Cationic PMMA nanoparticles bind and deliver antisense oligoribonucleotides allowing restoration of dystrophin expression in the mdx mouse

Paola Rimessi, Patrizia Sabatelli, Marina Fabris, Paola Braghetta, Elena Bassi, Pietro Spitali, Gaetano Vattemi, Giuliano Tomelleri, Lara Mari, Daniela Perrone, Alessandro Medici, Marcella Neri, Matteo Bovolenta, Elena Martoni, Nadir M. Maraldi, Francesca Gualandi, Luciano Merlini, Marco Ballestri, Luisa Tondelli, Katia SparnacciPaolo Bonaldo, Antonella Caputo, Michele Laus, Alessandra Ferlini

Research output: Contribution to journalArticlepeer-review

Abstract

For subsets of Duchenne muscular dystrophy (DMD) mutations, antisense oligoribonucleotide (AON)-mediated exon skipping has proven to be efficacious in restoring the expression of dystrophin protein. In the mdx murine model systemic delivery of AON, recognizing the splice donor of dystrophin exon 23, has shown proof of concept. Here, we show that using cationic polymethylmethacrylate (PMMA) (marked as T1) nanoparticles loaded with a low dose of 2′-O-methyl-phosphorothioate (2′OMePS) AON delivered by weekly intraperitoneal (IP) injection (0.9 mg/kg/week), could restore dystrophin expression in body-wide striated muscles. Delivery of an identical dose of naked AON did not result in detectable dystrophin expression. Transcription, western, and immunohistochemical analysis showed increased levels of dystrophin transcript and protein, and correct localization at the sarcolemma. This study shows that T1 nanoparticles have the capacity to bind and convoy AONs in body-wide muscle tissues and to reduce the dose required for dystrophin rescue. By immunofluorescence and electron microscopy studies, we highlighted the diffusion pathways of this compound. This nonviral approach may valuably improve the therapeutic usage of AONs in DMD as well as the delivery of RNA molecules with many implications in both basic research and medicine.

Original languageEnglish
Pages (from-to)820-827
Number of pages8
JournalMolecular Therapy
Volume17
Issue number5
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Genetics
  • Drug Discovery
  • Pharmacology

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