BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy
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 i...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Book |
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Elsevier,
2021-06-01T00:00:00Z.
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| 001 | doaj_a38e66f16de34830a7d74e6ea8d9e973 | ||
| 042 | |a dc | ||
| 100 | 1 | 0 | |a Vanessa Strings-Ufombah |e author |
| 700 | 1 | 0 | |a Alberto Malerba |e author |
| 700 | 1 | 0 | |a Shih-Chu Kao |e author |
| 700 | 1 | 0 | |a Sonal Harbaran |e author |
| 700 | 1 | 0 | |a Fanny Roth |e author |
| 700 | 1 | 0 | |a Ornella Cappellari |e author |
| 700 | 1 | 0 | |a Ngoc Lu-Nguyen |e author |
| 700 | 1 | 0 | |a Keiko Takahashi |e author |
| 700 | 1 | 0 | |a Sophie Mukadam |e author |
| 700 | 1 | 0 | |a Georgina Kilfoil |e author |
| 700 | 1 | 0 | |a Claudia Kloth |e author |
| 700 | 1 | 0 | |a Petrus Roelvink |e author |
| 700 | 1 | 0 | |a George Dickson |e author |
| 700 | 1 | 0 | |a Capucine Trollet |e author |
| 700 | 1 | 0 | |a David Suhy |e author |
| 245 | 0 | 0 | |a BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy |
| 260 | |b Elsevier, |c 2021-06-01T00:00:00Z. | ||
| 500 | |a 2162-2531 | ||
| 500 | |a 10.1016/j.omtn.2021.02.017 | ||
| 520 | |a 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. | ||
| 546 | |a EN | ||
| 690 | |a oculopharyngeal muscular dystrophy | ||
| 690 | |a OPMD | ||
| 690 | |a gene therapy | ||
| 690 | |a AAV | ||
| 690 | |a silence and replace | ||
| 690 | |a PABPN1 | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Molecular Therapy: Nucleic Acids, Vol 24, Iss , Pp 67-78 (2021) | |
| 787 | 0 | |n http://www.sciencedirect.com/science/article/pii/S2162253121000524 | |
| 787 | 0 | |n https://doaj.org/toc/2162-2531 | |
| 856 | 4 | 1 | |u https://doaj.org/article/a38e66f16de34830a7d74e6ea8d9e973 |z Connect to this object online. |