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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

Pending Publication Date: 2020-11-27
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 19

[1847] Example 19 describes various timelines suitable for experiments testing oligonucleotides (eg, DMD oligonucleotides) in vitro, eg, in patient-derived myoblasts.

[1848] Table 11B. Exemplary data for certain oligonucleotides.

[1849] The number indicates the skip efficiency, where 100.0 means 100% skip and 0.0 means 0% efficiency. PMO is the control oligonucleotide, which is the morpholino corresponding to iplesen. WV-942 is the oligonucleotide corresponding to iplesen. Oligonucleotides were delivered naked.

[1850]

[1851]

[1852]

[1853]

[1854] Table 11C. Exemplary data for certain oligonucleotides.

[1855] The number indicates the skip efficiency, where 100.0 means 100% skip and 0.0 means 0% efficiency. PMO is the control oligonucleotide, which is the morpholino corresponding to iplesen. WV-942 is the oligonucleotide corresponding to iplesen. Oligonucleotides were delivered naked.

[1856]

[1857]

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[1859]

[1860] In s...

example

[2153] The Tm of the oligonucleotides was also tested with Malat1 RNA (WV-7772). An example set of test conditions: 1 μΜ duplex in 1X PBS (pH 7.2); temperature range: 15°C-90°C; heating rate: 0.5°C / min; measurement interval: 0.5°C. The results showed the following duplex Tm (° C.) with WV-7772: WV-8556, 73.52; WV-8587, 69.57; and WV-11533, 68.67.

[2154] In some embodiments, oligonucleotides comprising non-negatively charged internucleotide linkages provide improved splicing regulatory activity. A variety of oligonucleotides containing non-negatively charged internucleotide linkages were prepared and / or tested for mediating exon skipping in DMD. Certain oligonucleotides comprising non-negatively charged internucleotide linkages are listed in Table Al.

[2155] Table 25A. Exemplary data for certain oligonucleotides.

[2156] Numbers indicate exon skipping levels; for example, 27.13 in column 2, row 2 indicates that 27.13% of DMD exons are skipped. Oligonucleotides were tes...

example 1

[3270] Example 1. Exemplary Synthesis of Oligonucleotide Compositions

[3271] Techniques for preparing oligonucleotides and compositions thereof are well 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.), cycle, reaction conditions (eg, time, temperature, etc.) etc.) to prepare oligonucleotides and oligonucleotide compositions of the present disclosure: US 9394333, US 9744183, US9605019, US 9598458 , US 2015 / 0211006, US 2017 / 0037399, WO 2017 / 015555, WO 2017 / 192664, WO 2017 / 015575, WO 2017 / 062862, WO 2017 / 160741, WO 2017 / 192679, WO 20307, ​​262 WO 2017 / 210 , WO 2018 / 237194 and WO 2019 / 055951.

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Abstract

Among other things, the present disclosure provides designed oligonucleotides, compositions, and methods of use thereof. In some embodiments, the present disclosure provides technologies useful for reducing levels of transcripts. In some embodiments, the present disclosure provides technologies useful for modulating transcript splicing. In some embodiments, provided technologies can alter splicingof a dystrophin (DMD) transcript. In some embodiments, the present disclosure provides methods for treating diseases, such as 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 / 656,949, filed April 12, 2018, U.S. Provisional Application No. 62 / 670,709, filed May 11, 2018, U.S. Provisional Application No., filed Aug. 07, 2018 Priority of 62 / 715,684, U.S. Provisional Application No. 62 / 723,375, filed August 27, 2018, and U.S. Provisional Application No. 62 / 776,432, filed December 06, 2018, each of which is incorporated by reference in its entirety 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 oligonucleotides and oligonucleotide ...

Claims

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Application Information

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IPC IPC(8): C12N15/11C07C317/28C12Q1/6883C07H21/02C07H21/04
CPCC07H21/04C07H21/02C07C317/28C12Q1/6883C12N15/111C12N2310/315C12N2320/33C12N2310/11C07H1/00C12N15/113C12N2310/312C12N2330/30C07H19/09C07H1/02A61K31/7125
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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