PMID- 27082765
OWN - NLM
STAT- MEDLINE
DCOM- 20170815
LR  - 20240325
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 23
IP  - 7
DP  - 2016 Jul
TI  - Development of an AAV9 coding for a 3XFLAG-TALEfrat#8-VP64 able to increase in 
      vivo the human frataxin in YG8R mice.
PG  - 606-14
LID - 10.1038/gt.2016.36 [doi]
AB  - Artificially designed transcription activator-like effector (TALE) proteins fused 
      to a transcription activation domain (TAD), such as VP64, are able to activate 
      specific eukaryotic promoters. They thus provide a good tool for targeted gene 
      regulation as a therapy. However, the efficacy of such an agent in vivo remains 
      to be demonstrated as the majority of studies have been carried out in cell 
      culture. We produced an adeno-associated virus 9 (AAV9) coding for a TALEfrat#8 
      containing 13 repeat variable diresidues able to bind to the proximal promoter of 
      human frataxin (FXN) gene. This TALEfrat#8 was fused with a 3XFLAG at its N 
      terminal and a VP64 TAD at its C terminal, and driven by a CAG promoter. This 
      AAV9_3XFLAG-TALEfrat#8-VP64 was injected intraperitoneally to 9-day-old and 
      4-month-old YG8R mice. After 1 month, the heart, muscle and liver were removed 
      and their FXN mRNA and FXN protein were analyzed. The results show that the 
      AAV9_3XFLAG-TALEfrat#8-VP64 increased the FXN mRNA and FXN protein in the three 
      organs studied. These results corroborate our previous in vitro studies in the 
      FRDA human fibroblasts. Our study indicates that an AAV coding for a TALE protein 
      coupled with a TAD may be used to increase gene expression in vivo as a possible 
      treatment not only for FRDA but also for other haploinsufficiency diseases.
FAU - Chapdelaine, P
AU  - Chapdelaine P
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Gerard, C
AU  - Gerard C
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Sanchez, N
AU  - Sanchez N
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Cherif, K
AU  - Cherif K
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Rousseau, J
AU  - Rousseau J
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Ouellet, D L
AU  - Ouellet DL
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Jauvin, D
AU  - Jauvin D
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
FAU - Tremblay, J P
AU  - Tremblay JP
AD  - Unite de Genetique Humaine, Axe Neurosciences, Centre de Recherche du Centre 
      Hospitalier de Universitaire de Quebec-Universite Laval, Quebec City, QC, Canada.
AD  - Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec 
      City, QC, Canada.
LA  - eng
PT  - Journal Article
DEP - 20160505
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Iron-Binding Proteins)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Dependovirus/*genetics
MH  - Friedreich Ataxia/*therapy
MH  - Gene Transfer Techniques
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/genetics
MH  - Humans
MH  - Injections, Intraperitoneal
MH  - Iron-Binding Proteins/*genetics/metabolism
MH  - Mice
MH  - Organ Specificity
MH  - Promoter Regions, Genetic
MH  - Frataxin
PMC - PMC4940929
COIS- JPT is conducting research on gene therapy for Friedreich's ataxia under a 
      research contract with Amorchem Inc. and a patent for such treatment has been 
      applied for by his university. The other authors declare no conflict of interest.
EDAT- 2016/04/16 06:00
MHDA- 2017/08/16 06:00
PMCR- 2016/07/12
CRDT- 2016/04/16 06:00
PHST- 2015/11/22 00:00 [received]
PHST- 2016/03/09 00:00 [revised]
PHST- 2016/04/07 00:00 [accepted]
PHST- 2016/04/16 06:00 [entrez]
PHST- 2016/04/16 06:00 [pubmed]
PHST- 2017/08/16 06:00 [medline]
PHST- 2016/07/12 00:00 [pmc-release]
AID - gt201636 [pii]
AID - 10.1038/gt.2016.36 [doi]
PST - ppublish
SO  - Gene Ther. 2016 Jul;23(7):606-14. doi: 10.1038/gt.2016.36. Epub 2016 May 5.