RNA-Based Therapy Utilizing Oculopharyngeal Muscular Dystrophy Transcript Knockdown and Replacement.
OPMD
PABPN1
RNA replacement therapy
microRNAs
polyalanine disorders
ribozymes
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
15 Apr 2019
15 Apr 2019
Historique:
received:
02
06
2018
revised:
08
02
2019
accepted:
10
02
2019
pubmed:
5
3
2019
medline:
5
3
2019
entrez:
5
3
2019
Statut:
ppublish
Résumé
Oculopharyngeal muscular dystrophy (OPMD) is caused by a small expansion of a short polyalanine (polyAla) tract in the poly(A)-binding protein nuclear 1 protein (PABPN1). Despite the monogenic nature of OPMD, no treatment is currently available. Here we report an RNA replacement strategy that has therapeutic potential in cell and C. elegans OPMD models. We develop selective microRNAs (miRNAs) against PABPN1, and we report that miRNAs and our previously developed hammerhead ribozymes (hhRzs) are capable of reducing the expression of both the mRNA and protein levels of PABPN1 by as much as 90%. Since OPMD derives from a very small expansion of GCG within the polyAla tract, our hhRz and miRNA molecules cannot distinguish between the wild-type and mutant mRNAs of PABPN1. Therefore, we designed an optimized-codon wild-type PABPN1 (opt-PABPN1) that is resistant to cleavage by hhRzs and miRNAs. Co-expression of opt-PABPN1 with either our hhRzs or miRNAs restored the level of PABPN1, concomitantly with a reduction in expanded PABPN1-associated cell death in a stable C2C12 OPMD model. Interestingly, knockdown of the PABPN1 by selective hhRzs in the C. elegans OPMD model significantly improved the motility of the PABPN1-13Ala worms. Taken together, RNA replacement therapy represents an exciting approach for OPMD treatment.
Identifiants
pubmed: 30831428
pii: S2162-2531(19)30033-2
doi: 10.1016/j.omtn.2019.02.003
pmc: PMC6403420
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
12-25Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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