Arrowhead Presents Preclinical Data on ARO-DUX4 at FSHD Society International Research Congress
Preclinical data demonstrated that Arrowhead’s Targeted RNAi Molecule (TRiM™) muscle delivery platform can achieve functional delivery to various types of skeletal muscle. Using RNAscope to detect RNAi, after a single 3 mg/kg intravenous (IV) dose in a mouse, 76-99% of myofibers in gastrocnemius contained TRiM™ RNAi. In addition, nonhuman primates receiving three doses of 10 mg/kg (day 1, 7, and 28) of a TRiM™ RNAi targeting myostatin achieved 79% serum myostatin knockdown with a greater than 70% reduction still being observed at week 12.
ARO-DUX4 also achieved dose-dependent knockdown of DUX4 and a deep reduction of DUX4 target gene expression in differentiated FSHD patient-derived myotubes. Additionally, ARO-DUX4 was evaluated in a transgenic FSHD-like mouse model, which has muscle-specific expression of human DUX4 and increased expression of DUX4 target genes. These animals develop a FSHD-like muscle phenotype which includes functional loss. In this model, ARO-DUX4 treatment:
- Prevented and reversed a tamoxifen-induced increase in DUX4 and DUX4 target gene expression
- Prevented DUX4-induced body weight loss
- Reversed DUX4-induced body weight loss by day 17 allowing a return to baseline body weight by day 22
- Prevented and reversed muscle fibrosis
- Prevented rotarod performance loss
- Reversed rotarod performance loss by day 15
A copy of the presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.
FSHD is an autosomal dominant disease associated with the failure to maintain complete epigenetic suppression of DUX4 expression in differentiated skeletal muscle, leading to overexpression of DUX4, which is myotoxic and can lead to muscle degeneration. As DUX4 expression is recognized as the cause of muscle pathology in FSHD patients, Arrowhead believes that the selective targeting and knockdown of DUX4 using RNAi may prevent or reverse downstream myotoxicity and lead to muscle repair and improvement in muscle function in patients. There are currently no effective treatments specifically for FSHD.
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