Abstract
Up-regulation of the dystrophin-related gene utrophin represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy (DMD). In order to re-program the utrophin expression level in muscle, we engineered artificial zinc finger transcription factors (ZF-ATFs) that target the utrophin ʻAʼ promoter. We have previously shown that the ZF-ATF “Jazz”, either by transgenic manipulation or by systemic adeno-associated viral delivery, induces significant rescue of muscle function in dystrophic “mdx” mice. We present the full characterization of an upgraded version of Jazz gene named “JZif1” designed to minimize any possible host immune response. JZif1 was engineered on the Zif268 gene-backbone using selective amino acid substitutions to address JZif1 to the utrophin ‘A’ promoter. Here, we show that JZif1 induces remarkable amelioration of the pathological phenotype in mdx mice. To investigate the molecular mechanisms underlying Jazz and JZif1 induced muscle functional rescue, we focused on utrophin related pathways. Coherently with utrophin subcellular localization and role in neuromuscular junction (NMJ) plasticity, we found that our ZF-ATFs positively impact the NMJ. We report on ZF-ATF effects on post-synaptic membranes in myogenic cell line, as well as in wild type and mdx mice. These results candidate our ZF-ATFs as novel therapeutic molecules for DMD treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 1172-1182 |
| Number of pages | 11 |
| Journal | Biochimica et Biophysica Acta - Molecular Basis of Disease |
| Volume | 1864 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Apr 1 2018 |
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Keywords
- AAV
- DMD
- Gene therapy
- NMJ
- Utrophin
- ZF-ATF
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
Cite this
Utrophin up-regulation by artificial transcription factors induces muscle rescue and impacts the neuromuscular junction in mdx mice. / Pisani, Cinzia; Strimpakos, Georgios; Gabanella, Francesca; Di Certo, Maria Grazia; Onori, Annalisa; Severini, Cinzia; Luvisetto, Siro; Farioli-Vecchioli, Stefano; Carrozzo, Irene; Esposito, Antonio; Canu, Tamara; Mattei, Elisabetta; Corbi, Nicoletta; Passananti, Claudio.
In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1864, No. 4, 01.04.2018, p. 1172-1182.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Utrophin up-regulation by artificial transcription factors induces muscle rescue and impacts the neuromuscular junction in mdx mice
AU - Pisani, Cinzia
AU - Strimpakos, Georgios
AU - Gabanella, Francesca
AU - Di Certo, Maria Grazia
AU - Onori, Annalisa
AU - Severini, Cinzia
AU - Luvisetto, Siro
AU - Farioli-Vecchioli, Stefano
AU - Carrozzo, Irene
AU - Esposito, Antonio
AU - Canu, Tamara
AU - Mattei, Elisabetta
AU - Corbi, Nicoletta
AU - Passananti, Claudio
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Up-regulation of the dystrophin-related gene utrophin represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy (DMD). In order to re-program the utrophin expression level in muscle, we engineered artificial zinc finger transcription factors (ZF-ATFs) that target the utrophin ʻAʼ promoter. We have previously shown that the ZF-ATF “Jazz”, either by transgenic manipulation or by systemic adeno-associated viral delivery, induces significant rescue of muscle function in dystrophic “mdx” mice. We present the full characterization of an upgraded version of Jazz gene named “JZif1” designed to minimize any possible host immune response. JZif1 was engineered on the Zif268 gene-backbone using selective amino acid substitutions to address JZif1 to the utrophin ‘A’ promoter. Here, we show that JZif1 induces remarkable amelioration of the pathological phenotype in mdx mice. To investigate the molecular mechanisms underlying Jazz and JZif1 induced muscle functional rescue, we focused on utrophin related pathways. Coherently with utrophin subcellular localization and role in neuromuscular junction (NMJ) plasticity, we found that our ZF-ATFs positively impact the NMJ. We report on ZF-ATF effects on post-synaptic membranes in myogenic cell line, as well as in wild type and mdx mice. These results candidate our ZF-ATFs as novel therapeutic molecules for DMD treatment.
AB - Up-regulation of the dystrophin-related gene utrophin represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy (DMD). In order to re-program the utrophin expression level in muscle, we engineered artificial zinc finger transcription factors (ZF-ATFs) that target the utrophin ʻAʼ promoter. We have previously shown that the ZF-ATF “Jazz”, either by transgenic manipulation or by systemic adeno-associated viral delivery, induces significant rescue of muscle function in dystrophic “mdx” mice. We present the full characterization of an upgraded version of Jazz gene named “JZif1” designed to minimize any possible host immune response. JZif1 was engineered on the Zif268 gene-backbone using selective amino acid substitutions to address JZif1 to the utrophin ‘A’ promoter. Here, we show that JZif1 induces remarkable amelioration of the pathological phenotype in mdx mice. To investigate the molecular mechanisms underlying Jazz and JZif1 induced muscle functional rescue, we focused on utrophin related pathways. Coherently with utrophin subcellular localization and role in neuromuscular junction (NMJ) plasticity, we found that our ZF-ATFs positively impact the NMJ. We report on ZF-ATF effects on post-synaptic membranes in myogenic cell line, as well as in wild type and mdx mice. These results candidate our ZF-ATFs as novel therapeutic molecules for DMD treatment.
KW - AAV
KW - DMD
KW - Gene therapy
KW - NMJ
KW - Utrophin
KW - ZF-ATF
UR - http://www.scopus.com/inward/record.url?scp=85041376501&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041376501&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2018.01.030
DO - 10.1016/j.bbadis.2018.01.030
M3 - Article
AN - SCOPUS:85041376501
VL - 1864
SP - 1172
EP - 1182
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 4
ER -