Antisense oligomers and methods of using the same for treating diseases associated with the acid alpha-glucosidase gene
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Publication Number
US-12139709-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The present disclosure relates to modified antisense oligonucleotides. The nucleotides described herein are of 10 to 40 nucleobases and include a targeting sequence complementary to a target region within intron 1 of a pre-mRNA of the human alpha glucosidase (GAA) gene. The target region includes at least one additional nucleobase compared to the targeting sequence, wherein the at least one additional nucleobase has no complementary nucleobase in the targeting sequence, and wherein the at least one additional nucleobase is internal to the target region.
Core Innovation
The invention relates to modified antisense oligonucleotides or antisense oligomers of 10 to 40 nucleobases, or pharmaceutically acceptable salts thereof, that comprise a targeting sequence complementary to a target region within intron 1 of a pre-mRNA of the human alpha glucosidase (GAA) gene (SEQ ID NO: 1). The target region comprises at least one additional nucleobase compared to the targeting sequence, and the at least one additional nucleobase is internal to the target region. The disclosure also includes specific target regions, targeting sequences, and sequence design rules with complementarity thresholds and mismatch allowances.
The patent links targeting within intron 1 of human GAA pre-mRNA to splice modulation at exon 2. The modified antisense oligonucleotides promote retention of exon 2 in GAA mRNA and can increase GAA mRNA, GAA protein, and enzyme activity. The document further reports that the oligonucleotides can induce GAA enzyme activity at least two-fold versus a fully complementary antisense oligonucleotide in an enzyme activity test using the target region.
The disclosure includes extensive chemical definitions for antisense oligomer backbones and conjugates, including PMO, PNA, LNA, ENA, phosphorothioates, tricyclo-DNA, 2′-O-Me, 2′-O-MOE, 2′-F, MCE, and morpholino-based oligomers, together with formula embodiments, linker moieties, and optional cell-penetrating peptide conjugation. The structural definitions also include nucleobase and substituent options such as Nu, R1, R2, Ra, and Z parameters, while maintaining the same intron 1 targeting concept.
Claims Coverage
The consolidated claim coverage includes two independent claims: one directed to a modified antisense oligonucleotide and one directed to a pharmaceutical composition comprising that oligonucleotide and a pharmaceutically acceptable carrier. Across the independent claims, the core inventive feature is targeting intron 1 of human GAA pre-mRNA (SEQ ID NO: 1) with a targeting sequence complementary to a target region that contains at least one additional internal nucleobase relative to the targeting sequence. Dependent features further specify the number and identity of the additional nucleobase, functional splice and enzyme activity outcomes, and selection of targeting sequences by SEQ ID NOs.
Targeting intron 1 of human GAA pre-mRNA with an internal additional nucleobase
A modified antisense oligonucleotide of 10 to 40 nucleobases, or a pharmaceutically acceptable salt thereof, comprising a targeting sequence complementary to a target region within intron 1 of a pre-mRNA of the human alpha glucosidase (GAA) gene (SEQ ID NO: 1), wherein the target region comprises at least one additional nucleobase compared to the targeting sequence, and wherein the at least one additional nucleobase is internal to the target region.
Pharmaceutical composition with intron 1 targeting antisense oligonucleotide
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a modified antisense oligonucleotide of 10 to 40 nucleobases, or a pharmaceutically acceptable salt thereof, comprising a targeting sequence complementary to a target region within intron 1 of a pre-mRNA of the human alpha glucosidase (GAA) gene (SEQ ID NO: 1), wherein the target region comprises at least one additional nucleobase compared to the targeting sequence, and wherein the at least one additional nucleobase is internal to the target region.
One to three additional nucleobases in the target region
The target region comprises from one to three additional nucleobases compared to the targeting sequence.
Additional nucleobase is cytosine
The at least one additional nucleobase is cytosine.
Promotes retention of exon 2 in GAA mRNA
Upon binding the targeting sequence to the target region, the modified antisense oligonucleotide promotes retention of exon 2 in GAA mRNA.
Induces GAA enzyme activity at least two-fold versus a fully complementary control
The modified antisense oligonucleotide induces GAA enzyme activity at least two-fold versus a fully complementary antisense oligonucleotide in an enzyme activity test using the target region within SEQ ID NO: 1.
Targeting sequence restricted to SEQ ID NOs 33-42
The targeting sequence is selected from SEQ ID NOs 33-42.
The claims center on modified antisense oligonucleotides and pharmaceutical compositions that target intron 1 of human GAA pre-mRNA with a target region defined by at least one internal additional nucleobase beyond the targeting sequence. The dependent claim features narrow the scope by additional nucleobase count and identity, specified targeting sequences, and functional outcomes including exon 2 retention and increased GAA enzyme activity.
Stated Advantages
Promotes retention of exon 2 in GAA mRNA.
Can increase GAA mRNA, GAA protein, and enzyme activity.
Induces GAA enzyme activity at least two-fold versus a fully complementary antisense oligonucleotide.
Documented Applications
Modulating splice outcomes in human alpha glucosidase (GAA) pre-mRNA by promoting exon 2 retention.
Achieving increased GAA mRNA, GAA protein, and enzyme activity through antisense-mediated splice modulation.
Treatment of GSD-II/Pompe disease.
Formulation of the modified antisense oligonucleotide as a pharmaceutical composition with a pharmaceutically acceptable carrier.
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