Conjugated antisense compounds and their use
Inventors
Oestergaard, Michael • Seth, Punit P. • Rigo, Frank • Dwyer, Chrissa A.
Assignees
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Publication Number
US-12275940-B2
Publication Date
2025-04-15
Expiration Date
Abstract
The present disclosure provides half duplex compounds comprising a first oligomeric compound and a second, shorter, oligomeric compound, wherein the first oligomeric compound is complementary to a target nucleic acid and the second oligomeric compound is complementary to the first oligomeric compound. In certain embodiments, the compounds disclosed herein are useful for modulating the expression of extra-hepatic target nucleic acids.
Core Innovation
The invention provides a compound comprising a first oligomeric compound and a second oligomeric compound. The first oligomeric compound includes a first modified oligonucleotide consisting of 14-30 linked nucleosides and having a nucleobase sequence complementary to the nucleobase sequence of the second oligomeric compound and to a nucleic acid target. The second oligomeric compound includes a second modified oligonucleotide consisting of 6-12 linked nucleosides.
The invention further defines a sugar motif for the first modified oligonucleotide, including a 5′-region consisting of 1-5 linked 5′-nucleosides, a central region consisting of 6-10 linked central region nucleosides, and a 3′-region consisting of 1-5 linked 3′-nucleosides. In this motif, each 5′-region nucleoside and each 3′-region nucleoside comprises a modified sugar moiety, while each central region nucleoside comprises an unmodified DNA sugar moiety.
The described arrangement forms a half-duplex pairing concept in which the longer first modified oligonucleotide is complementary to both the shorter second modified oligonucleotide and the nucleic acid target, while the shorter modified oligonucleotide has 6-12 linked nucleosides. The background problem addressed is the need for nucleic-acid-targeting compounds having suitability for extra-hepatic nucleic acid targets such as CNS and muscle, including improved tolerability and improved tissue uptake/distribution and blood-brain barrier penetration.
Claims Coverage
The provided partial content includes one independent claim. The claim coverage centers on two main inventive aspects: a compound built from two modified oligonucleotides with defined lengths and complementarity to each other and to a nucleic acid target, and a structured sugar motif for the longer first modified oligonucleotide with modified sugars in the 5′ and 3′ regions and unmodified DNA sugars in the central region.
Two modified oligonucleotides with defined lengths and dual complementarity to each other and to a nucleic acid target
A compound comprising a first oligomeric compound and a second oligomeric compound, where the first modified oligonucleotide consists of 14-30 linked nucleosides and has a nucleobase sequence complementary to the nucleobase sequence of the second oligomeric compound and to a nucleic acid target, and where the second modified oligonucleotide consists of 6-12 linked nucleosides.
Structured sugar motif with modified sugars in the 5′- and 3′-regions and unmodified DNA sugar in the central region
A sugar motif for the first modified oligonucleotide comprising a 5′-region consisting of 1-5 linked 5′-nucleosides, a central region consisting of 6-10 linked central region nucleosides, and a 3′-region consisting of 1-5 linked 3′-nucleosides, wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises an unmodified DNA sugar moiety.
Across the provided independent claim, the inventive scope is defined by a half-duplex-style compound architecture using two modified oligonucleotides of different lengths with nucleobase complementarity to each other and to a nucleic acid target, combined with a regionally defined sugar motif on the longer first modified oligonucleotide that places modified sugars at the 5′ and 3′ regions while keeping the central region as unmodified DNA sugar.
Stated Advantages
Improved tolerability.
Improved tissue uptake/distribution.
Enhanced blood-brain barrier penetration versus single-strand analogs.
Enhanced CNS activity versus single-stranded.
Documented Applications
Targeting extra-hepatic nucleic acid targets including CNS and muscle.
Use involving DMPK in mouse muscle, including reduction of DMPK by RT-PCR with improved tolerability and activity versus single-strand and full duplex analogs.
Systemic CNS-targeting with Malat-1 half-duplexes, including improved CNS activity versus single-stranded.
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