Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes transdifferentiated from DMD patient fibroblasts

PloS One
Joshua LeeToshifumi Yokota

Abstract

Antisense-mediated exon skipping has made significant progress as a therapeutic platform in recent years, especially in the case of Duchenne muscular dystrophy (DMD). Despite FDA approval of eteplirsen-the first-ever antisense drug clinically marketed for DMD-exon skipping therapy still faces the significant hurdles of limited applicability and unknown truncated protein function. In-frame exon skipping of dystrophin exons 45-55 represents a significant approach to treating DMD, as a large proportion of patients harbor mutations within this "hotspot" region. Additionally, patients harboring dystrophin exons 45-55 deletion mutations are reported to have exceptionally mild to asymptomatic phenotypes. Here, we demonstrate that a cocktail of phosphorodiamidate morpholino oligomers can effectively skip dystrophin exons 45-55 in vitro in myotubes transdifferentiated from DMD patient fibroblast cells. This is the first report of substantive exons 45-55 skipping in DMD patient cells. These findings help validate the use of transdifferentiated patient fibroblast cells as a suitable cell model for dystrophin exon skipping assays and further emphasize the feasibility of dystrophin exons 45-55 skipping in patients.

References

Aug 1, 1986·Molecular and Cellular Biology·A D Miller, C Buttimore
Jul 27, 2001·Human Molecular Genetics·J C van DeutekomG J van Ommen
Apr 2, 2003·Human Molecular Genetics·Annemieke Aartsma-RusJudith C T van Deutekom
Feb 12, 2008·Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia·Akinori NakamuraShu-Ichi Ikeda
Dec 3, 2008·BMC Medical Genetics·Laura van VlietAnnemieke Aartsma-Rus
Jan 14, 2009·Archives of Neurology·Toshifumi YokotaEric P Hoffman
Jan 22, 2009·Human Mutation·Annemieke Aartsma-RusJohan T den Dunnen
Feb 23, 2010·Biochimica Et Biophysica Acta·Hong M Moulton, Jon D Moulton
Dec 24, 2010·Molecular Therapy : the Journal of the American Society of Gene Therapy·Bo WuQi Long Lu
Mar 15, 2011·Journal of Neurology·Francesca MagriGiacomo Pietro Comi
Mar 28, 2012·Annals of Neurology·Jerry R MendellRobert B Weiss
Aug 8, 2012·Proceedings of the National Academy of Sciences of the United States of America·Yoshitsugu AokiShin'ichi Takeda
Sep 4, 2012·Physical Medicine and Rehabilitation Clinics of North America·Nanette C JoyceLee-Way Jin
May 2, 2014·Neuromuscular Disorders : NMD·Jean K MahNathalie Jette
Jul 20, 2014·Neurologic Clinics·Kevin M Flanigan
Jan 1, 2013·Journal of Personalized Medicine·Joshua J A Lee, Toshifumi Yokota
Nov 18, 2015·Annals of Neurology·Jerry R MendellUNKNOWN Eteplirsen Study Group and Telethon Foundation DMD Italian Network
Apr 21, 2016·ACS Applied Materials & Interfaces·Didem MumcuogluMustafa O Guler
Dec 9, 2016·Nucleic Acid Therapeutics·Annemieke Aartsma-Rus, Arthur M Krieg
Dec 13, 2016·Expert Opinion on Biological Therapy·Erik H Niks, Annemieke Aartsma-Rus
Mar 11, 2017·Drug Design, Development and Therapy·Kenji Rowel Q LimToshifumi Yokota
Jan 6, 2018·Biomedicines·Tejal AsleshToshifumi Yokota

❮ Previous
Next ❯

Citations

Dec 14, 2018·Journal of Personalized Medicine·Yusuke EchigoyaToshifumi Yokota
Jul 26, 2019·Current Opinion in Neurology·Megan A Waldrop, Kevin M Flanigan
Feb 11, 2021·European Journal of Human Genetics : EJHG·Vratko Himič, Kay E Davies
Dec 20, 2020·International Journal of Molecular Sciences·Wei ChiuHao-Min Cheng

❮ Previous
Next ❯

Datasets Mentioned

BETA
GM05017
GM05162
GM23815

Methods Mentioned

BETA
biopsy
transfection
flow
Flow Cytometry

Clinical Trials Mentioned

NCT02958202
NCT02667483
NCT03375255
NCT03167255

Software Mentioned

Gene Tools

Related Concepts

Related Feeds

Aminoglycosides (ASM)

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Antisense Oligonucleotides: ND

This feed focuses on antisense oligonucleotide therapies such as Inotersen, Nusinursen, and Patisiran, in neurodegenerative diseases including amyotrophic lateral sclerosis.

Aminoglycosides

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.