Muscle targeting complexes and uses thereof for treating dystrophinopathies

Abstract

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 promotes the expression or activity of a functional dystrophin protein. In some embodiments, the molecular payload is an oligonucleotide, such as an antisense oligonucleotide, e.g., an oligonucleotide that causes exon skipping in a mRNA expressed from a mutant DMD allele.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of the filing date of U.S. Provisional Application No. 62 / 714,031, entitled “MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES”, filed Aug. 2, 2018; and U.S. Provisional Application No. 62 / 855,766, entitled “MUSCLE TARGETING COMPLEXES AND USES THEREOF FOR TREATING DYSTROPHINOPATHIES”, filed May 31, 2019; the contents of each of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present application relates to targeting complexes for delivering molecular payloads (e.g., oligonucleotides) to cells and uses thereof, particularly uses relating to treatment of disease.REFERENCE TO THE SEQUENCE LISTING[0003]The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled D082470008WO00-SEQ.txt created on Jul. 31, 2019 which is 102 kilobytes in size. The information in electronic format...

AI Technical Summary

Benefits of technology

The patent text describes complexes that can deliver molecular payloads to muscle cells for treating Duchenne Muscle Dystrophy (DMD). The complexes comprise a muscle-targeting agent that specifically binds to receptors on the surface of muscle cells and promotes the expression or activity of a DMD gene. The complexes can also contain oligonucleotides that can promote exon skipping or in-frame exon skipping to produce functional dystrophin mRNA. The complexes can be taken up into cells via receptor-mediated internalization and the molecular payload can perform its function inside the cells. The complexes can be cross-reactive with extracellular epitopes of a transferrin receptor and promote transferrin receptor-mediated internalization of the molecular payload. The complexes can also be designed to suppress a truncating mutation in a DMD allele and promote exon skipping to produce in-frame dystrophin mRNA. The complexes can be administered through intraveneous injection and can target specific cells or tissues in the body.

Problems solved by technology

Numerous mutations in DMD, including exonic frameshift, deletion, substitution, and duplicative mutations, are able to diminish the expression of functional dystrophin, leading to dystrophinopathies.

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