FSHD is a rare genetic muscular disorder, usually presenting with slow progressing and asymmetric muscle weakness. The cause of FSHD is an expression of the transcription factor DUX4 in skeletal muscle, leading to a series of downstream events that result in skeletal muscle degeneration and wasting. Strategies aimed at reducing DUX4 expression in the skeletal muscle of FSHD patients are promising therapeutic approaches. The main challenge that has limited the 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 Transferrin receptor (TFRC) monoclonal antibodies to bind to and be internalized by muscle cells with the potency and specificity of siRNA payloads to downregulate target RNA.
We have conducted a comprehensive in vitro screening of a DUX4 siRNA library in 11 FSHD patient-derived muscle cells, that allowed us to select highly potent siRNA sequences with minimal off-target profile. The selected lead DUX4 siRNAs were conjugated to the murine TFRC antibody to generate DUX4 AOCs. The pharmacology of the DUX4 AOCs was characterized in ACTA1-MCM; FLExDUX4 mouse model of FSHD. A robust dose responsive activity was observed at least one month after single IV dose of DUX4 AOC, with over 75% downregulation of DUX4-target genes in skeletal muscles. Data presented herein provide rationale and support for entering the clinic with the DUX4 AOC for the treatment of FSHD in 2022.