A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins

被引：22

作者：

Chapdelaine, Pierre ^{[1
,2
]}

Coulombe, Zoe ^{[1
,2
]}

Chikh, Amina ^{[1
,2
]}

Gerard, Catherine ^{[1
,2
]}

Tremblay, Jacques P. ^{[1
,2
]}

机构：

[1] Ctr Hosp Univ Quebec, Ctr Rech, Quebec City, PQ, Canada

[2] Univ Laval, Fac Med, Dept Mol Med, Quebec City, PQ G1K 7P4, Canada

来源：

MOLECULAR THERAPY-NUCLEIC ACIDS | 2013年 / 2卷

关键词：

Friedreich ataxia; frataxin; gene expression; TAL effector; transcription factor; EFFICIENT CONSTRUCTION; TRANSCRIPTION; GENE; EFFECTORS; MOUSE; IRON; TRANSDUCTION; PATHOGENESIS; DELIVERY;

D O I：

10.1038/mtna.2013.41

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

TALEs targeting a promoter sequence and fused with a transcription activation domain (TAD) may be used to specifically induce the expression of a gene as a potential treatment for haploinsufficiency. This potential therapeutic approach was applied to increase the expression of frataxin in fibroblasts of Friedreich ataxia (FRDA) patients. FRDA fibroblast cells were nucleofected with a pCR3.1 expression vector coding for TALE(Frat#8) fused with VP64. A twofold increase of the frataxin mRNA (detected by quantitative reverse transcription-PCR (qRT-PCR)) associated with a similar increase of the mature form of the frataxin protein was observed. The frataxin mRNA and protein were also increased by this TALE in the fibroblasts of the YG8R mouse model. The addition of 5-aza-2'-deoxycytidine (5-Aza-dC) or of valproic acid (VPA) to the TALE treatment did not produce significant improvement. Other TADs (i.e., p65, TFAP2 alpha, SRF, SP1, and MyoD) fused with the TALE(Frat#8) gene did not produce a significant increase in the frataxin protein. Thus the TALE(Frat#8)-VP64 recombinant protein targeting the frataxin promoter could eventually be used to increase the frataxin expression and alleviate the FRDA symptoms.

引用

页数：9

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