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AMYLOID PRECURSOR PROTEIN (APP) RNAi AGENT COMPOSITIONS AND METHODS OF USE THEREOF

A precursor protein, amyloid technology, applied in DNA/RNA fragments, biochemical equipment and methods, single-stranded DNA viruses, etc., can solve problems such as limited efficacy

Pending Publication Date: 2021-09-28
ALNYLAM PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

To date, approved drug treatments for APP-related diseases or conditions are symptomatic rather than prophylactic or curative, and such treatments have limited efficacy, especially when APP-related diseases or conditions develop in affected individuals

Method used

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  • AMYLOID PRECURSOR PROTEIN (APP) RNAi AGENT COMPOSITIONS AND METHODS OF USE THEREOF
  • AMYLOID PRECURSOR PROTEIN (APP) RNAi AGENT COMPOSITIONS AND METHODS OF USE THEREOF
  • AMYLOID PRECURSOR PROTEIN (APP) RNAi AGENT COMPOSITIONS AND METHODS OF USE THEREOF

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0350] Additional representative U.S. patents and U.S. patent publications that teach the preparation of locked nucleic acid nucleotides include, but are not limited to, the following: U.S. Patent No. 6,268,490; U.S. Patent No. 6,525,191; U.S. Patent No. 6,670,461; U.S. Patent No. 6,770,748; U.S. Patent No. 6,794,499; U.S. Patent No. 6,998,484; U.S. Patent No. 7,053,207; U.S. Patent No. 7,034,133; U.S. Patent No. 8,022,193; U.S. Patent No. 8,030,467; U.S. Patent No. 8,278,425; U.S. Patent No. 8,278,426; U.S. Patent No. 8,278,283; The entire content of one article is incorporated herein by reference.

[0351] Any of the foregoing bicyclic nucleosides may be prepared with one or more stereochemical sugar configurations, including for example alpha-L-ribofuranose and beta-D-ribofuranose (see WO 99 / 14226).

[0352] The modified RNAi agents disclosed herein can also include one or more restricted ethyl nucleotides. As used herein, a "constrained ethyl nucleotide" or "cEt" is a lo...

example

[0918] Example 1. RNAi reagent design, synthesis, selection and in vitro evaluation

[0919] This example describes methods for the design, synthesis, selection and in vitro evaluation of APP RNAi agents.

[0920] Reagent source

[0921] Where the source of an agent is not specifically given herein, such agents can be obtained from any supplier of molecular biology agents in quality / purity standards for molecular biology applications.

[0922] Bioinformatics

[0923] siRNA agents targeting a group of human amyloid-beta precursor genes (APP; human NCBI refseqNM_201414; NCBI GeneID:351; SEQ ID NO:1), and APP orthologues in the toxicology species from cynomolgus monkeys ( Cynomolgus monkey: XM_005548883.2; SEQ ID NO:12) was designed using custom R and Python. All siRNA designs were perfectly matched to the human APP transcript, and a subset were perfectly or near-perfectly matched to the cynomolgus monkey ortholog. Human NM_201414 REFSEQ mRNA, version 2, 3423 bases in length....

example 2

[1016] Example 2: In vivo evaluation of RNAi agents

[1017] Selected APP-targeting RNAi agents were evaluated for in vivo efficacy in a proof-of-concept and lead identification screen for human APP knockout in AAV mice. Selected RNAi agents for such studies include AD-392911, AD-392912, AD-392911, AD-392912, AD-392913, AD-392843, AD-392844, AD-392824, AD-392704, AD-392790, AD-392703, AD-392866, AD-392927, AD-392916, AD-392714 and AD-392926, having the sequence as above in Table 2A of the right, the corresponding unmodified sequence as in Table 3 above, and As depicted graphically in Fig. 1A and Fig. In Figure 1B, each of the RNAi agents tested in this example further presents a triantennary GalNAc moiety attached at the 3' residue of the sense strand in order to aid the liver targeting of such RNAi agents when subcutaneously administered to mice (for intrathecal administration, the lack of a conjugated GalNAc moiety is also explicitly considered).

[1018] In such studies...

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Abstract

The disclosure relates to double stranded ribonucleic acid (dsRNAi) agents and compositions targeting the APP gene, as well as methods of inhibiting expression of an APP gene and methods of treating subjects having an APP-associated disease or disorder, such as cerebral amyloid angiopathy (CAA) and early onset familial Alzheimer disease (EOFAD or eFAD), using such dsRNAi agents and compositions.

Description

technical field [0001] The present application relates generally to RNAi agents and methods targeting APP. [0002] sequence listing [0003] This application contains a Sequence Listing, which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy was created on December 18, 2019 and is named 53433_500WO01_SequenceListing_ST25.txt and is 632kB in size. Background technique [0004] The amyloid precursor protein (APP) gene encodes an integral membrane protein expressed in neurons and glia. Although the primary function of APP is unknown, secretase-cleaved forms of APP—especially Aβ-cleaved forms, for example, Aβ(1-42) (aka Aβ42) and Aβ(1-40) (aka Aβ40 ) is often found as the major protein in the beta-amyloid plaque block - which has long been described as being associated with the development and progression of Alzheimer's disease (AD) in affected individuals. Indeed, identification of β-amyloid plaque block...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113A61P25/28
CPCC12N2750/14143A61K48/005C12N2310/14C12N2310/321C12N2310/322C12N2310/3515C12N2310/315C12N2310/3183C12N15/113A61P25/28A61K31/713C12N2310/3521C12N2310/3533A61K9/0085C07K14/4711C12N2310/11C12N2310/31
Inventor 斯图尔特·米尔斯坦柯克·布朗贾亚普拉卡什·奈尔马丁·迈尔瓦桑特·贾达夫马克·基廷亚当·卡斯托雷诺帕特里克·哈斯莱特曼加拉·M·桑达拉潘迪安凯文·菲茨杰拉德
Owner ALNYLAM PHARMA INC
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