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 AAVs, one expressing three short hairpin RNAs (shRNAs) to silence both mutant and wildtype 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 siRNAs against PABPN1 modeled into 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 wildtype levels as well as improves other physiological hallmarks of the disease in a mouse model of OPMD.