Hsd17b13 variants and uses thereof

A DNA targeting and guiding technology, applied in vectors, polymorphic use, nucleic acid vectors, etc., can solve problems such as protective gene variants of chronic liver diseases that have not been described

Pending Publication Date: 2019-11-12
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

A protective gene variant for chronic liver disease has not been described so far

Method used

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  • Hsd17b13 variants and uses thereof
  • Hsd17b13 variants and uses thereof
  • Hsd17b13 variants and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0456] Example 1. Variant 17β-hydroxysteroid dehydrogenase 13 prevents chronic liver disease

[0457] In the United States, chronic liver disease and cirrhosis are the main causes of higher mortality and morbidity (Kochanek et al., (2016) Natl Vital Stat Rep 65:1-122, the entire content of which is incorporated herein by reference). The most common causes of liver cirrhosis are alcoholic liver disease, chronic hepatitis C and non-alcoholic fatty liver (NAFLD), which results in approximately 80% of patients waiting for liver transplantation (Wong et al., (2015) Gastroenterology 148:547-555 , The entire contents of which are incorporated herein by reference). It is worth noting that in the United States, the prevalence of NAFLD is estimated to reach 19% to 46% (Browning et al., (2004) Hepatology 40:1387-1395; Lazo et al., (2013) Am J Epidemiol 178:38-45 ; And Williams et al., (2011) Gastroenterology 140:124-131, the entire contents of which are incorporated herein by reference) an...

Embodiment 2

[0505] Example 2. rs72613567: The role of TA in HSD17B13 mRNA and HSD17B13 protein expression

[0506] This example examined the effect of the HSD17B13 rs72613567:TA allele on the expression of known and new transcripts of the gene. RNA sequencing was used to evaluate the expression of HSD17B13 mRNA in the histologically normal liver samples of 22 T / T homozygous, 30 T / TA heterozygous and 17 TA / TA homozygous carriers derived from the HSD17B13 rs72613567 splice variant . In addition to the two known HSD17B13 transcripts A and B, a transcript C lacking exon 6 and a transcript D containing an insertion of a guanine nucleotide located at the 3'end of exon 6 were also identified , The insertion of guanine nucleotides can be expected to cause premature truncation of the protein. The transcripts were verified by RT-PCR and Sanger sequencing (data not shown). Long-read cDNA sequencing was also used to verify the D transcript. The expression level of these transcripts varies according ...

Embodiment 3

[0513] Example 3. Variant 17β hydroxysteroid dehydrogenase 13 prevents chronic liver disease

[0514] In order to identify the genetic factors that contribute to chronic liver disease, we used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetic study. We identified gene variants associated with known liver injury biomarkers (serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) to designate candidate variants that may be associated with chronic liver disease. Subsequently, the association of repeated candidate variants in three additional cohorts (12,527 individuals) with the clinical diagnosis of chronic liver disease in DiscovEHR and two independent cohorts (37,892 individuals in total) was evaluated. We also tested the association with the histopathological severity of liver disease in an independent bariatric surgery group (n=2,391 human liver samples).

[0515] The splice variant (rs72613567:TA) in HSD...

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Abstract

Provided are compositions related to HSD17B13 variants, including isolated nucleic acids and proteins related to variants of HSD17B13, and cells comprising those nucleic acids and proteins. Also provided are methods related to HSD17B13 variants. Such methods include methods for modifying a cell through use of any combination of nuclease agents, exogenous donor sequences, transcriptional activators, transcriptional repressors, and expression vectors for expressing a recombinant HSD17B13 gene or a nucleic acid encoding an HSD17B13 protein. Also provided are therapeutic and prophylactic methods for treating a subject having or at risk of developing chronic liver disease.

Description

[0001] Cross references to related applications [0002] This application claims the rights of the U.S. application US62 / 449,335 filed on January 23, 2017, the U.S. application US62 / 472,972 filed on March 17, 2017, and the U.S. application US62 / 581,918 filed on November 6, 2017. The entire contents of each of the aforementioned US applications are incorporated herein by reference. [0003] The sequence table of the text format file is submitted through the EFS website as a reference [0004] The sequence listing with the file name 507242SEQLIST.txt has a size of 507 kilobytes, which was generated on January 19, 2018, and is incorporated herein by reference. Background technique [0005] In the United States, chronic liver disease and cirrhosis are the main causes of higher morbidity and mortality. In 2014, there were 38,170 deaths (1.5% of total deaths) (Kochanek et al., (2016) Natl Vital Stat Rep65 :1-122, the entire content of the reference is incorporated herein by reference). I...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/113C12Q1/6883
CPCC12Q1/6883C12Y101/01062C12N15/1137C12N2310/14C12N2310/531C12N2320/34C12Q2600/156C12N2310/20C12N9/0006C12Y101/01051A61P1/16A61K38/443A61K38/465C12N9/22C12N9/96A61K47/61A61K48/00C12N15/11C12N15/85C12N15/907C12N2800/24C12N2800/80C12Q1/32C12Q1/6827C12Q1/6876C12Q2600/118C12Q2600/158G01N2333/4704G01N33/5067A61K31/713G01N2800/085A61K48/0066C12N2320/30C12N15/113C12N5/067C12N2510/00
Inventor 诺拉·S·阿布-胡森奥姆里·戈特斯曼亚历山大·李程希平辛玉蓉埃万盖洛斯·普凡尼斯苏珊娜·哈特福德杰斯珀·格罗马达弗雷德里克·E·杜威阿里斯·巴拉斯艾伦·舒尔迪纳
Owner REGENERON PHARM INC
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