Utrophin up-regulation by artificial transcription factors induces muscle rescue and impacts the neuromuscular junction in mdx mice

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1864

Article

Pisani, Cinzia¹  Strimpakos, Georgios^2,3  Gabanella, Francesca²  Di Certo, Maria Grazia²  Onori, Annalisa¹  Severini, Cinzia²  Luvisetto, Siro^2,3  Farioli-Vecchioli, Stefano^2,3  Carrozzo, Irene¹  Esposito, Antonio⁴  Canu, Tamara⁴  Mattei, Elisabetta^2,3  Corbi, Nicoletta¹  Passananti, Claudio¹ 

[1] Sapienza Univ, Inst Mol Biol & Pathol, CNR, Dept Mol Med, Viale Regina Elena 291, I-00161 Rome, Italy

[2] CNR Cell Biol & Neurobiol Inst, Rome, Italy

[3] IRCCS Santa Lucia Fdn, Rome, Italy

[4] Univ Vita Salute San Raffaele, Preclin Imaging Facil Expt Imaging Ctr, IRCCS San Raffaele Sci Inst, Milan, Italy

关键词: ZF-ATF;    Utrophin;    DMD;    NMJ;    AAV;    Gene therapy;   

DOI  :  10.1016/j.bbadis.2018.01.030

来源: Elsevier

【 摘 要 】

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 'A' 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.

【 授权许可】

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