Exon skipping oligomer conjugates for muscular dystrophy
Inventors
Passini, Marco A. • Hanson, Gunnar J.
Assignees
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Publication Number
US-12377150-B2
Publication Date
2025-08-05
Expiration Date
Abstract
Antisense oligomer conjugates complementary to a selected target site in the human dystrophin gene to induce exon 45 skipping are described.
Core Innovation
The invention provides an antisense oligomer conjugate of Formula (IV) for use in methods for treating Duchenne muscular dystrophy (DMD) in a human subject having a mutation of the dystrophin gene amenable to exon 45 skipping. The treatment comprises administering the antisense oligomer conjugate of Formula (IV) or a pharmaceutically acceptable salt thereof to the human subject.
The invention also provides methods of restoring an mRNA reading frame to induce dystrophin production and methods of affecting dystrophin mRNA processing in exon 45 skipping contexts. The claims encompass restoring an mRNA reading frame, excluding exon 45 from dystrophin pre-mRNA during mRNA processing, and binding exon 45 of dystrophin pre-mRNA, with some embodiments comprising a pharmaceutical composition including a pharmaceutically acceptable carrier.
The disclosed conjugate is characterized by extensive structural definitions and chemical choices relevant to antisense oligomer conjugates. The description focuses on morpholino/PMO and other oligomer chemistries, with multiple backbone chemistries and linkers, together with nucleobase and base pairing moiety definitions for the antisense functionality.
Claims Coverage
The independent claims cover six related method purposes using the same antisense oligomer conjugate of Formula (IV), optionally in the form of a pharmaceutically acceptable salt, and optionally formulated with a pharmaceutically acceptable carrier. Across the independent claims, the main inventive features are the use of Formula (IV) antisense oligomer conjugates and the exon 45 skipping–amenable dystrophin mutation context.
Treating DMD with an antisense oligomer conjugate of Formula (IV) for exon 45 skipping–amenable mutations
Administering to a human subject having a dystrophin gene mutation amenable to exon 45 skipping an antisense oligomer conjugate of Formula (IV), or a pharmaceutically acceptable salt thereof.
Restoring an mRNA reading frame to induce dystrophin production using Formula (IV)
Administering to a human subject having a dystrophin gene mutation amenable to exon 45 skipping an antisense oligomer conjugate of Formula (IV), or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition for treating DMD using Formula (IV) with a pharmaceutically acceptable carrier
Administering to a human subject having a dystrophin gene mutation amenable to exon 45 skipping a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Excluding exon 45 from dystrophin pre-mRNA using Formula (IV)
Administering to a human subject having a dystrophin gene mutation amenable to exon 45 skipping a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Binding exon 45 of dystrophin pre-mRNA using Formula (IV)
Administering to a human subject having a dystrophin gene mutation amenable to exon 45 skipping a pharmaceutical composition comprising an antisense oligomer conjugate of Formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The independent claims primarily focus on administering antisense oligomer conjugates of Formula (IV) and pharmaceutically acceptable salts to human subjects with dystrophin gene mutations amenable to exon 45 skipping, including treatment and mRNA-processing effects such as restoring an mRNA reading frame, excluding exon 45 from dystrophin pre-mRNA, and binding exon 45 of dystrophin pre-mRNA, with optional inclusion of a pharmaceutically acceptable carrier in a pharmaceutical composition.
Stated Advantages
Increased nuclease resistance for 2′-O-[2-(N-methylcarbamoyl)ethyl] (MCE) oligomers.
Documented Applications
Treatment of Duchenne muscular dystrophy (DMD) in a human subject having a dystrophin gene mutation amenable to exon 45 skipping.
Restoring an mRNA reading frame to induce dystrophin production in a human subject having a dystrophin gene mutation amenable to exon 45 skipping.
Excluding exon 45 from dystrophin pre-mRNA during mRNA processing in a human subject having a dystrophin gene mutation amenable to exon 45 skipping.
Binding exon 45 of dystrophin pre-mRNA in a human subject having a dystrophin gene mutation amenable to exon 45 skipping.
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