MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING MYOTONIC DYSTROPHY
Aspects of the disclosure relate to complexes comprising a muscle-targeting agent covalently linked to a molecular payload. In some embodiments, the muscle-targeting agent specifically binds to an internalizing cell surface receptor on muscle cells. In some embodiments, the molecular payload inhibits expression or activity of a DMPK allele comprising a disease-associated-repeat. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide or RNAi oligonucleotide.
1 . A method of treating a subject having an expansion of a disease-associated-repeat of a DMPK allele that is associated with myotonic dystrophy, the method comprising administering a muscle-targeting complex to the subject,
wherein the complex comprises a muscle-targeting agent covalently linked to a molecular payload configured for inhibiting expression or activity of a DMPK allele, and wherein the administration results in inhibition of DMPK expression in muscle tissues by 40-60%, relative to a control, for a duration of time in the range of 4-8, 5-10, 8-12, 10-14, or 8-16 weeks following administration of the complex.
2 . A method of inhibiting DMPK expression in a subject, the method comprising administering a muscle-targeting complex to the subject,
wherein the complex comprises a muscle-targeting agent covalently linked to a molecular payload configured for inhibiting expression of a DMPK allele, and
wherein the administration results in inhibition of DMPK expression in muscle tissues by 40-60%, relative to a control, for a duration of time in the range of 4-8, 5-10, 8-12, 10-14, or 8-16 weeks following administration of the complex.
3 . The method of claim 1 or claim 2 , wherein the complex is administered at a molecular payload dose of 1-15 mg/kg, optionally wherein the complex is administered at a molecular payload dose of 10 mg/kg.
4 . The method of any one of claims 1 - 3 , wherein the complex is administered to the subject in a single dose.
5 . The method of any one of claims 1 - 4 , wherein the muscle-targeting agent is a muscle-targeting antibody.
6 . The method of claim 5 , wherein the muscle-targeting antibody is a transferrin receptor antibody, optionally wherein the muscle-targeting antibody binds to an epitope of a sequence in the range of C89 to F760 of SEQ ID NO: 1-3.
7 - 23 . (canceled)