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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: Vanessa Strings-Ufombah (Author), Alberto Malerba (Author), Shih-Chu Kao (Author), Sonal Harbaran (Author), Fanny Roth (Author), Ornella Cappellari (Author), Ngoc Lu-Nguyen (Author), Keiko Takahashi (Author), Sophie Mukadam (Author), Georgina Kilfoil (Author), Claudia Kloth (Author), Petrus Roelvink (Author), George Dickson (Author), Capucine Trollet (Author), David Suhy (Author)
Format: Book
Published: Elsevier, 2021-06-01T00:00:00Z.
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Summary: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.
Item Description:2162-2531
10.1016/j.omtn.2021.02.017

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