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Characterizing Exon Skipping Efficiency in DMD Patient Samples in Clinical Trials of Antisense Oligonucleotides
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Shorter Phosphorodiamidate Morpholino Splice-Switching Oligonucleotides May Increase Exon-Skipping Efficacy in DMD

Ugur Akpulat1, Haicui Wang2, Kerstin Becker2

  • 1Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne 50931, Germany; Department of Pediatrics, University Hospital Cologne, Cologne 50937, Germany; Department of Medical Biology, Faculty of Medicine, Kastamonu University, Kastamonu 37100, Turkey.

Molecular Therapy. Nucleic Acids
|November 6, 2018
PubMed

Insights

Shorter phosphorodiamidate morpholino splice-switching oligonucleotides (PMO-SSOs) show promise for Duchenne muscular dystrophy treatment. These PMO-SSOs may enable higher, more cost-effective dosing for improved dystrophin restoration in muscles.

Area of Science:

  • Molecular Biology
  • Genetics
  • Pharmacology

Background:

  • Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the DMD gene, resulting in a lack of functional dystrophin.
  • Current treatments using phosphorodiamidate morpholino splice-switching oligonucleotides (PMO-SSOs) like eteplirsen aim to restore dystrophin by skipping specific exons, but face challenges with low muscle uptake and high costs.
  • Eteplirsen (EXONDYS51), a 30-mer PMO targeting exon 51, is the first FDA-approved drug for DMD, though clinical trials showed variable dystrophin restoration.

Purpose of the Study:

  • To investigate the efficacy of shorter 25-mer PMO-SSOs targeting the same exon 51 region as eteplirsen.
  • To determine if shorter PMOs can achieve comparable dystrophin restoration to longer PMOs.
  • To assess the potential for shorter PMOs to enable economically feasible higher dosing strategies for DMD treatment.

Main Methods:

  • Design and synthesis of 25-mer PMO-SSOs targeting the eteplirsen-responsive region of DMD exon 51.
  • In vitro and in vivo comparative efficacy studies using the mdx52 murine model of DMD.
  • Assessment of exon-skipping efficacy and subsequent skipped-dystrophin induction.

Main Results:

  • One of the designed 25-mer PMO-SSOs demonstrated comparable skipped-dystrophin induction to the 30-mer PMO eteplirsen.
  • Other 25-mer PMO sequences exhibited lower exon-skipping efficacy.
  • These findings suggest that optimized shorter PMOs can be as effective as longer ones in restoring dystrophin.

Conclusions:

  • Shorter PMO-SSOs targeting exon 51 are a viable alternative to longer PMOs for Duchenne muscular dystrophy.
  • The development of cost-effective shorter PMOs could facilitate higher dosing regimens.
  • Higher dosing of PMO-SSOs is expected to improve drug uptake, enhance dystrophin restoration levels, and ultimately increase clinical efficacy in DMD patients.
Keywords:
DMDPMOdystrophineteplirsenexon skippingexondys51mdxmyopathyphosphorodiamidate morpholinophosphorothiorateshorter PMO-SSOs

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