SERUM AMYLOID P COMPONENT (APCS) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

a technology of amyloid p component and irna composition, which is applied in the direction of peptides, biochemistry apparatus and processes, organic active ingredients, etc., can solve the problems of affecting the function of tissues and organs, no amyloidosis cure, and often delayed diagnosis

Pending Publication Date: 2022-09-29
ALNYLAM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The iRNA compositions effectively inhibit APCS gene expression, potentially mitigating amyloid deposit formation and associated disease symptoms, providing a therapeutic approach for amyloidosis, Alzheimer's disease, and cardiovascular diseases.

Problems solved by technology

The amyloid deposits disrupt the normal tissue architecture, damaging the function of tissues and organs and causing disease.
The clinical manifestations of amyloidosis are accordingly highly variable and confirmation of the presence of amyloid in the tissues can be challenging, so that diagnosis is often delayed.
There is no cure for amyloidosis.

Method used

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  • SERUM AMYLOID P COMPONENT (APCS) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
  • SERUM AMYLOID P COMPONENT (APCS) iRNA COMPOSITIONS AND METHODS OF USE THEREOF
  • SERUM AMYLOID P COMPONENT (APCS) iRNA COMPOSITIONS AND METHODS OF USE THEREOF

Examples

Experimental program
Comparison scheme
Effect test

example 1

iRNA Synthesis

Source of Reagents

[0528]Where the source of a reagent is not specifically given herein, such reagent can be obtained from any supplier of reagents for molecular biology at a quality / purity standard for application in molecular biology.

Bioinformatics

[0529]A set of siRNAs targeting the human SAP or APCS, “amyloid P component, serum” (human: NCBI refseqID NM_001639; NCBI GeneID: 325) as well as toxicology-species APCS orthologs (cynomolgus monkey: XM_005541312; mouse: NM_011318; rat: NM_017170) were designed using custom R and Python scripts. The human NM_001639 REFSEQ mRNA, version 3, has a length of 960 bases. The rationale and method for the set of siRNA designs is as follows: the predicted efficacy for every potential 19mer siRNA from position 10 through the end was determined with a linear model derived the direct measure of mRNA knockdown from more than 20,000 distinct siRNA designs targeting a large number of vertebrate genes. A subset of the APCS siRNAs was design...

example 2

iRNA Design, Synthesis, Selection, and In Vitro Evaluation

Bioinformatics

[0534]An additional set of siRNAs targeting the human APCS (SAP), “amyloid P component, serum” (human: NCBI refseqID NM_001639.3; NCBI GeneID: 325) as well the toxicology-species APCS ortholog from cynomolgus monkey: XM_005541312.2) was designed using custom R and Python scripts. All the siRNA designs are a perfect match to the human APCS transcript and a subset have either perfect or near-perfect matches to the cynomolgus monkey ortholog. The human NM_001639 REFSEQ mRNA, version 3, has a length of 960 bases.

[0535]A detailed list of the unmodified SAP sense and antisense strand sequences is shown in Table 6. A detailed list of the modified SAP sense and antisense strand sequences is shown in Table 7.

In Vitro Screen

[0536]Dual-Glo® Luciferase Assay

[0537]Cos7 cells (ATCC, Manassas, Va.) were grown to near confluence at 37° C. in an atmosphere of 5% CO2 in DMEM (ATCC) supplemented with 10% FBS, before being released...

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PUM

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Abstract

The invention relates to iRNA, e.g., double stranded ribonucleic acid (dsRNA), compositions targeting the serum amyloid P component (APCS) gene, and methods of using such iRNA, e.g., dsRNA, compositions to inhibit expression of an APCS gene and to treat subjects having an APCS-associated disease, e.g., amyloidosis, Alzheimer's disease or coronary atherosclerotic heart disease.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 16 / 877,586, filed May 19, 2020, which is a 35 § U.S.C. 111(a) continuation application which claims the benefit of priority to PCT / US2018 / 061906, filed on Nov. 20, 2018, which claims the benefit of priority to U.S. Provisional Application No. 62 / 588,506, filed on Nov. 20, 2017. The entire contents of each of the foregoing applications are incorporated herein by reference.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Nov. 1, 2021, is named 121301_06504_SL.txt and is 276,286 bytes in size.BACKGROUND OF THE INVENTION[0003]Serum amyloid P component (SAP), also referred to as as APCS or pentraxin-2 (PTX-2), is a 25 kDa pentameric protein that is identical to the amyloid P component (AP), but is located in the serum. In humans,...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K31/713A61K47/54C12N15/113
CPCA61K31/713A61K47/549C12N15/113C12N2310/14C12N2310/315C12N2310/3515C07K14/4711
InventorFITZGERALD, KEVINHINKLE, GREGORY
OwnerALNYLAM PHARMA INC