Treatment Of Sepsis With PCSK9 And LDLR Modulators
AssigneeRegeneron Pharmaceuticals, Inc.
InventorsJulie Horowitz, Luca Andrea Lotta, Manuel Allen Revez Ferreira, Amy Damask, Charles Paulding, Garen Manvelian, Michael Cantor, Aris Baras
Life of this patent
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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.
Claims30
A method of treating a subject having sepsis, systemic inflammatory response syndrome (SIRS), septic shock, or multiple organ dysfunction syndrome (MODS), the method comprising administering a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitor and/or a Low Density Lipoprotein Receptor (LDLR) agonist to the subject in need thereof.
2-5. (canceled)
10-15. (canceled)
21-35. (canceled)
A method of treating a subject with a therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS, wherein the subject has sepsis, SIRS, septic shock, and/or MODS, the method comprising the steps of:
- determining whether the subject has:
- i) a PCSK9 variant nucleic acid molecule encoding a PCSL9 predicted loss-of-function polypeptide;
- and/or ii) an LDLR variant nucleic acid molecule encoding an LDLR predicted loss-of-function polypeptide;
- by:
- obtaining or having obtained a biological sample from the subject;
- and
- performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising:
- i) the PCSK9 variant nucleic acid molecule;
- and/or ii) the LDLR variant nucleic acid molecule;
- and
- when the subject is PCSK9 reference and LDLR reference, then also administering or continuing to administer to the subject the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in a standard dosage amount, and administering to the subject a PCSK9 inhibitor and/or an LDLR agonist;
- when the subject is LDLR reference and heterozygous for the PCSK9 variant nucleic acid molecule, then also administering or continuing to administer to the subject the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in an amount that is the same as or less than a standard dosage amount, and administering to the subject a PCSK9 inhibitor and/or an LDLR agonist;
- when the subject is PCSK9 reference and heterozygous for the LDLR variant nucleic acid molecule, then also administering or continuing to administer to the subject the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in an amount that is the same as or less than a standard dosage amount, and administering to the subject a PCSK9 inhibitor and/or an LDLR agonist;
- when the subject is LDLR reference and homozygous for the PCSK9 variant nucleic acid molecule, then also administering or continuing to administer to the subject the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in an amount that is the same as or less than a standard dosage amount, and administering to the subject an LDLR agonist;
- when the subject is PCSK9 reference and homozygous for the LDLR variant nucleic acid molecule, then also administering or continuing to administer to the subject the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in an amount that is the same as or less than a standard dosage amount, and administering to the subject a PCSK9 inhibitor;
- when the subject is heterozygous for both the PCSK9 variant nucleic acid molecule and the LDLR variant nucleic acid molecule, then also administering or continuing to administer to the subject the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in an amount that is the same as or less than a standard dosage amount, and administering to the subject a PCSK9 inhibitor and/or an LDLR agonist;
- and
- when the subject is homozygous for both the PCSK9 variant nucleic acid molecule and the LDLR variant nucleic acid molecule, the subject is also administered the therapeutic agent that treats or inhibits sepsis, SIRS, septic shock, and/or MODS in a dosage amount that is the same as or less than a standard dosage amount;
- wherein the presence of a genotype having both the PCSK9 variant nucleic acid molecule, and the LDLR variant nucleic acid molecule indicates the subject has a decreased risk of developing sepsis, SIRS, septic shock, and/or MODS.
37-42. (canceled)
46-60. (canceled)
63-69. (canceled)
A method of identifying a subject having a risk of developing sepsis, SIRS, septic shock, and/or MODS, the method comprising:
- determining or having determined the presence or absence of a PCSK9 variant nucleic acid molecule encoding a PCSL9 predicted loss-of-function polypeptide, and/or an LDLR variant nucleic acid molecule encoding an LDLR predicted loss-of-function polypeptide in a biological sample obtained from the subject;
- wherein when the subject is PCSK9 reference and LDLR reference, the subject has an increased risk of developing sepsis, SIRS, septic shock, and/or MODS;
- and when the subject is heterozygous or homozygous for an LDLR variant nucleic acid molecule, and/or heterozygous or homozygous for a PCSK9 variant nucleic acid molecule, the subject has a decreased risk of developing sepsis, SIRS, septic shock, and/or MODS.
72-89. (canceled)
A method of detecting a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) variant nucleic acid molecule in a subject comprising assaying a sample obtained from the subject to determine whether a nucleic acid molecule in the sample is:
- a genomic nucleic acid molecule comprising a nucleotide sequence comprising a thymine at a position corresponding to position 427 according to SEQ ID NO:2, or the complement thereof;
- an mRNA molecule having a nucleotide sequence comprising a uracil at a position corresponding to:
- position 428 according to SEQ ID NO:17, or the complement thereof;
- position 217 according to SEQ ID NO:18, or the complement thereof;
- or position 137 according to SEQ ID NO:19, or the complement thereof;
- or
- a cDNA molecule produced from an mRNA molecule, wherein the cDNA molecule has a nucleotide sequence comprising a thymine at a position corresponding to:
- position 428 according to SEQ ID NO:32, or the complement thereof;
- position 217 according to SEQ ID NO:33, or the complement thereof;
- or position 137 according to SEQ ID NO:34, or the complement thereof.
A method of detecting a Low Density Lipoprotein Receptor (LDLR) variant nucleic acid molecule in a subject comprising assaying a sample obtained from the subject to determine whether a nucleic acid molecule in the sample is a genomic nucleic acid molecule comprising a nucleotide sequence comprising a thymine at a position corresponding to position 2,269 according to SEQ ID NO:4, or the complement thereof.
92-111. (canceled)
A method of detecting the presence of a Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Arg46Leu variant polypeptide, comprising performing an assay on a sample obtained from a subject to determine whether a PCSK9 protein in the sample comprises a leucine at a position corresponding to position 46 according to SEQ ID NO:42.
113-130. (canceled)
Dependencies are inferred from the claim text.