Daman Katelyn, Yan Jing, Biscans Annabelle, Echeverria Dimas, Shmushkovich Taisia, Wolfson Alexey, Alterman Julia F, Khvorova Anastasia, Emerson Charles P
Wellstone Muscular Dystrophy Program, Department of Neurology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Li Weibo Institute for Rare Disease Research, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA.
Mol Ther Methods Clin Dev. 2025 Jun 16;33(3):101513. doi: 10.1016/j.omtm.2025.101513. eCollection 2025 Sep 11.
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, 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 . 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, as a disease-targeting therapeutic for clinical development.
面肩肱型肌营养不良症（FSHD）是第三大最常被诊断出的肌营养不良症。该疾病由遗传和表观遗传干扰引起，导致生殖系转录因子DUX4在骨骼肌中错误表达，从而导致肌肉毒性和更新。作为一种仅在肌肉中错误表达的基因，DUX4适合进行肌肉靶向小干扰RNA（siRNA）敲低治疗。在这里，我们鉴定出一种靶向DUX4的siRNA，即DU01，它能有效敲低FSHD患者来源的肌管中DUX4靶基因的表达。此外，与脂质二十二烷酸（DCA）偶联的DU01可通过皮下注射全身递送至小鼠体内，从而在FSHD患者肌肉异种移植中实现对DUX4靶基因超过50%的敲低。这些发现确定了与DCA偶联的DUX4 siRNA（DCA-siRNA）作为一种用于临床开发的疾病靶向治疗药物。
