US2004058869A1PendingUtilityA1

Methods and reagents for modulating cholesterol levels

54
Priority: Mar 15, 1999Filed: Jul 10, 2003Published: Mar 25, 2004
Est. expiryMar 15, 2019(expired)· nominal 20-yr term from priority
Inventors:Michael HaydenAngela WilsonSimon Pimstone
A61P 35/00A61P 9/10A61P 3/00A61P 25/28A61K 38/00A01K 2217/05A61K 2039/53A61P 25/00C07K 14/705A61P 25/14A61K 48/00C07K 14/70567
54
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Claims

Abstract

The invention features ABC1 nucleic acids and polypeptides for the diagnosis and treatment of abnormal cholesterol regulation. The invention also features methods for identifying compounds for modulating cholesterol levels in an animal (e.g., a human).

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . A method of treating a mammal having a disorder of cholesterol metabolism comprising administering to said mammal a therapeutically effective amount of a compound that modulates the biological activity of ABCA1 polypeptide.  
     
     
         2 . The method of  claim 1 , wherein said biological activity is in vitro lipid transport across a membrane.  
     
     
         3 . The method of  claim 2 , wherein said lipid is a member selected from the group consisting of phospholipid and cholesterol.  
     
     
         4 . The method of  claim 2 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         5 . The method of  claim 2 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         6 . The method of  claim 1 , wherein said biological activity is in vitro ion transport across a membrane.  
     
     
         7 . The method of  claim 6 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         8 . The method of  claim 6 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         9 . The method of  claim 1 , wherein said biological activity is in vitro interleukin-1 transport across a membrane.  
     
     
         10 . The method of  claim 9 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         11 . The method of  claim 9 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         12 . The method of  claim 1 , wherein said biological activity is in vitro ATP-hydrolysis.  
     
     
         13 . The method of  claim 12 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         14 . The method of  claim 12 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         15 . The method of  claim 1 , wherein said biological activity is in vitro ATP-binding.  
     
     
         16 . The method of  claim 15 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         17 . The method of  claim 15 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         18 . The method of  claim 1  wherein said mammal is a mouse.  
     
     
         19 . The method of  claim 1  wherein said mammal is a human.  
     
     
         20 . The method of  claim 1 , wherein said mammal has low HDL cholesterol levels relative to normal.  
     
     
         21 . The method of  claim 20  wherein said mammal is a mouse.  
     
     
         22 . The method of  claim 20  wherein said mammal is a human.  
     
     
         23 . The method of  claim 1  wherein said modulation is an increase in biological activity.  
     
     
         24 . A method of treating a mammal having or at risk of developing a cardiovascular disease, comprising administering to said mammal a therapeutically effective amount of a compound that modulates the biological activity of ABCA1 polypeptide.  
     
     
         25 . The method of  claim 24 , wherein said biological activity is in vitro lipid transport across a membrane.  
     
     
         26 . The method of  claim 25 , wherein said lipid is a member selected from the group consisting of phospholipid and cholesterol.  
     
     
         27 . The method of  claim 25 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         28 . The method of  claim 25 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         29 . The method of  claim 24 , wherein said biological activity is in vitro ion transport across a membrane.  
     
     
         30 . The method of  claim 29 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         31 . The method of  claim 29 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         32 . The method of  claim 24 , wherein said biological activity is in vitro interleukin-1 transport across a membrane.  
     
     
         33 . The method of  claim 32 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         34 . The method of  claim 32 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         35 . The method of  claim 24 , wherein said biological activity is in vitro ATP-hydrolysis.  
     
     
         36 . The method of  claim 35 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         37 . The method of  claim 35 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         38 . The method of  claim 24 , wherein said biological activity is in vitro ATP-binding.  
     
     
         39 . The method of  claim 38 , wherein said ABCA1 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.  
     
     
         40 . The method of  claim 38 , wherein said ABCA1 polypeptide comprises amino acids 1-60 of SEQ ID NO: 1.  
     
     
         41 . The method of  claim 24  wherein said mammal is a mouse.  
     
     
         42 . The method of  claim 24  wherein said mammal is a human.  
     
     
         43 . The method of  claim 24 , wherein said mammal has low HDL cholesterol levels relative to normal.  
     
     
         44 . The method of  claim 43  wherein said mammal is a mouse.  
     
     
         45 . The method of  claim 43  wherein said mammal is a human.  
     
     
         46 . The method of  claim 1  wherein said disease is selected from the group consisting of Alzheimer's disease, Niemann-Pick disease, Huntington's disease, x-linked adrenoleukodystrophy, and cancer.  
     
     
         47 . The method of  claim 46  wherein said mammal is a mouse.  
     
     
         48 . The method of  claim 46  wherein said mammal is a human.  
     
     
         49 . The method of  claim 24 , wherein said cardiovascular disease is coronary artery disease, cerebrovascular disease, coronary restenosis, or peripheral vascular disease.  
     
     
         50 . A method of preventing cardiovascular disease in a human, said method comprising administering to said human an expression vector comprising an ABCA1 polynucleotide operably linked to a promoter, said ABCA1 polynucleotide encoding an ABCA1 polypeptide having in vitro ABCA1 biological activity.  
     
     
         51 . A method of preventing or ameliorating the effects of a disease-causing mutation in an ABCA1 gene in a human, said method comprising introducing into said human an expression vector comprising a promoter operably linked to an ABCA1 polynucleotide encoding an ABCA1 polypeptide having in vitro ABCA1 biological activity.  
     
     
         52 . A method of treating or preventing cardiovascular disease in an animal, said method comprising administering to said animal a compound that mimics the activity of wild-type ABCA1.  
     
     
         53 . The method of  claim 52 , wherein said animal is a human.  
     
     
         54 . The method of  claim 52  wherein said compound is a member selected from a group consisting of protein kinase A, protein kinase C, vanadate, okadaic acid, IBMX1, fibrates, γ-estradiol, arachidonic acid derivatives, WY-14,643, LTB4, 8(s)HETE, thiozolidinedione antidiabetic drugs, 9-HODE, 13-HODE, nicotinic acid, HMG CoA reductase inhibitors, and compounds that increase PPAR-mediated ABCA1 expression.  
     
     
         55 . The method of  claim 52 , wherein said cardiovascular disease is coronary artery disease, cerebrovascular disease, coronary restenosis, or peripheral vascular disease.  
     
     
         56 . The method of  claim 53  wherein said compound is a member selected from a group consisting of protein kinase A, protein kinase C, vanadate, okadaic acid, IBMX1, fibrates, γ-estradiol, arachidonic acid derivatives, WY-14,643, LTB4, 8(s)HETE, thiozolidinedione antidiabetic drugs, 9-HODE, 13-HODE, nicotinic acid, HMG CoA reductase inhibitors, and compounds that increase PPAR-mediated ABCA1 expression.

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