Factor xii (Hagemann factor) (f12), kallikrein b, plasma (Fletcher factor) 1 (klkb1) and kininogen 1 (kng1) irna compositions and methods of use thereof

A factor-inhibitor technology for the combination of factor XII (Hagemann factor) (F12), kallikrein B, plasma (Fletcher factor) 1 (KLKB1) and kininogen 1 (KNG1) iRNAs drug and its field of use, able to address negative effects, lack of safety, efficacy, and need for drug delivery

Active Publication Date: 2022-07-15
ALNYLAM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Androgens are not suitable for short-term treatment of acute attacks because they take several days to become effective, and they can have significant side effects and can negatively affect growth and development
As a result, androgens are used only for long-term prophylaxis and are typically not administered to pregnant women or children
In addition, current treatments for acute attacks must be administered intravenously multiple times per week or may cause side effects that require dosing or follow-up hospitalization, limiting their routine prophylactic use for long-term management of the disease
Therefore, due to the lack of a safe, effective, and more convenient route of administration and a program for the treatment of acute angioedema attacks and preventive management of recurrent attacks in a large proportion of patients, including pregnant women and children, for patients with HAE There is a need for alternative therapies for test subjects

Method used

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  • Factor xii (Hagemann factor) (f12), kallikrein b, plasma (Fletcher factor) 1 (klkb1) and kininogen 1 (kng1) irna compositions and methods of use thereof
  • Factor xii (Hagemann factor) (f12), kallikrein b, plasma (Fletcher factor) 1 (klkb1) and kininogen 1 (kng1) irna compositions and methods of use thereof
  • Factor xii (Hagemann factor) (f12), kallikrein b, plasma (Fletcher factor) 1 (klkb1) and kininogen 1 (kng1) irna compositions and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0695] Example 1: Synthesis of KLKB1 iRNA

[0696] source of reagents

[0697] Herein, if the source of a reagent is not specified, the reagent can be obtained from any supplier of reagents for molecular biology in quality / purity for molecular biology applications.

[0698] transcript

[0699] siRNA design

[0700]For human KLKB1, "Kallikrein B, Plasma (Fletcher Factor) 1" (REFSeq Accession No. NM_000892.3, GI:78191797, GeneID:3818, SEQ ID NO:1 and SEQ ID NO.2) and KLKB1 xenologs from virulent species (Cynomolgus: RefSeq Accession No. XM_005556482, GI: 544436072; Rhesus: RefSeqJU329355, GI: 380802470; Mouse: RefSeqNM_008455, GI: 236465804; Rat RefSeqNM_012725, GI: 16213890) A targeted set of siRNAs was designed using custom R and Python scripts. Human KLKB1 RefSeq mRNA is 2252 bases in length. The rationale and methodology for this set of siRNA designs are as follows: Using a linear model that predicts direct measures of mRNA knockdown, based on over 20,000 distinct siRNA...

example 2

[0706] Example 2. In vitro screening of KLKB1 siRNA duplexes

[0707] Cell Culture and Transfection

[0708] Cos7 cells (ATCC, Manassas, VA) were grown at 37°C, 5% CO 2 They were grown to near confluence in DMEM (ATCC) supplemented with 10% FBS under atmosphere and released from the plate by trypsinization. Luciferase constructs were generated in psiCHECK2 plastids containing approximately 2.2 kb of human KLKB1 genomic sequence or 2.5 kb of xenologous mouse KLKB1 genomic sequence. Dual-luciferase plastids were each transfected with siRNA at 15x10 using Lipofectamine 2000 (Invitrogen, Carlsbad CA. cat#11668-019). 4 in the cell. For each well of a 96-well plate, 0.2 μl of Lipofectamine was added to 10 ng of plastid vector and single siRNA (Tables 3 and 4) in 14.8 μL of Opti-MEM, and the complex was left at room temperature for 15 minutes. The mixture was then added to the cells, which were resuspended in 80 [mu]l of fresh complete medium. After incubating the cells for 24 ...

example 3

[0737] Example 3. Synthesis of F12iRNA

[0738] source of reagents

[0739] Herein, if the source of a reagent is not specified, the reagent can be obtained from any supplier of reagents for molecular biology in quality / purity for molecular biology applications.

[0740] transcript

[0741] siRNA design

[0742] For human F12, "Factor XII" (Human: NCBI refseqID NM_000505; NCBI GeneID: 2161) and F12 xenologs from virulent species (Cynomolgus: XM_005558647; Mouse: NM_021489; Rat: NM_001014006) were A targeted set of siRNAs was designed using custom R and Python scripts. Human F12RefSeq mRNA is 2060 bases in length. The rationale and methodology for this set of siRNA designs are as follows: Human F12 mRNA (containing the coding region and Predicted potency of each potential 19mer siRNA from position 50 to position 2060 (coding region and 3'UTR) of the 3'UTR. A subset of this F12 siRNA is designed to be a perfect or near-perfect match between humans, cynomolgus monkeys and r...

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Abstract

The present invention relates to RNAi agents targeting kallikrein B, plasma (Fletcher factor) 1 (KLKB1) gene, factor XII (Hagemann factor) (F12) gene, or kininogen 1 (KNG1) gene, Such as double-stranded RNAi agents, and methods of using these RNAi agents to inhibit the expression of the KLKB1 gene, F12 gene, and / or KNG1 gene, and to treat patients with hereditary angioedema (HAE) and / or disorders associated with the contact activation pathway tester's method.

Description

[0001] Related applications [0002] This application claims US Patent Provisional Application No. 62 / 157,890, filed May 6, 2015, US Patent Provisional Application No. 62 / 260,887, filed November 30, 2015, and December 14, 2015 Priority of U.S. Patent Provisional Application No. 62 / 266,958. The entire contents of each of the foregoing applications are incorporated herein by reference. [0003] sequence listing [0004] This 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 May 3, 2016, is named 121301-03120_SL.txt and has a size of 721,827 bytes. Background technique [0005] The coagulation system is essential for hemostasis, which in response to vascular injury locally produces a blood clot formed from a fibrin network and activated platelets. Coagulation, thrombin production, and fibrin formation can be initiated by two distinct pathways, te...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N15/113A61K31/713
CPCC12N15/113C12N15/1137C12Q1/6883A61K31/713A61K47/549A61K45/06A61P9/12A61P7/10A61P7/02A61P9/10C12N2310/14C12N2310/344C12N2310/321C12N2310/322C12N2310/31C12N2310/3521C12N2310/3533A61P43/00
Inventor A·阿金克G·辛克尔M·迈尔J·巴特勒刘璟璇
Owner ALNYLAM PHARMA INC
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