Oligonucleotide compositions and methods thereof

A technology of oligonucleotide and composition, applied in oligonucleotide composition and its field, can solve the problems of poor cell permeability and distribution, instability, limitation and the like

Inactive Publication Date: 2019-03-15
WAVE LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Naturally occurring nucleic acids (e.g., unmodified DNA or RNA) can be compromised when used therapeutically, for example due to their instability to extracellular and intracellular nucleases and / or their poor cellular permeability and distribution. limit

Method used

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  • Oligonucleotide compositions and methods thereof
  • Oligonucleotide compositions and methods thereof
  • Oligonucleotide compositions and methods thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[2012] A non-limiting example of a method of conjugating lipids to oligonucleotides is presented in Example 1.

[2013] A non-limiting example of a linker is a C6 amino linker.

[2014] target component

[2015] In some embodiments, provided compositions also include a targeting component (targeting compound or moiety). Targeting components may or may not be conjugated to lipids or bioactive agents. In some embodiments, the target component is conjugated to a biologically active agent. In some embodiments, the bioactive agent is conjugated to both the lipid and the targeting component. As described herein, in some embodiments, the bioactive agent is a provided oligonucleotide. Accordingly, in some embodiments, provided oligonucleotide compositions include targeting elements in addition to lipids and oligonucleotides. A variety of targeting components can be used in accordance with the present disclosure, such as lipids, antibodies, peptides, carbohydrates, and the like. ...

example

[3540]The foregoing are descriptions of certain non-limiting examples of the present disclosure. Therefore, it should be understood that some of the embodiments of the disclosure described herein are merely illustrative of the application of the principles of the disclosure. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims.

[3541] Reality Example 1. In Vitro Metabolic Stability of Human Chiromersen in Pre-Incubated Rat Whole Liver Homogenate

[3542] This example describes a comparison of the in vitro whole rat liver homogenate stability of mipomersen (stereochemical mixture) and a chirally controlled oligonucleotide composition of mipomersen ("chiromersen"). The method is particularly useful for screening chemicals for prediction of in vivo half-life.

[3543] As known in the art, mipomersen (formerly ISIS 301012, marketed under the trade name Kynamro) is a 20-mer oligonucleotide whose base sequence is antisense...

example 2

[3584] Example 2. Exemplary Chiral Controlled siRNA Molecules

[3585]

[3586] Despite teachings in the art to the contrary, the present disclosure recognizes that the stereochemistry of internucleotide linkages can be used to enhance the stability and activity of oligonucleotides through chirality-controlled oligonucleotide composition. As demonstrated in this disclosure, such chirality-controlled oligonucleotide combinations can provide better results than chirality-uncontrolled oligonucleotides.

[3587] RNA complexed with human Argonaute-2 protein (hAgo2) has two reported crystal structures: "The Crystal Structure of Human Argonaute-2", Science, 2012 (PDB-4ei3); and The Structure of Human Argonaute-2 in Complex with miR-20a Cell, 2012 (PDB-4f3t). Additionally, Let-7 RNA in complex with human Argo-1 protein (hAgo-1) has a reported crystal structure: The Making of a Slicer: Activation of Human Argonaute -1)", "Cell Report (CellRep.)" 2013 (PDB-4krf).

[3588] Based ...

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PUM

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Abstract

Among other things, the present disclosure relates to chirally controlled oligonucleotides of select designs, chirally controlled oligonucleotide compositions, and methods of making and using the same. In some embodiments, a provided chirally controlled oligonucleotide composition provides different cleavage patterns of a nucleic acid polymer than a reference oligonucleotide composition. In some embodiments, a provided chirally controlled oligonucleotide composition provides single site cleavage within a complementary sequence of a nucleic acid polymer. In some embodiments, a chirally controlled oligonucleotide composition has any sequence of bases, and / or pattern or base modifications, sugar modifications, backbone modifications and / or stereochemistry, or combination of these elements, described herein.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 331,960, filed May 4, 2016 and U.S. Provisional Application No. 62 / 447,832, filed January 18, 2017, and PCT Application No. PCT / The priority of US2016 / 043542, each of which is incorporated herein by reference in its entirety. technical field Background technique [0003] Oligonucleotides are useful in a variety of applications such as therapeutics, diagnostics, research, and nanomaterials applications. Naturally occurring nucleic acids (e.g., unmodified DNA or RNA) can be compromised when used therapeutically, for example due to their instability to extracellular and intracellular nucleases and / or their poor cellular permeability and distribution. limit. There is a need for new and improved oligonucleotides and oligonucleotide compositions, such as novel antisense and siRNA oligonucleotides and oligonucleotide compositions. Contents of the invention [...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113A61K48/00
CPCC12N15/111C12N2310/11C12N2310/14C12N2310/315C12N2320/50C12N15/113C12N2310/34C12N2310/346C12N2310/321A61P25/14A61P43/00C12N2310/50
Inventor 钱德拉·瓦尔格赛米纳内纳德·斯夫尔齐卡帕苏索万·莫哈帕特拉克里斯多佛·J·弗朗西斯格雷戈里·L·韦尔迪安娜·索科洛夫斯卡
Owner WAVE LIFE SCI LTD
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