Exon skipping oligomer conjugates for muscular dystrophy

Inventors

Passini, Marco A. • Hanson, Gunnar J.

Assignees

Sarepta Therapeutics Inc

Abstract

Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 51 skipping are described.

Core Innovation

The invention relates to antisense oligomer conjugates defined by Formula (III), including pharmaceutically acceptable salt forms and specific hydrochloride salt forms. The disclosed antisense oligomer includes nucleobases such as A, C, G, T, U, 5-methylcytosine, hypoxanthine, pseudouracil, Super T, and Super G, with additional nucleobase definitions used within the oligomer structure.

The disclosure describes antisense oligomer chemistry variations incorporated into antisense conjugates, including PS-containing internucleoside linkages for 2′-O-methyl, 2′-O-MOE, and 2′-F oligomers, 2′-O-[2-(N-methylcarbamoyl)ethyl] modified subunits, morpholino oligomer embodiments including phosphorodiamidate morpholino oligomers, stereospecific antisense oligomers having defined R_P/S_P phosphorous-containing linkages, and stereopure oligomers and stereorandom oligomers. It also describes conjugates that bind an exon 51 target region of dystrophin pre-mRNA and are designed for exon-skipping amenability.

The document further provides pharmaceutical compositions of the antisense oligomer conjugates with pharmaceutically acceptable carriers, including saline with phosphate buffer and PEG/liposomes. It also describes peptide and tail features such as an R6 arginine-based peptide and an activated PEG/EG3 tail, along with example assemblies and explicit sequence reference to SEQ ID NO:1.

Claims Coverage

The claim coverage centers on one independent claim for an antisense oligomer conjugate of Formula (III), or a pharmaceutically acceptable salt thereof. Dependent claims add alternative structural formula embodiments, salt forms including hydrochloride salt support, and a pharmaceutical composition embodiment including a pharmaceutically acceptable carrier, for a total of six inventive features beyond the independent claim scope.

Across the provided claims, the scope centers on antisense oligomer conjugates defined by Formula (III), with dependent refinements to alternative formulas, pharmaceutically acceptable salt forms including hydrochloride salt support, and a pharmaceutical composition embodiment including a pharmaceutically acceptable carrier.

Stated Advantages

Documented Applications