Facioscapulohumeral muscular dystrophy (FSHD) is a severe muscle wasting disease caused by the aberrant expression of DUX4. Activation of DUX4 in skeletal muscle triggers a cascade of transcriptional changes, ultimately leading to myocyte cell death. Genetic silencing of DUX4 represents a promising disease modifying therapy for FSHD.
Soufflé Therapeutics has leveraged a propriety discovery platform to enable muscle-selective functional delivery of genetic therapeutics. This receptor-mediated delivery pathway offers a differentiated selectivity and safety profile compared to other approaches. Our proprietary antibody to the myocyte receptor was used to generate antibody-siRNA conjugates that can be administered intravenously or subcutaneously. In mouse, a single administration achieves both potent (IC50 <0.05 mg/kg) and sustained silencing of target transcripts in striated muscle, while sparing off-target tissues. This muscle-specific delivery has been confirmed in non-human primates. SFL-0821 is a covalent conjugate comprised of Soufflé’s proprietary myocyte-targeting antibody and an siRNA that is highly specific for the human DUX4 transcript. We administered SFL-0821 into Acta-MCM;FLExDUX4 mice, which express tamoxifen-inducible human DUX4 and show FSHD-like pathophysiology upon induction. A single intravenous administration of SFL-0821 resulted in potent and dose-dependent silencing of DUX4 mRNA (>80%) in skeletal muscle that persisted for 3 months. Immunohistochemical analysis revealed a substantial reduction of nuclear DUX4 protein expression, consistent with an observed downregulation of DUX4-regulated transcripts. Knockdown of DUX4 was associated with increased muscle mass and improved muscle function in tamoxifen-induced mice. Our non-clinical data support the potential of SFL-0821 as a novel therapeutic to help people living with FSHD and we are planning to initiate a clinical trial in 2026.