BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy - Sorbonne Université Access content directly
Journal Articles Molecular Therapy - Nucleic Acids Year : 2021

BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy

Abstract

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 codonoptimized 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.
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Dates and versions

hal-03176223 , version 1 (22-03-2021)

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Vanessa Strings-Ufombah, Alberto Malerba, Shih-Chu Kao, Sonal Harbaran, Fanny Roth, et al.. BB-301: a silence and replace AAV-based vector for the treatment of oculopharyngeal muscular dystrophy. Molecular Therapy - Nucleic Acids, 2021, 24, pp.67 - 78. ⟨10.1016/j.omtn.2021.02.017⟩. ⟨hal-03176223⟩
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