To develop a therapy for Facioscapulohumeral Dystrophy (FSHD), a progressive muscular disease with no approved therapy, that arises from aberrant expression of the DUX4 gene in muscle.

FSHD is a rare genetic muscular disorder, usually presenting with slow progressing and asymmetric muscle weakness. The cause of FSHD is an 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 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 the oligonucleotides into muscle cells. Avidity’s Antibody-Oligonucleotide Conjugate (AOC) platform combines the power of Transferrin receptor (TFRC) monoclonal antibodies to bind to and be internalized by muscle cells with the potency and specificity of siRNA payloads to downregulate target RNA.

We conducted biochemical and cell-based studies with the lead DUX4 siRNA, as well as pharmacological evaluation of the clinical candidate DUX4 siRNA conjugated to murine TFRC antibody in Acta1-MCM; FLExDUX4 mouse model of FSHD.

We have conducted a comprehensive in vitro screening of a DUX4 siRNA library in 11 FSHD patient-derived muscle cells, that allowed us to select highly potent siRNA sequences with minimal off-target profile. The selected lead DUX4 siRNAs were conjugated to the murine TFRC antibody to generate DUX4 AOCs. The pharmacology of the DUX4 AOCs was characterized in mouse model of FSHD. A robust dose responsive activity was observed 3 weeks after single IV dose of DUX4 AOC, with over 75% downregulation of DUX4-target genes in skeletal muscles.

Data presented herein provide rationale and support for entering the clinic with the DUX4 AOC for the treatment of FSHD in 2022.

Disclosure: Dr. Malecova has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Malecova has received stock or an ownership interest from Avidity Biosciences. Dr. Sala has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Sala has received stock or an ownership interest from Avidity Biosciences. Ms. Melikian has received personal compensation for serving as an employee of Avidity Biosciences, Inc.. Ms. Melikian has received stock or an ownership interest from Avidity Biosciences, Inc. Dr. Erdogan has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Erdogan has received stock or an ownership interest from Avidity Biosciences. Dr. Johns has received personal compensation for serving as an employee of Avidity Biosciences, Inc. Dr. Johns has received stock or an ownership interest from Avidity Biosciences, Inc. Ms. Young has nothing to disclose. Dr. Ventre has received personal compensation for serving as an employee of CYTOO. Dr. Gatto has received personal compensation for serving as an employee of Monoceros Biosystems. The institution of an immediate family member of Dr. Gatto has received research support from NIH. Mr. Onorato has nothing to disclose. Dr. Pavlicek has nothing to disclose. Dr. Kiraly has received personal compensation for serving as an employee of The Jackson Laboratory. Dr. Koegler has nothing to disclose. Dr. Levin has received personal compensation for serving as an employee of Avidity Biosciences. Dr. Levin has received stock or an ownership interest …