Compositions and methods for inhibiting LPA expression
Inventors
Brown, Bob Dale • Dudek, Henryk T. • Abrams, Marc • HAN, Wen • Turanov, Anton
Assignees
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Publication Number
US-12252691-B2
Publication Date
2025-03-18
Expiration Date
Abstract
Oligonucleotides are provided herein that inhibit apolipoprotein(a) (LPA) expression. Also provided are compositions including the same and uses thereof, particularly uses relating to treating diseases, disorders and/or conditions associated with LPA expression.
Core Innovation
The invention relates to RNAi oligonucleotides for reducing apolipoprotein(a) (LPA) expression. The oligonucleotide comprises a sense strand and an antisense strand that form a duplex region, and the strands are defined by specific modified nucleotide compositions and linkage patterns.
The antisense strand includes MePhosphonate-40-mUs and a defined pattern of 2′-OMe and 2′-F nucleotides, including 3′-phosphorothioate-linked forms such as fAs, fGs, mAs, and mGs. The sense strand includes a duplex-forming region with 2′-OMe and 2′-F nucleotides and multiple ademA-GalNAc elements, wherein ademA-GalNAc represents 2′-aminodiethoxymethanol-adenine-GalNAc.
The invention further includes delivery and formulation concepts for administering the LPA-reducing RNAi oligonucleotides. The described pharmaceutical compositions include pharmaceutically acceptable carriers, delivery agents, or excipients, including phosphate buffered saline and water, as well as lipid-based carriers such as liposomes and lipid nanoparticles.
Claims Coverage
The claim set identifies one independent inventive concept directed to a duplex-forming RNAi oligonucleotide for reducing apolipoprotein(a) (LPA) expression, with dependent claims adding pharmaceutical composition and carrier limitations. Across the claims, the inventive features center on the defined modified antisense and sense strand compositions, including 2′-OMe/2′-F nucleotide definitions and a GalNAc modification on the sense strand.
Duplex-forming RNAi oligonucleotide for reducing LPA expression
An RNAi oligonucleotide for reducing apolipoprotein(a) (LPA) expression, comprising a sense strand and an antisense strand that form a duplex region.
Defined modified antisense strand composition
The antisense strand is 5′-[MePhosphonate-40-mUs][fAs][fAs][fGs][fA][fU][mG][fA][mC][mC][fA][mA][mG][mC][fU][mU][mG][mG][mC][mA][mAs][mGs][mG]-3′ (SEQ ID NO: 793), with mA/mC/mG/mU defined as 2′-OMe nucleotides and fA/fC/fG/fU defined as 2′-F nucleotides, including specified 3′-phosphorothioate linkage forms.
Defined modified sense strand composition with GalNAc modification
The sense strand is 5′-[mUs][mU][mG][mC][mC][mA][mA][fG][fC][fU][fU][mG][mG][mU][mC][mA][mU][mC][mU][mA][mG][mC][mA][mG][mC][mC][mG][ademA-GalNAc][ademA-GalNAc][ademA-GalNAc][mG][mG][mC][mU][mG][mC]-3′ (SEQ ID NO: 393), wherein ademA-GalNAc represents 2′-aminodiethoxymethanol-adenine-GalNAc.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition that includes the RNAi oligonucleotide and a pharmaceutically acceptable carrier, delivery agent, or excipient.
Phosphate buffered saline carrier
The pharmaceutical composition includes a carrier comprising phosphate buffered saline.
Water carrier
The pharmaceutical composition includes a carrier comprising water.
The inventive concept is a duplex-forming RNAi oligonucleotide with explicitly defined modified antisense and sense strand chemistries for reducing LPA expression. The claims also extend to pharmaceutical compositions of the oligonucleotide with pharmaceutically acceptable carriers, including phosphate buffered saline and water.
Stated Advantages
Reduces apolipoprotein(a) (LPA) expression.
Documented Applications
Therapeutic/medical use for reducing apolipoprotein(a) (LPA) expression in cells and in vivo by delivering ds RNAi oligonucleotides.
In vivo evaluation in an HDI mouse model with dose-dependent LPA mRNA reduction.
Non-human primate evaluation with reduced LPA/apo(a) readouts.
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