Treatment Of Increased Lipid Levels With Sterol Regulatory Element Binding Protein Cleavage-Activating Protein (SCAP) Inhibitors

Abstract

The present disclosure provides methods of treating subjects having increased lipid levels and/or increased triglyceride levels, methods of identifying subjects having an increased risk of developing an increased lipid level and/or increased triglyceride level, methods of detecting human Sterol Regulatory Element Binding Protein Cleavage-Activating Protein (SCAP) variant nucleic acid molecules and variant polypeptides, and SCAP variant nucleic acid molecules and variant polypeptides.

1 . A method of treating a subject having increased total cholesterol, increased low density lipoprotein (LDL), increased serum lipid level, or increased triglycerides, the method comprising administering a SCAP inhibitor to the subject. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . The method according to  claim 1 , wherein the SCAP inhibitor comprises a small interfering RNA (siRNA) or a short hairpin RNA (shRNA) that hybridizes to a SCAP mRNA. 
     
     
         6 . (canceled) 
     
     
         7 . The method according to  claim 1 , further comprising detecting the presence or absence of a SCAP variant nucleic acid molecule encoding a human SCAP polypeptide in a biological sample from the subject, wherein the SCAP variant nucleic acid molecule is: i) a genomic nucleic acid molecule having a nucleotide sequence comprising the nucleotide sequence according to SEQ ID NO:12 at positions corresponding to positions 61,695 to 62,267 according to SEQ ID NO:2, or the complement thereof, ii) an mRNA molecule having a nucleotide sequence comprising the nucleotide sequence according to SEQ ID NO:14 at positions corresponding to positions 4,116 to 4,417 according to SEQ ID NO:4, or the complement thereof, or iii) a cDNA molecule having a nucleotide sequence comprising the nucleotide sequence according to SEQ ID NO:16 at positions corresponding to positions 4,116 to 4,417 according to SEQ ID NO:6, or the complement thereof; and when the subject is SCAP reference, the subject is also administered a therapeutic agent that treats or inhibits an increased lipid level and/or an increased triglyceride level in a standard dosage amount, and when the subject is heterozygous for a SCAP variant nucleic acid molecule, the subject is also administered a therapeutic agent that treats or inhibits an increased lipid level and/or an increased triglyceride level in a dosage amount that is the same as or lower than the standard dosage amount. 
     
     
         8 . A method of treating a subject with a therapeutic agent that treats or inhibits an increased lipid level and/or an increased triglyceride level, wherein the subject is suffering from an increased lipid level and/or an increased triglyceride level, the method comprising the steps of:
 determining whether the subject has a SCAP variant nucleic acid molecule encoding a human SCAP polypeptide by:
 obtaining or having obtained a biological sample from the subject; and 
 performing or having performed a genotyping assay on the biological sample to determine if the subject has a genotype comprising the SCAP variant nucleic acid molecule; and 
   when the subject is SCAP reference, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the increased lipid level and/or an increased triglyceride level in a standard dosage amount, and administering to the subject a SCAP inhibitor; and   when the subject is heterozygous for the SCAP variant nucleic acid molecule, then administering or continuing to administer to the subject the therapeutic agent that treats or inhibits the increased lipid level and/or an increased triglyceride level in an amount that is the same as or lower than a standard dosage amount, and administering to the subject a SCAP inhibitor;   wherein the presence of a genotype having the SCAP variant nucleic acid molecule encoding the human SCAP polypeptide indicates the subject has a reduced risk of developing the increased lipid level and/or an increased triglyceride level; and   wherein the SCAP variant nucleic acid molecule is: i) a genomic nucleic acid molecule having a nucleotide sequence comprising the nucleotide sequence according to SEQ ID NO:12 at positions corresponding to positions 61,695 to 62,267 according to SEQ ID NO:2, or the complement thereof, ii) an mRNA molecule having a nucleotide sequence comprising the nucleotide sequence according to SEQ ID NO:14 at positions corresponding to positions 4,116 to 4,417 according to SEQ ID NO:4, or the complement thereof, or iii) a cDNA molecule having a nucleotide sequence comprising the nucleotide sequence according to SEQ ID NO:16 at positions corresponding to positions 4,116 to 4,417 according to SEQ ID NO:6, or the complement thereof.   
     
     
         9 - 12 . (canceled) 
     
     
         13 . An isolated alteration-specific probe or alteration-specific primer comprising at least about 15 nucleotides, wherein the alteration-specific probe or alteration-specific primer comprises a nucleotide sequence which is complementary to a portion of a nucleotide sequence encoding a human Sterol Regulatory Element Binding Protein Cleavage-Activating Protein (SCAP) polypeptide, wherein the portion comprises a position corresponding to: i) positions 61,694 to 61,695 according to SEQ ID NO:2, or the complement thereof; ii) positions 4,115 to 4,116 according to SEQ ID NO:4, or the complement thereof or iii) positions 4,115 to 4,116 according to SEQ ID NO:6, or the complement thereof. 
     
     
         14 - 25 . (canceled) 
     
     
         26 . The method according to  claim 1 , wherein the subject has increased total cholesterol. 
     
     
         27 . The method according to  claim 1 , wherein the subject has increased LDL. 
     
     
         28 . The method according to  claim 1 , wherein the subject has increased increased serum lipid level. 
     
     
         29 . The method according to  claim 1 , wherein the subject has increased triglycerides. 
     
     
         30 . The method according to  claim 1 , wherein the SCAP inhibitor comprises an siRNA that hybridizes to a SCAP mRNA.