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Oligonucleotide compositions and methods of use thereof

A technology of oligonucleotides and compositions, applied in biochemical equipment and methods, chemical instruments and methods, sugar derivatives, etc., can solve the problems of nucleic acid cell penetration and poor distribution, etc.

Pending Publication Date: 2021-01-12
WAVE LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The therapeutic use of naturally occurring nucleic acids (e.g., unmodified DNA or RNA) may be limited, for example, because of the instability of naturally occurring nucleic acids to extracellular and intracellular nucleases and / or the Poor cell penetration and distribution of

Method used

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  • Oligonucleotide compositions and methods of use thereof
  • Oligonucleotide compositions and methods of use thereof
  • Oligonucleotide compositions and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[1042] Example 1. Example Synthesis of DMD Oligonucleotide Compositions

[1043] Certain techniques for preparing DMD oligonucleotides and compositions thereof are widely known in the art. In some embodiments, techniques described in one or more of the following (e.g., reagents (e.g., solid supports, coupling reagents, cleavage reagents, phosphoramidites, etc.), chiral auxiliaries, solvents (e.g., , for reaction, washing, etc.), circulation, reaction conditions (for example, time, temperature, etc.) etc.) to prepare the DMD oligonucleotide and DMD oligonucleotide composition of the present disclosure: US 9394333, US9744183, US 9605019, US 9598458, US 2015 / 0211006, US 2017 / 0037399, WO 2017 / 015555, WO 2017 / 192664, WO 2017 / 015575, WO2017 / 062862, WO 2017 / 160741, PC US / TUS / 1961479, 8WO20 35687, PCT / US18 / 38835, and PCT / US18 / 51398.

example 2

[1044] Example 2. Exemplary synthesis of phosphoramidate internucleotide linkages comprising a cyclic guanidine moiety

[1045] As illustrated herein, according to the present disclosure, phosphoramidate internucleotide linkages can be readily prepared from phosphite internucleotide linkages, including stereopure phosphite internucleotide linkages.

[1046]

[1047] Amidite (474 ​​mg, 0.624 mmol, 1.5 equiv, predried by co-evaporation with dry acetonitrile and under vacuum for a minimum of 12 h) and TBS-protected alcohol (150 mg, 0.41 mmol, via Co-evaporated with dry acetonitrile and pre-dried under vacuum for a minimum of 12h) To a stirred solution in dry acetonitrile (5.2ml) was added 5-(ethylthio)-1H-tetrazole (ETT, 2.08ml, 0.6M , 3 equivalents). The reaction mixture was stirred for 5 min and then monitored by LCMS before a solution of 2-azido-1,3-dimethylimidazoline hexafluorophosphate (356 mg, 1.24 mmol, 3 eq) in acetonitrile (1 ml) was added. Once the reaction was ...

example 31

[1054] in instance 31 In P NMR (phosphoric acid internal standard at δ0.0), the stereorandom preparation shows two peaks at -1.34 and -1.98, respectively; the stereopure Rp preparation shows a peak at -1.93, and the stereopure Sp preparation shows a peak at -1.38 peak.

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Abstract

Among other things, the present disclosure provides designed DMD oligonucleotides, compositions, and methods of use thereof. In some embodiments, the present disclosure provides technologies useful for repairing mutant DMD transcripts by skipping exon 51 or exon 53, so that the transcript can be translated into an internally truncated but at least partially functional Dystrophin protein variant. In some embodiments, the present disclosure provides technologies useful for modulating DMD transcript splicing. In some embodiments, provided technologies can alter splicing of a dystrophin (DMD)DMD transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as muscular dystrophy, including but not limited to Duchenne muscular dystrophy, Becker's muscular dystrophy, etc.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 670,709 filed May 11, 2018, U.S. Provisional Application No. 62 / 715,684 filed Aug. 7, 2018, U.S. Provisional Application No. filed Aug. 27, 2018 62 / 723,375, U.S. Provisional Application No. 62 / 776,432, filed December 6, 2018, and PCT Application No. PCT / US19 / 27109, filed April 11, 2019, the entire contents of each are incorporated by reference Incorporated into this article. Background technique [0003] Oligonucleotides are useful in therapeutic, diagnostic, research, and nanomaterial applications. The therapeutic use of naturally occurring nucleic acids (e.g., unmodified DNA or RNA) may be limited, for example, because of the instability of naturally occurring nucleic acids to extracellular and intracellular nucleases and / or the Poor cell penetration and distribution. There is a need for new and improved DMD oligonucleotides and DMD oligonucleotide composit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00
CPCC12N15/113C12N2310/312C12N2310/315C12N2310/11C12N2320/33C12N2330/30C07H21/00C07H21/02C07H1/00C12N2310/321C12N2310/3521C12N2310/322C12N2310/3533
Inventor 詹森·敬新·张钱德拉·瓦尔格赛岩本直树西科都·夏克提·希瓦利拉纳扬塔拉·科塔里安·菲根·杜宾塞尔维·拉马萨米帕查穆图·坎德萨米贾亚坎森·库马拉萨米戈帕尔·雷迪·博米涅尼苏布拉马尼安·马拉潘塞苏马德哈万·迪娃卡奥门奈大卫·查尔斯·唐奈·巴特勒陆根良杨海琳清水护普拉肖特·莫尼安
Owner WAVE LIFE SCI LTD
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