Treatment of sepsis with PCSK9 and LDLR modulators

Patent metadata

Field	Value
Publication number	US-12378557-B2
Application number	US-202117411460-A
Country	US
Kind code	B2
Filing date	Aug 25, 2021
Priority date	Aug 25, 2020
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The present disclosure provides methods of treating subjects having sepsis, SIRS, septic shock, and/or MODS, methods of identifying subjects having an increased risk of developing sepsis, SIRS, septic shock, and/or MODS, and methods of detecting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) and/or Low Density Lipoprotein Receptor (LDLR) variant nucleic acid molecules and variant polypeptides.

First claim

What is claimed is:

1. A method of identifying a subject having a risk of developing sepsis, systemic inflammatory response syndrome (SIRS), septic shock, and/or multiple organ dysfunction syndrome (MODS), the method comprising:
determining or having determined in a biological sample obtained from the subject the presence or absence of: i) a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) variant nucleic acid molecule encoding PCSK9 Arg46Leu; and ii) a Low Density Lipoprotein Receptor (LDLR) variant nucleic acid molecule comprising the single nucleotide polymorphism rs6511720;
wherein when the subject does not have a PCSK9 variant nucleic acid molecule encoding PCSK9 Arg46Leu, the subject has an increased risk of developing sepsis, SIRS, septic shock, and/or MODS;
wherein when the subject has a PCSK9 variant nucleic acid molecule encoding PCSK9 Arg46Leu and is heterozygous for an LDLR variant nucleic acid molecule comprising rs6511720 , the subject has a decreased risk of developing sepsis, SIRS, septic shock, and/or MODS; and
wherein when the subject does not have a PCSK9 variant nucleic acid molecule encoding PCSK9 Arg46Leu and is not heterozygous for an LDLR variant nucleic acid molecule comprising rs6511720, administering a PCSK9 inhibitor.

2. The method according to claim 1 , wherein the PCSK9 inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA), that hybridizes to PCSK9 mRNA.

3. The method according to claim 1 , wherein the PCSK9 inhibitor comprises alirocumab or evolocumab, or a combination thereof.

4. The method according to claim 1 , wherein the PCSK9 inhibitor comprises alirocumab.

5. The method according to claim 1 , wherein the PCSK9 inhibitor comprises the monoclonal antibody SAR236553/REGN727 or AMG145, or a combination thereof.

6. The method according to claim 1 , wherein the PCSK9 inhibitor comprises lupin peptide, resveratrol, lycopene, or eugenol, or any combination thereof.

Assignees

• Regeneron Pharma

Inventors

• Horowitz Julie
• Lotta Luca Andrea
• Ferreira Manuel Allen Revez
• Damask Amy
• Paulding Charles
• Manvelian Garen
• Cantor Michael
• Baras Aris

Classifications

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q1/6883

  for diseases caused by alterations of genetic material · CPC title

• C12N15/11

  DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} · CPC title

• C12N9/22

  Ribonucleases {[RNase]; Deoxyribonucleases [DNase]} · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title