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Compositions and methods for inhibiting aldh2 expression

A technology of S1-L-S2 and oligonucleotides, applied in the field of compositions and methods for inhibiting ALDH2 expression, capable of solving problems such as poor patient compliance

Pending Publication Date: 2020-08-28
DICERNA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, disulfiram has clinical limitations due to a range of side effects such as drowsiness, headache and, less commonly, neurotoxicity
Also, because disulfiram and similar therapeutics typically require daily administration to be effective, patient compliance with these drugs is extremely poor

Method used

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  • Compositions and methods for inhibiting aldh2 expression
  • Compositions and methods for inhibiting aldh2 expression
  • Compositions and methods for inhibiting aldh2 expression

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0162] Example 1: Development of ALDH2 oligonucleotide inhibitors using human and mouse cell-based assays

[0163] figure 1 The workflow for developing candidate oligonucleotides for the inhibition of ALDH2 expression using human and mouse based assays is shown. First, a computer-based algorithm was used to generate candidate oligonucleotide sequences (25-27-mers) for ALDH2 inhibition. Cell-based assays and PCR assays were then used to assess the ability of candidate oligonucleotides to reduce ALDH2 expression.

[0164] A computer-based algorithm provided oligonucleotides complementary to human ALDH2 mRNA (SEQ ID NO:608, Table 1), some of which were also complementary to cynomolgus ALDH2 mRNA (SEQ ID NO:609, Table 1) and / or or mouse ALDH2 mRNA (SEQ ID NO:610, Table 1) complementation.

[0165] Table 1. Sequences of human, cynomolgus monkey and mouse ALDH2 mRNA

[0166] species GenBank RefSeq # SEQ ID NO. people NM_000690.3 608 cynomolgus monk...

Embodiment 2

[0184] Example 2: Duration study of GalNAc-conjugated ALDH2 oligonucleotides in non-human primates (NHP) study

[0185] The study was designed to evaluate single doses of GalNAc-conjugated GGs with different modification patterns (e.g., with different numbers of 2'-fluoro modifications and / or different numbers of phosphorothioate linkages in the antisense strand). Pharmacodynamics of ALDH2 oligonucleotides. The GalNAc-conjugated ALDH2 oligonucleotides tested in this study were: S585-AS595-M14, S585-AS595-M15, S585-AS595-M16, S585-AS595-M17, S587-AS597-M23 and S587- AS597-M24. A single dose of GalNAc-conjugated ALDH2 oligonucleotide was injected subcutaneously at 3 mg / kg in non-human primates (n=4 per group). Animals were fasted overnight, and serum samples and liver biopsies were collected the next morning before feeding. One biopsy sample per dose was collected for each animal during the acclimatization period and 3 biopsies were collected at 4, 8, 12 or 16 weeks post-...

Embodiment 3

[0188] Example 3: Improvement of GalNAc-conjugated ALDH2 oligonucleotides using different modifications

[0189] This study was designed to evaluate the effect of different modification patterns on the activity of GalNAc-conjugated ALDH2 oligonucleotides in reducing ALDH2 mRNA levels. Such as Figure 9 Two GalNAc-conjugated ALDH2 oligonucleotides (S585- AS595 and S587-AS597). Five GalNAc-conjugated ALDH2 oligonucleotides showed higher activity in reducing ALDH2 mRNA levels (S585-AS595-M23, S585-AS595-M24, S585-AS595-M16, S585-AS595-M17 and S587-AS597- M23).

[0190] Also tested for its in vivo activity in reducing ALDH2 mRNA levels in mice Figure 9 Several GalNAc-conjugated ALDH2 oligonucleotides tested in . A single dose of GalNAc-conjugated ALDH2 oligonucleotide was administered subcutaneously to mice at 0.5 mg / kg, and the level of ALDH2 mRNA in mouse liver was assessed by qPCR 4 days after administration. The results showed that the modification patterns M22, M15, ...

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Abstract

This disclosure relates to oligonucleotides, compositions and methods useful for reducing ALDH2 expression, particularly in hepatocytes. Disclosed oligonucleotides for the reduction of ALDH2 expression may be double-stranded or single-stranded, and may be modified for improved characteristics such as stronger resistance to nucleases and lower immunogenicity. Disclosed oligonucleotides for the reduction of ALDH2 expression may also include targeting ligands to target a particular cell or organ, such as the hepatocytes of the liver, and may be used to treat alcoholism and related conditions.

Description

[0001] related application [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 617692, filed January 16, 2018, and entitled "COMPOSITIONSAND METHODS FOR INHIBITING ALDH2 EXPRESSION," the entire contents of which are incorporated by reference under 35 U.S.C. § 119(e) into this article. [0003] field of invention [0004] The present application relates to oligonucleotides and their uses, in particular in relation to the treatment of alcoholism and related conditions. [0005] References to Sequence Listings [0006] This application is filed with a sequence listing in electronic format. The sequence listing is provided as a file entitled D0800.70010WO00-SEQ.txt (128 kilobytes in size) created on January 15, 2019. The information in electronic format of the Sequence Listing is incorporated herein by reference in its entirety. [0007] Background of the invention [0008] Acetaldehyde is an intermediary in the oxidation of alcohol by the body....

Claims

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Application Information

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IPC IPC(8): C12N15/113A61K31/713A61K31/712A61K31/7115
CPCA61K31/713C12N15/1137C12N2310/14C12N2310/315C12N2310/351C12N2310/531C12N2320/32C12N15/113C12N2310/321C12N2310/3521C12N2310/322C12N2310/3533A61P25/32
Inventor U·萨克塞纳
Owner DICERNA PHARM INC
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