Injectable hydrogel microspheres for sustained gene delivery of antisense oligonucleotides to restore the expression of dystrophin protein in duchenne muscular dystrophy

Shani Attias Cohen, Haneen Simaan-Yameen, Claudia Fuoco, Cesare Gargioli, Dror Seliktar

Research output: Contribution to journalReview articlepeer-review

7 Scopus citations

Abstract

Duchenne muscular dystrophy (DMD) is a genetic disease characterized by the absence of functional dystrophin protein. Antisense oligonucleotides (AONs) exon-skipping is one of the most promising therapeutic strategies for the treatment of DMD. In order to increase stability and enhance the cellular uptake of the AONs, polymeric carriers have been used as an efficient approach for AON delivery. Here we designed a hydrogel-based strategy for encapsulation of therapeutic, chemically modified 2′-O-methyl phosphorothioate (2OMePs) AONs in injectable PEG-Fibrinogen (PF) microspheres. The PF microspheres function as a controlled-release system that can improve the pharmacokinetic properties, increase their stability and greatly decrease the overall administered dosage. The PF microspheres were fabricated using a dual photo-initiator emulsion method: they were successfully loaded with 2OMePs AONs and proved to be injectable and cytocompatible with in vitro cultures of C2C12 mouse myoblasts. The in vitro release of the 2OMePs AONs was sustained for several weeks, concurrent to the degradation of the PF hydrogel. The released 2OMePs AONs were incorporated into murine myoblasts from an mdx dystrophic mouse model, showing sustained cellular uptake achieved using this controlled release strategy. The AON-laden PF microspheres were also administered intramuscularly into the tibialis anterior muscle of mdx dystrophic mice. Histology after 30 days revealed a marked reduction in both inflammation and fibrosis scores when compared to naked AON controls. The study concludes that the injectable PF microspheres are a good candidate for the controlled release of 2OMePs AONs, particularly in the development of better modalities for treating DMD.

Original languageEnglish
Article number111038
JournalEuropean Polymer Journal
Volume166
DOIs
StatePublished - 5 Mar 2022
Externally publishedYes

Keywords

  • Antisense oligonucleotides (AONs)
  • Controlled release
  • Duchenne muscular dystrophy (DMD)
  • Gene delivery
  • Hydrogel
  • PEG-Fibrinogen

ASJC Scopus subject areas

  • General Physics and Astronomy
  • Polymers and Plastics
  • Organic Chemistry
  • Materials Chemistry

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