Muscle targeting complexes and uses thereof for treating dystrophinopathies

A composition comprising complexes comprising an anti-transferrin receptor (TfR) antibody covalently linked to at least one oligonucleotide, wherein the antibody is a Fab and comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:

• 101 and a light chain comprising the amino acid sequence of SEQ ID NO:
• 90, and wherein each anti-TfR antibody of the complexes is on average covalently linked to 1 to 3 oligonucleotides, and wherein the oligonucleotide induces dystrophin exon 45 skipping, wherein the complexes of the composition comprise a structure of:
• wherein n is 3 and m is 4, wherein L1 comprises a spacer that is a substituted or unsubstituted aliphatic, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, —O—, —N(RA)—, —S—, —C(═O)—, —C(═O)O—, —C(═O)NRA—, —NRAC(═O)—, —NRAC(═O)RA—, —C(═O)RA—, —NRAC(═O)O—, —NRAC(═O)N(RA)—, —OC═—, —O(═O)—, —OC(═O)N(RA)—, —S(O)2NRA—, —NRAS(O)2—, or a combination thereof, wherein each RA is independently hydrogen or substituted or unsubstituted alkyl.