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Gene editing of pcsk9

An editing and encoding technology, applied in genetic engineering, metabolic diseases, extracellular fluid diseases, etc., can solve problems such as genome instability and off-target effects

Pending Publication Date: 2019-10-18
PRESIDENT & FELLOWS OF HARVARD COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, current methods for generating protective and loss-of-function mutants of PCSK9 in vivo are ineffective due to the need to modify large numbers of cells to regulate cholesterol levels
Additional concerns relate to possible off-target effects, genome instability, or oncogenic modifications caused by genome editing

Method used

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  • Gene editing of pcsk9
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  • Gene editing of pcsk9

Examples

Experimental program
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Effect test

Embodiment 1

[0596] Example 1: Guide-guide nucleotide sequences-programmable DNA-binding protein domains, deaminase domains and base editors

[0597] Non-limiting examples of suitable leader nucleotide sequences-programmable DNA binding protein domains are provided. The present disclosure provides Cas9 variants, such as Cas9 proteins from one or more organisms, which may comprise one or more mutations (eg, to generate dCas9 or a Cas9 nickase). In some embodiments, one or more of the amino acid residues of the Cas9 protein (identified with an asterisk below) can be mutated. In some embodiments, the D10 and / or H840 residues of the amino acid sequence provided in SEQ ID NO: 1, or the corresponding mutations in any of the amino acid sequences provided in SEQ ID NO: 11-260, are mutated. In some embodiments, the D10 residue of the amino acid sequence provided in SEQ ID NO: 1, or the corresponding mutation in any of the amino acid sequences provided in SEQ ID NO: 11-260, is mutated to any resi...

Embodiment 2

[0689] Example 2: Methods for modifying PCSK9 and other liver proteins to improve circulating cholesterol and lipid levels CRISPR / Cas9 genome / base editing method

[0690] Approximately 70% of circulating cholesterol is transported within low-density lipoproteins (LDL), which are cleared in the liver by LDL receptor (LDL-R)-mediated endocytosis, along with endogenous Additional consequences of downregulation of the cholesterol biosynthetic pathway. PCSK9 is a secreted, globular serine protease capable of proteolytic autoprocessing of its N-terminal prodomain into a potent endogenous inhibitor that permanently blocks its catalytic site ( Figures 1A to 1C ). A list of agents used to block PCSK9 function can be found in Table 12. Mature PCSK9 exits through the secretory pathway and functions as a protein-binding linker in clathrin-coated vesicles to bridge the pH-dependent interaction with the LDL receptor during endocytosis of LDL particles, which prevents LDL receptor re...

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Abstract

Provided herein are systems, compositions, and methods of introducing loss-of-function mutations in to protein factors involved in the LDL-R-mediated cholesterol clearance pathway, e.g., PCSK9, APOC3,LDL-R, or IDOL. Loss-of-function mutations may be introduced using a CRISPR / Cas9-based nucleobase editor described in. Further provided herein are compositions and methods of treating conditions related to high circulating cholesterol levels.

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application U.S.S.N. 62 / 438,869, filed December 23, 2016, which is incorporated herein by reference. [0003] governmental support [0004] This invention was made with Government support under Grant No. GM065865 awarded by the National Institutes of Health. The government has certain rights in this invention. [0005] Background of the invention [0006] Hepatic proprotein convertase subtilisin / Kexin type 9 (PCSK9) is a secreted, globular, autoactivating serine protease that functions as a protein-binding linker within endosomal vesicles to bind low-density lipoprotein (LDL ) bridges a pH-dependent interaction with the LDL receptor (LDL-R) during endocytosis of granules, thereby preventing recycling of LDL-R to the cell surface and resulting in reduced LDL-cholesterol clearance. Blocking or inhibiting the function of PCSK9 to enhance LDL-R-mediated clearance of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/22C12N9/78C12N15/10
CPCC12N9/22C12N9/78C07K2319/00A61P1/16A61P25/00A61P25/28A61P3/04A61P3/06A61P3/10A61P43/00A61P7/02A61P9/00A61P9/10A61P9/12C12N15/102C12N15/1082C12N15/113C12N15/74C12N15/8509C12N15/907C12N2310/20C12N2310/3519C12N2310/531C12N15/85C12N15/62A61K48/005
Inventor J.P.麦安蒂D.R.刘
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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