BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy.
AAV
OPMD
PABPN1
gene therapy
oculopharyngeal muscular dystrophy
siRNA
silence and replace
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:
04 Jun 2021
04 Jun 2021
Historique:
received:
02
07
2020
accepted:
14
02
2021
entrez:
19
3
2021
pubmed:
20
3
2021
medline:
20
3
2021
Statut:
epublish
Résumé
Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant disease that results from an alanine expansion in the N-terminal domain of Poly-A Binding Protein Nuclear-1 (PABPN1). We have recently demonstrated that a two-vector gene therapy strategy significantly ameliorated the pathology in a mouse model of OPMD. This approach entailed intramuscular injection of two recombinant adeno-associated viruses (AAVs), one expressing three short hairpin RNAs (shRNAs) to silence both mutant and wild-type PABPN1 and one expressing a codon-optimized version of PABPN1 that is insensitive to RNA interference. Here we report the continued development of this therapeutic strategy by delivering "silence and replace" sequences in a single AAV vector named BB-301. This construct is composed of a modified AAV serotype 9 (AAV9) capsid that expresses a unique single bifunctional construct under the control of the muscle-specific Spc5-12 promoter for the co-expression of both the codon-optimized PABPN1 protein and two small inhibitory RNAs (siRNAs) against PABPN1 modeled into microRNA (miRNA) backbones. A single intramuscular injection of BB-301 results in robust inhibition of mutant PABPN1 and concomitant replacement of the codon-optimized PABPN1 protein. The treatment restores muscle strength and muscle weight to wild-type levels as well as improving other physiological hallmarks of the disease in a mouse model of OPMD.
Identifiants
pubmed: 33738139
doi: 10.1016/j.omtn.2021.02.017
pii: S2162-2531(21)00052-4
pmc: PMC7940701
doi:
Types de publication
Journal Article
Langues
eng
Pagination
67-78Informations de copyright
© 2021 The Authors.
Déclaration de conflit d'intérêts
V.S., S.H., K.T., and D.S. are former employees of Benitec Biopharma. S.-C.K., C.K., S.M., and P.R. are current employees of Benitec Biopharma and have financial interest in the development of BB-301 products. A patent named “Reagents for treatment of oculopharyngeal muscular dystrophy (OPMD) and use thereof” has been filed by Benitec Biopharma and includes D.S., A.M., G.D., and C.T. as named inventors. All other authors have no conflict of interest.
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