A systemically deliverable lipid-conjugated siRNA targeting DUX4 as an facioscapulohumeral muscular dystrophy therapeutic.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most diagnosed muscular dystrophy. The disease is caused by genetic and epigenetic disruptions that result in misexpression of the germline transcription factor DUX4 in skeletal muscle, leading to muscle toxicity and turnover. As a gene misexpressed exclusively in muscle, DUX4 is a suitable for muscle-targeted small interfering RNA (siRNA) knockdown therapy. Here we identify a DUX4-targeting siRNA, DU01, that potently knocks down the expression of DUX4 target genes in FSHD patient-derived myotubes ex vivo. Further, DU01 conjugated with the lipid docosanoic acid (DCA) is systemically deliverable to mice by subcutaneous injection to achieve greater than 50% knockdown of DUX4 target genes in FSHD patient muscle xenografts. These findings identify the DCA-conjugated DUX4 siRNA, DCA-siRNA(DUX4), as a disease-targeting therapeutic for clinical development.