Development of a <i>DUX4</i> -targeting antibody oligonucleotide conjugate as a therapy for FSHD

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease in which genetic mutations activate DUX4 expression in skeletal muscle. Currently, there are no approved therapies for FSHD. We developed Delpacibart braxlosiran (del-brax, also known as AOC 1020), an antibody oligonucleotide conjugate (AOC), for the treatment of FSHD that is designed to specifically target and reduce DUX4 mRNA in skeletal muscle. AOC 1020 is composed of DUX4 mRNA-targeting small interfering RNA (siRNA), siDUX4.6, conjugated to a human transferrin receptor 1 (TfR1)-targeting monoclonal antibody to facilitate productive siRNA delivery to muscle. We demonstrate that siDUX4.6 reduces DUX4-regulated gene expression in FSHD patient-derived myotubes in vitro and in skeletal muscle of the ACTA1-MCM; FLExDUX4 FSHD mouse model in vivo. Single systemic intravenous treatment was sufficient to prevent DUX4-induced muscle weakness and fibrosis in this FSHD mouse model and reduce DUX4-regulated genes by ∼75% 8 weeks post-dose. The pharmacokinetic profiles of AOCs with siDUX4.6 were comparable in murine and non-human primate muscle. These data demonstrate the potential of AOC 1020 to treat the underlying cause of FSHD by suppressing DUX4 expression in muscles of patients with FSHD. The safety and efficacy of AOC 1020 is currently being investigated in clinical trials.