Muscle targeting complexes and formulations for treating myotonic dystrophy
Aspects of the disclosure relate to complexes and other aspects relate to formulations (e.g., aqueous, lyophilized forms) comprising such complexes comprising an oligonucleotide (e.g., useful for targeting DMPK) covalently linked to an antibody (e.g., anti-TfR1 antibody).
1. A complex comprising a structure of formula (I): [R 1 ] n1 —R 2 , wherein each R 1 comprises a group of the formula (Ic):
wherein R 1 comprises a Fab comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO: 20;
wherein R 1 is covalently linked at attachment point A to R 2 wherein n1 is an integer representing the number of instances of R 1 and wherein each instance of R 1 is covalently linked to a different amino acid residue of the Fab.
2. The complex of claim 1 , wherein each different amino acid residue is a lysine.
3. The complex of claim 1 , wherein the heavy chain of the Fab comprises an N-terminal pyroglutamate.
4. A method of reducing DMPK expression in a subject, the method comprising administering to the subject an effective amount of a composition comprising the complex of claim 1 .
5. A method of treating myotonic dystrophy in a subject, the method comprising administering to the subject an effective amount of a composition comprising the complex of claim 1 .
6. The method of claim 5 , wherein the subject has an expansion of a disease-associated repeat of a DMPK allele that is associated with myotonic dystrophy.
7. The method of claim 6 , wherein the disease-associated repeat comprises repeating units of a CTG trinucleotide sequence.