Facioscapulohumeral Muscular Dystrophy (FSHD) is a rare genetic muscular disease and is one of the most common forms of muscular dystrophy with onset typically in teens and young adults. The cause of FSHD is an aberrant expression of the transcription factor DUX4 in skeletal muscle, leading to a gene deregulation cascade that results in progressive skeletal muscle loss and wasting. There are currently no approved disease modifying treatments available. Strategies aimed at reducing DUX4 expression in the skeletal muscle of FSHD patients offer a promising therapeutic approach. The main challenge limiting clinical development of oligonucleotide therapeutics for muscular diseases has been the difficulty of delivering the oligonucleotides into muscle cells. Avidity’s Antibody-Oligonucleotide Conjugate (AOC™) platform combines the power of monoclonal antibodies to bind to and be internalized by specific cells with the potency and specificity of siRNAs to reduce target mRNA. Our goal is to leverage the activity of Avidity’s AOC™ platform in skeletal muscle and develop an AOC™ consisting of the human Transferrin Receptor 1 (TFRC) antibody conjugated to a DUX4 siRNA as a treatment for FSHD. To this aim, we have performed a series of in vitro DUX4 siRNA screening studies in a variety of FSHD patient-derived myotubes, that have allowed us to select the most potent siRNA sequences with minimal off-target profile. Ultimately, the best DUX4 siRNA will be conjugated to the TFRC antibody to generate the therapeutic AOC™ for FSHD that will be further characterized in vivo.