Modulators of apol1 expression

A technology of -O-2 and oligonucleotide, which is applied in the direction of recombinant DNA technology, DNA/RNA fragments, medical preparations containing active ingredients, etc., can solve the problem that the disease cannot be completely prevented from progressing, so as to slow down the progress and achieve high The effect of therapeutic value

Pending Publication Date: 2021-02-26
IONIS PHARMA INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Antihypertensive and anti-inflammatory treatments have been found to slow progression and reduce symptoms in some typ

Method used

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  • Modulators of apol1 expression
  • Modulators of apol1 expression
  • Modulators of apol1 expression

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0355]Instance

[0356]The following example describes the screening process used to identify lead compounds targeting APOL1. For example, ION793406, 904763, 905469, 905505, 905634, 905665, 972190, and 972163 lead to high potency and tolerance. ION 972190 exhibits high potency and tolerance.

[0357]Non-restricted disclosure and incorporation by reference

[0358]Although the sequence listing attached to this document identifies each sequence as "RNA" or "DNA" as needed, in fact those sequences can be modified with any combination of chemical modifications. Those skilled in the art should readily recognize that names such as "RNA" or "DNA" describe modified oligonucleotides that are arbitrary in some cases. For example, oligonucleotides containing nucleosides containing 2'-OH sugar moieties and thymine bases can be described as DNA with modified sugars (natural 2'-H for DNA is 2'-OH) or with RNA of modified bases (the natural uracil for RNA is thymine (methylated uracil)).

[0359]Therefore, th...

Example Embodiment

[0363]Example 1: Antisense suppression of human APOL1 in A431 cells

[0364]Antisense oligonucleotides with various chemical motifs targeting APOL1 nucleic acid were designed and tested for their effects on APOL1 mRNA in vitro.

[0365]3-10-3 cEt notch body

[0366]The newly designed chimeric antisense oligonucleotides in the table below were designed as 3-10-3 cEt notches. These gap bodies are 16 nucleosides in length, of which the central gap segment consists of ten 2'-deoxynucleosides and flanks wing segments in the 5’ and 3’ directions, and each wing segment includes three nucleosides. . Each nucleoside in the 5'wing segment and each nucleoside in the 3'wing segment has a cEt modification. The internucleoside linkages throughout each gap body are phosphorothioate (P=S) linkages. All cytosine residues throughout each gap are 5-methylcytosine.

[0367]The "start site" indicates the most 5'nucleoside in the human gene sequence targeted by the gap body. "Stop site" indicates the most 3'nucleos...

Example Embodiment

[0554]Example 2: Dose-dependent antisense inhibition of human APOL1 in A431 cells

[0555]Notch bodies showing significant in vitro inhibition of APOL1 mRNA from Example 1 were selected and tested in A431 cells at different doses. These antisense oligonucleotides were tested in a series of experiments with similar culture conditions. The results of each experiment are presented in a separate table as shown below.

[0556]The cells were plated at a density of 10,000 cells per well and transfected with 3-10-3cEt notches at different concentrations as specified in the table below. After a treatment period of approximately 16 hours, RNA was isolated from the cells, and APOL1 mRNA levels were measured by quantitative real-time PCR. The human primer probe set RTS35962 was used to measure mRNA levels. As passedThe measurement of APOL1 mRNA is adjusted according to the total RNA content. The results are presented as the percentage of APOL1 inhibition relative to untreated control cells.

[0557]The ...

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Abstract

The present embodiments provide methods, compounds, and compositions useful for inhibiting APOL1 expression, which may be useful for treating, preventing, or ameliorating a disease associated with APOL1.

Description

[0001] sequence listing [0002] This application is filed together with a Sequence Listing in electronic format. The sequence listing is provided as a file titled 200779-WO-PCT-SeqListingUpdated.txt created on May 20, 2019, which is 465 kb in size. The information of the sequence listing in electronic format is hereby incorporated by reference in its entirety. technical field [0003] This example provides methods, compounds, and compositions that can be used to inhibit the expression of APOL1 (apolipoprotein L, 1), and in some cases reduce the amount of APOL1 protein in cells or animals. These methods, compounds, and combinations The substances can be used for treating, preventing, or alleviating diseases related to APOL1. Background technique [0004] End-stage kidney disease (ESKD) affects more than half a million individuals in the United States. In the United States, individuals of African ancestry were approximately twice as likely to develop ESKD as those observe...

Claims

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Application Information

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IPC IPC(8): A61K48/00C07H21/02
CPCA61P13/02C12N15/113C12N2310/11C12N2310/341C12N2310/315C12N2310/346C12N2320/30C12N2310/3231A61K31/7088C12N2310/321C12N2310/3525C12N2310/3341C12N2320/32C12N2320/35A61K48/00
Inventor S·M·弗雷尔
Owner IONIS PHARMA INC
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