Burghes
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-05-16     Completed Date:  2013-12-31     Revised Date:  2014-05-07    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  489-98     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Exons
Genetic Therapy
Humans
Mice
Muscular Atrophy, Spinal / genetics,  therapy*
Oligonucleotides, Antisense / genetics,  therapeutic use*
RNA Splicing
RNA, Messenger / genetics
Spinal Cord / pathology
Survival of Motor Neuron 1 Protein
Survival of Motor Neuron 2 Protein
Grant Support
ID/Acronym/Agency:
R01 HD060586/HD/NICHD NIH HHS; R01 HD060586/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Oligonucleotides, Antisense; 0/RNA, Messenger; 0/Survival of Motor Neuron 1 Protein; 0/Survival of Motor Neuron 2 Protein
Comments/Corrections

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


Previous Document:  Phosphino-Boryl-Naphthalenes: Geometrically Enforced, Yet Lewis Acid Responsive P ? B Interactions.
Next Document:  HUVEC biocompatibility and platelet activation of segmented polyurethanes prepared with either gluta...