Document Detail

Restoration of Cytoskeleton Homeostasis After Gigaxonin Gene Transfer for Giant Axonal Neuropathy.
MedLine Citation:
PMID:  23316953     Owner:  NLM     Status:  Publisher    
Giant axonal neuropathy (GAN) is caused by loss of function of the gigaxonin protein. On a cellular level GAN is characterized by intermediate filament (IF) aggregation, leading to a progressive and fatal peripheral neuropathy in humans. This study sought to determine if re-introduction of the GAN gene into GAN-deficient cells and mice would restore proper cytoskeleton IF homeostasis. Treatment of primary skin fibroblast cultures from three different GAN patients with an adeno-associated virus type 2 (AAV2) vector containing a normal human GAN transgene significantly reduced the number of cells displaying vimentin IF aggregates. A proteomic analysis of these treated cells was also performed, wherein the abundance of 32/780 identified proteins significantly changed in response to gigaxonin gene transfer. While 29 of these responding proteins have not been directly described in association with gigaxonin, 3 were previously identified as being disregulated in GAN and were now shifted toward normal levels. To assess the potential application of this approach in vivo and eventually in humans, GAN mice received an intracisternal injection of an AAV9/GAN vector to globally deliver the GAN gene to the brainstem and spinal cord. The treated mice showed a nearly complete clearance of peripherin IF accumulations at three weeks post-injection. These studies demonstrate that gigaxonin gene transfer can reverse the cellular IF aggregate pathology associated with GAN.
Silke Mussche; Bart Devreese; Sahana Nagabhushan Kalburgi; Lavanya Bachaboina; Jonathan Clay Fox; Hung-Jui Sophia Shih; R Jude Samulski; Rudy Van Coster; Steven James Gray
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  Human gene therapy     Volume:  -     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Ghent University Hospital, Department of Pediatrics, Ghent, Belgium;
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