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

Cinzia Pisani, Georgios Strimpakos, Francesca Gabanella, Maria Grazia Di Certo, Annalisa Onori, Cinzia Severini, Siro Luvisetto, Stefano Farioli-Vecchioli, Irene Carrozzo, Antonio Esposito, Tamara Canu, Elisabetta Mattei, Nicoletta Corbi, Claudio Passananti

Research output: Contribution to journalArticlepeer-review

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 languageEnglish
Pages (from-to)1172-1182
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1864
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

Keywords

  • AAV
  • DMD
  • Gene therapy
  • NMJ
  • Utrophin
  • ZF-ATF

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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