A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins
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 fibroblast...
| Main Authors: | , , , , |
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| Language: | English |
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Elsevier
2013-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253116301779 |
| _version_ | 1819209568929972224 |
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| author | Pierre Chapdelaine Zoé Coulombe Amina Chikh Catherine Gérard Jacques P Tremblay |
| author_facet | Pierre Chapdelaine Zoé Coulombe Amina Chikh Catherine Gérard Jacques P Tremblay |
| author_sort | Pierre Chapdelaine |
| collection | DOAJ |
| description | 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 TALEFrat#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, TFAP2α, SRF, SP1, and MyoD) fused with the TALEFrat#8 gene did not produce a significant increase in the frataxin protein. Thus the TALEFrat#8-VP64 recombinant protein targeting the frataxin promoter could eventually be used to increase the frataxin expression and alleviate the FRDA symptoms. |
| first_indexed | 2024-12-23T05:57:22Z |
| format | Article |
| id | doaj.art-afb32bc8f95b4e60af938a918e7fc410 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-23T05:57:22Z |
| publishDate | 2013-01-01 |
| publisher | Elsevier |
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| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-afb32bc8f95b4e60af938a918e7fc4102022-12-21T17:57:46ZengElsevierMolecular Therapy: Nucleic Acids2162-25312013-01-012C10.1038/mtna.2013.41A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE ProteinsPierre Chapdelaine0Zoé Coulombe1Amina Chikh2Catherine Gérard3Jacques P Tremblay4Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, CanadaCentre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, CanadaTALEs 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 TALEFrat#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, TFAP2α, SRF, SP1, and MyoD) fused with the TALEFrat#8 gene did not produce a significant increase in the frataxin protein. Thus the TALEFrat#8-VP64 recombinant protein targeting the frataxin promoter could eventually be used to increase the frataxin expression and alleviate the FRDA symptoms.http://www.sciencedirect.com/science/article/pii/S2162253116301779Friedreich ataxiafrataxingene expressionTAL effectortranscription factor |
| spellingShingle | Pierre Chapdelaine Zoé Coulombe Amina Chikh Catherine Gérard Jacques P Tremblay A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins Molecular Therapy: Nucleic Acids Friedreich ataxia frataxin gene expression TAL effector transcription factor |
| title | A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins |
| title_full | A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins |
| title_fullStr | A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins |
| title_full_unstemmed | A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins |
| title_short | A Potential New Therapeutic Approach for Friedreich Ataxia: Induction of Frataxin Expression With TALE Proteins |
| title_sort | potential new therapeutic approach for friedreich ataxia induction of frataxin expression with tale proteins |
| topic | Friedreich ataxia frataxin gene expression TAL effector transcription factor |
| url | http://www.sciencedirect.com/science/article/pii/S2162253116301779 |
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