Inhibition of hsd17b13 in treatment of liver disease in patients expressing pnpla3 i148m variation

A technology of I148M and mutation, applied in the field of precision medicine, can solve the problem of not identifying gene variants of chronic liver disease

Pending Publication Date: 2020-05-19
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

To date, no gene variants that protect again

Method used

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  • Inhibition of hsd17b13 in treatment of liver disease in patients expressing pnpla3 i148m variation
  • Inhibition of hsd17b13 in treatment of liver disease in patients expressing pnpla3 i148m variation
  • Inhibition of hsd17b13 in treatment of liver disease in patients expressing pnpla3 i148m variation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0332] Example 1: Genetic Interaction Between PNPLA3 rs738409 (p.I148M) and HSD17B13 rs72613567 - Study Design

[0333] In this study, exome sequencing was used to identify Variants associated with serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as markers of hepatocellular injury. Associations between implicated genetic variants and clinical diagnoses of chronic liver disease were also investigated in DiscovEHR and two independent cohorts. The association between one of these variants and the histopathological severity of liver disease was also investigated in an independent cohort of obese surgical patients undergoing liver biopsy.

[0334] Study Design and Participants

[0335] Human genetics studies were performed using genomic DNA samples and data from six cohorts. These studies included two Regeneron Genetics Center and Geisinger Health System (GHS) DiscovEHR research populations derived from the GHS20 The first 50,726 adult consenti...

Embodiment 2

[0374] Example 2: Gene expression analysis of HSD17B13 and PNPLA3 in 66 human liver samples

[0375] Gene expression of HSD17B13 and PNPLA3 was analyzed with 66 human liver samples. All samples were from control donors without steatosis, lobular inflammation, or fibrosis. The distribution of HSD17B13 rs72613567 (T / T, T / TA and TA / TA) and PNPLA3 rs738409 (C / C, C / G and G / G) genotypes is shown in Table 1.

[0376] genotype C / C C / G G / G ND T / T 12 8 1 0 T / TA 15 12 0 2 TA / TA 12 4 0 0

[0377] Expression of PNPLA3 was significantly reduced in homozygous alternate carriers of the HSD17B13 rs72613567 splice variant (see Figure 7 ). mRNA expression is shown in FPKM units. A 1.6-fold decrease compared to T / T with FDR 0.0071 was observed. The expression of the variant PNPLA3 C / C vector with the HSD17B13 TA / TA genotype was significantly reduced when compared to the HSD17B13 T / T vector: 1.7-fold decrease (FDR 0.017). Variant PNPLA3 C / G v...

Embodiment 3

[0380] Example 3: Gene expression analysis of HSD17B13 and PNPLA3 in 66 human liver samples

[0381] Association of exonic variants with aspartate and alanine aminotransferases

[0382] In a study from DiscovEHR (“GHS Discovery Cohort”; figure 1 The association of 502,219 biallelic single genetic variants with serum ALT or AST levels was examined in 46,544 individuals of European ancestry in Base Demographics in . A total of 35 variants in 19 genes were found with P-7 Related to ALT or AST (see Figure 14 and figure 2 ). see Figure 14 , shows a Manhattan plot (left) and a quantile-quantile plot (right) of the association of single nucleotide variants with serum transaminase levels in the GHS discovery cohort. 31 variants in 16 genes with P-7 Significantly correlated with alanine aminotransferase (ALT) levels (see panel A). 12 variants in 10 genes with P-7 Significantly correlated with aspartate aminotransferase (AST) levels (see panel B). All significant associations ...

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Abstract

The disclosure provides methods of identifying a human subject as a candidate for treating or inhibiting a liver disease by inhibiting HSD17B13. The disclosure also provides methods of treating a subject who is PNPLA3 Ile148Met+ by administering an inhibitor of HSD17B13. The disclosure also provides method of detecting a PNPLA3 Ile148Met variant and functional HSD17B13 in a subject. The disclosurealso provides method of identifying a subject having a protective effect against liver disease. The disclosure also provides inhibitors of HSD17B13 for use in the treatment of a liver disease.

Description

[0001] References to Sequence Listings [0002] This application includes a Sequence Listing electronically filed as a text file named 18923801002SEQ, created on October 10, 2018, and 238 kilobytes in size. The Sequence Listing is incorporated herein by reference. technical field [0003] The present disclosure generally relates to the field of precision medicine. More specifically, the present disclosure relates to methods of identifying subjects and treating such subjects with inhibitors of hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13), said subjects being patatin-like phospholipase domain 3-containing (PNPLA3) Ile148Met positive and have or are predisposed to liver disease. Background technique [0004] Various references, including patents, patent applications, registration numbers, technical articles, and scholarly articles, are cited throughout the specification. Each reference is hereby incorporated by reference in its entirety and for all purposes. [0005] ...

Claims

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Application Information

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IPC IPC(8): C12Q1/6883
CPCC12Q2600/106C12Q1/6883C12Q2600/158C12Q2600/156C12N15/113A61K31/713A61P1/16
Inventor 辛玉蓉J·格罗马达程希平F·杜威T·特斯洛维奇·多斯塔尔C·舒尔曼
Owner REGENERON PHARM INC
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