Facioscapulohumeral muscular dystrophy (FSHD) is a rare progressive genetic muscular disorder, usually presenting with asymmetric muscle weakness. The cause of FSHD is the aberrant ectopic 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 via oligonucleotides 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 oligonucleotides into muscle cells. Avidity’s AOC platform overcomes this challenge by combining the specificity of monoclonal antibodies with the precision of oligonucleotides to successfully deliver siRNA to muscle.
The AOC 1020 therapeutic candidate for FSHD consists of DUX4-targeted siRNA (siDUX4.6) conjugated to a humanized anti-transferrin receptor 1 (TfR1) antibody AV01mAb to facilitate delivery to muscle. SiDUX4.6 was selected via in vitro screening of a DUX4 siRNA library in 11 FSHD patient-derived primary myotubes to maximize potency and specificity.
The pharmacology of siDUX4.6 was characterized in an ACTA1-MCM; FLExDUX4 mouse model of FSHD expressing human DUX4. Robust activity in skeletal muscle was observed 8 weeks after single IV dose of murine TfR1 antibody-based DUX4 AOC, with over 75% reduction of DUX4-regulated genes at 6 mg/kg of siRNA dose. Single systemic treatment with DUX4 AOC also resulted in functional improvement of FSHD-like muscle phenotype in this mouse model. Transcriptomic analysis revealed the dysregulation of many genes and pathways upon induction of DUX4 expression in muscle of this mouse model, which was largely prevented with DUX4 AOC treatment. These data support the evaluation of DUX4-targeting AOC 1020 in the ongoing Phase 1/2 FORTITUDE trial in adults with FSHD.