Methods and compositions for inhibiting expression of cyp27a1

A technology related to CYP27A1, which is applied in the field of inhibiting the expression and composition of CYP27A1, and can solve problems such as enhancing liver cytotoxicity and affecting lipid balance

Pending Publication Date: 2021-11-23
DICERNA PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Shifts in the amount of bile acids leading to their increase have the potential to induce and enhance hepatotoxicity through pro-inflammatory mechanisms, membrane damage and cytotoxic responses, and can have effects on lipid homeostasis

Method used

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  • Methods and compositions for inhibiting expression of cyp27a1
  • Methods and compositions for inhibiting expression of cyp27a1
  • Methods and compositions for inhibiting expression of cyp27a1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1: Development of CYP27A1 oligonucleotide inhibitors using human and mouse cell-based assays

[0158] figure 1 The workflow for developing candidate oligonucleotides for inhibition of CYP27A1 expression using human and mouse based assays is shown. First, a computer-based algorithm was used to generate candidate oligonucleotide sequences for CYP27A1 inhibition. Cell-based assays and PCR assays were then used to assess the ability of candidate oligonucleotides to reduce CYP27A1 expression.

[0159] A computer algorithm provided 2114 oligonucleotides complementary to human CYP27A1 mRNA (SEQ ID NO:782, Table 1), 1084 of which were also complementary to rhesus monkey CYP27A1 mRNA (SEQ ID NO:783, Table 1), and 24 were also complementary to mouse CYP27A1 mRNA (SEQ ID NO: 784, Table 1). Eight oligonucleotides are complementary to human, mouse and rhesus monkey CYP27A1 mRNA. Examples of CYP27A1 mRNA sequences are summarized in Table 1:

[0160] Table 1. Sequences o...

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PUM

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Abstract

This disclosure relates to oligonucleotides, compositions and methods useful for reducing CYP27A1 expression, particularly in hepatocytes. Disclosed oligonucleotides for the reduction of CYP27A1 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 CYP27A1 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 hepatobiliary disease and related conditions (e.g., liver fibrosis).

Description

[0001] related application [0002] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No. 62 / 804,410, filed February 12, 2019, which is incorporated herein by reference in its entirety. technical field [0003] The present application relates to oligonucleotides and their uses, especially those related to the regulation of liver metabolic functions. [0004] References to Sequence Listings [0005] This application is filed together with a Sequence Listing in electronic format. The sequence listing is provided as a file entitled 400930-012WO_SEQ.txt created on February 6, 2020, and the size of the file is 162 kilobytes. The information in the sequence listing in electronic format is incorporated herein by reference in its entirety. Background technique [0006] Among the many metabolic functions performed by the liver, the synthesis and flow of bile is important for optimal functioning of the enterohepatic system. Bile is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113C12N15/11A61K31/713
CPCC12N15/1137C12N2310/14C12N2310/531C12N2320/11C12N15/111C12N2310/3515C12N2310/321C12Y114/15C12N2310/3521C12N9/0077A61K31/7105A61P1/16C12N2310/11C12N2310/315
Inventor U·萨克森纳
Owner DICERNA PHARM INC
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