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Silencing primary dystonia: lentiviral-mediated RNA interference therapy for DYT1 dystonia.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2005 Nov 09; Vol. 25 (45), pp. 10502-9. - Publication Year :
- 2005
-
Abstract
- DYT1 is the most common inherited dystonia. Currently, there are no preventive or curative therapies for this dominantly inherited disease. DYT1 dystonia is caused by a common three-nucleotide deletion in the TOR1A gene that eliminates a glutamic acid residue from the protein torsinA. Recent studies suggest that torsinA carrying the disease-linked mutation, torsinA(DeltaE) acts through a dominant-negative effect by recruiting wild-type torsinA [torsinA(wt)] into oligomeric structures in the nuclear envelope. Therefore, suppressing torsinA(DeltaE) expression through RNA interference (RNAi) could restore the normal function of torsinA(wt), representing a potentially effective therapy regardless of the biological role of torsinA. Here, we have generated short hairpin RNAs (shRNAs) that mediate allele-specific suppression of torsinA(DeltaE) and rescue cells from its dominant-negative effect, restoring the normal distribution of torsinA(wt). In addition, delivery of this shRNA by a recombinant feline immunodeficiency virus effectively silenced torsinA(DeltaE) in a neural model of the disease. We further establish the feasibility of this viral-mediated RNAi approach by demonstrating significant suppression of endogenous torsinA in mammalian neurons. Finally, this silencing of torsinA is achieved without triggering an interferon response. These results support the potential use of viral-mediated RNAi as a therapy for DYT1 dystonia and establish the basis for preclinical testing in animal models of the disease.
- Subjects :
- Animals
Blotting, Western methods
Cell Count methods
Cells, Cultured
Cerebral Cortex cytology
Chlorocebus aethiops
Ciprofloxacin analogs & derivatives
Cloning, Molecular methods
Doxycycline
Dystonia metabolism
Embryo, Mammalian
Fluorescent Antibody Technique methods
Gene Expression Regulation genetics
Gene Expression Regulation physiology
Gene Silencing drug effects
Green Fluorescent Proteins metabolism
Humans
Interferons pharmacology
Mice
Molecular Chaperones genetics
Mutagenesis physiology
Neurons drug effects
Neurons metabolism
Organotechnetium Compounds
RNA, Small Interfering genetics
Sequence Deletion physiology
Transfection methods
Dystonia drug therapy
Gene Silencing physiology
Lentivirus physiology
Molecular Chaperones metabolism
RNA, Small Interfering therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 25
- Issue :
- 45
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 16280588
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.3016-05.2005