Enhanced exon skipping and prolonged dystrophin restoration achieved by TfR1-targeted delivery of antisense oligonucleotide using FORCE conjugation in mdx mice

Cody A Desjardins, Monica Yao, John Hall, Emma O’Donnell, Reshmii Venkatesan, Sean Spring, Aiyun Wen, Nelson Hsia, Peiyi Shen, Ryan Russo, Bo Lan, Tyler Picariello, Kim Tang, Timothy Weeden, Stefano Zanotti, Romesh Subramanian, Oxana Ibraghimov-Beskrovnay

Nucleic Acids Research, gkac641, https://doi.org/10.1093/nar/gkac641

Duchenne muscular dystrophy (DMD) results from mutations in the DMD gene that lead to loss of dystrophin, a protein critical for normal muscle function. Oligonucleotide-induced exon skipping enables the expression of a shortened but functional dystrophin. The efficacy of oligonucleotide-based approaches for DMD has been hampered by insufficient delivery to muscle. Here, we describe the development and application of FORCETM, a novel platform consisting of an antigen-binding fragment to the transferrin receptor 1 (TfR1) conjugated to an oligonucleotide. By leveraging TfR1 biology, we successfully delivered an exon-skipping phosphorodiamidate morpholino oligonucleotide to cardiac and skeletal muscle, restored dystrophin expression, and improved function in a mouse model of DMD. These results support the potential of FORCE conjugates for the treatment of DMD.

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