US2007264249A1PendingUtilityA1

Gene-based lipid hydrolysis therapy for atherosclerosis and related diseases

61
Individually held — no corporate assignee on recordPriority: Feb 4, 2000Filed: Jan 12, 2007Published: Nov 15, 2007
Est. expiryFeb 4, 2020(expired)· nominal 20-yr term from priority
Inventors:Gregory GrabowskiHong Du
C12N 2799/04A23L 33/18A61K 38/465A61K 48/005C12Y 301/01013A61K 38/18A61P 3/06A61P 9/10A61K 9/0019C12N 2799/021A61K 48/00C12N 7/00A61K 38/40A61P 9/00A61P 43/00C12N 9/20
61
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Claims

Abstract

The present invention comprises a method to diminish and/or eliminate atherosclerotic plaques, in mammals, through direct and indirect treatment of these plaques, in situ, using suitable substances which are capable of lipid removal, primarily through hydrolysis, either by a catalytic or stoichiometric process, wherein the substance targets receptors in and/or on the cell which lead to uptake into the lysosome. Such substances used to diminish and/or eliminate atherosclerotic plaques are generally comprised of lipid hydrolyzing proteins and/or polypeptides.

Claims

exact text as granted — not AI-modified
1 ) A process for reducing atherosclerotic plaques in a mammal comprising administering to said mammal a safe and effective amount of a lipid hydrolyzing protein or polypeptide, or mixtures thereof, sufficient to effect a reduction in the amount of atherosclerotic plaques in said mammal.  
   
   
       2 ) The process of  claim 1  wherein said lipid hydrolyzing protein or polypeptide targets a receptor site for uptake into lysosomes.  
   
   
       3 ) The process of  claim 2  wherein said receptor site is selected from the group consisting of oligosaccharide recognition receptors and peptide sequence recognition receptors.  
   
   
       4 ) The process of  claim 3  wherein said receptor site is a mannose receptor site.  
   
   
       5 ) The process of  claim 2  wherein said lipid hydrolyzing protein or polypeptide is the protein lysosomal acid lipase.  
   
   
       6 ) The process of  claim 2  wherein said lipid hydrolyzing protein or polypeptide is a protein which shows at least 85% sequence homology to the protein lysosomal acid lipase.  
   
   
       7 ) The process of  claim 2  wherein said lipid hydrolyzing protein or polypeptide is a polypeptide possessing similar biological activity as lysosomal acid lipase.  
   
   
       8 ) The process of  claim 2  wherein said lipid hydrolyzing protein or polypeptide is a protein having a Ser 153  residue.  
   
   
       9 ) The process of  claim 2  wherein said lipid hydrolyzing protein or polypeptide is a polymorphic variant protein of lysosomal acid lipase with substitution of amino acid Pro(−6) to Thr and Gly2 to Arg.  
   
   
       10 ) The process of  claim 5  wherein the lysosomal acid lipase has fewer than six N-linked acetylglycosylation residues.  
   
   
       11 ) The process of  claim 5  wherein the lysosomal acid lipase has more than six N-linked acetylglycosylation residues.  
   
   
       12 ) The process of  claim 10  wherein the N-acetylglycosylation residue is oligosaccharide-terminated.  
   
   
       13 ) The process of  claim 12  wherein the oligosaccharide terminating residue is a mannose residue.  
   
   
       14 ) The process of  claim 11  wherein the N-acetylglycosylation residue is oligosaccharide-terminated.  
   
   
       15 ) The process of  claim 14  wherein the oligosaccharide terminating residue is a mannose residue.  
   
   
       16 ) The process of claims  5 ,  6 ,  7 ,  8  or  9  wherein the lipid hydrolyzing protein or polypeptide is exogenously produced.  
   
   
       17 ) The process of  claim 16  wherein said lipid hydrolyzing protein or polypeptide is in a pharmaceutically acceptable carrier and is administered either orally, parenterally, by injection, intravenous infusion, inhalation, controlled dosage release or by intraperitoneal administration.  
   
   
       18 ) The process of claims  17  wherein said lipid hydrolyzing protein or polypeptide is administered by intravenous infusion.  
   
   
       19 ) A method for treatment of atherosclerosis in a mammal comprising administering to said mammal a safe and effective amount of a lipid hydrolyzing protein or polypeptide, or mixtures thereof, sufficient to treat said condition.  
   
   
       20 ) The method of  claim 19  wherein said lipid hydrolyzing protein or polypeptide targets a receptor site for uptake into lysosomes.  
   
   
       21 ) The method of  claim 20  wherein said receptor site is selected from the group consisting of oligosaccharide recognition receptors and peptide sequence recognition receptors.  
   
   
       22 ) The method of  claim 21  wherein said receptor site is a mannose receptor site.  
   
   
       23 ) The method of  claim 20  wherein said lipid hydrolyzing protein or polypeptide is the protein lysosomal acid lipase.  
   
   
       24 ) The method of  claim 20  wherein said lipid hydrolyzing protein or polypeptide is a protein which shows at least 85% sequence homology to the protein lysosomal acid lipase.  
   
   
       25 ) The method of  claim 20  wherein said lipid hydrolyzing protein or polypeptide is a polypeptide possessing similar biological activity as lysosomal acid lipase.  
   
   
       26 ) The method of  claim 20  wherein said lipid hydrolyzing protein or polypeptide is a protein having a Ser 153  residue.  
   
   
       27 ) The method of  claim 20  wherein said lipid hydrolyzing protein or polypeptide is a polymorphic variant protein of lysosomal acid lipase with substitution of amino acid Pro(−6) to Thr and Gly2 to Arg.  
   
   
       28 ) The method of  claim 23  wherein the lysosomal acid lipase has fewer than six N-linked acetylglycosylation residues.  
   
   
       29 ) The method of  claim 23  wherein the lysosomal acid lipase has more than six N-linked acetylglycosylation residues.  
   
   
       30 ) The method of  claim 28  wherein the N-acetylglycosylation residue is oligosaccharide-terminated.  
   
   
       31 ) The method of  claim 30  wherein the oligosaccharide terminating residue is a mannose residue.  
   
   
       32 ) The method of  claim 29  wherein the N-acetylglycosylation residue is oligosaccharide-terminated.  
   
   
       33 ) The method of  claim 32  wherein the oligosaccharide terminating residue is a mannose residue.  
   
   
       34 ) The method of claims  23 ,  24 ,  25 ,  26  or  27  wherein the lipid hydrolyzing protein or polypeptide is exogenously produced.  
   
   
       35 ) The method of claims  34  wherein said lipid hydrolyzing protein or polypeptide is in a pharmaceutically acceptable carrier and is administered either orally, parenterally, by injection, intravenous infusion, inhalation, controlled dosage release or by intraperitoneal administration  
   
   
       36 ) The method of claims  35  wherein the lipid hydrolyzing protein or polypeptide is administered by intravenous infusion.  
   
   
       37 ) A composition comprising a safe and effective amount of a lipid hydrolyzing protein or polypeptide and a pharmaceutically acceptable carrier.  
   
   
       38 ) The composition of  claim 37  wherein the lipid hydrolyzing protein or polypeptide is the protein lysosomal acid lipase.  
   
   
       39 ) The composition of  claim 37  wherein the lipid hydrolyzing protein or polypeptide is a protein showing at least 85% sequence homology to lysosomal acid lipase.  
   
   
       40 ) The composition of  claim 37  wherein said lipid hydrolyzing protein or polypeptide is a polypeptide possessing similar biological activity as lysosomal acid lipase.  
   
   
       41 ) The composition of  claim 37  wherein said lipid hydrolyzing protein or polypeptide is a protein having a Ser 153  residue.  
   
   
       42 ) The composition of  claim 37  wherein said lipid hydrolyzing protein or polypeptide is a polymorphic variant protein of lysosomal acid lipase with substitution of amino acid Pro(−6) to Thr and Gly2 to Arg.  
   
   
       43 ) The composition of  claim 38  wherein the lysosomal acid lipase has fewer than six N-linked acetylglycosylation residues.  
   
   
       44 ) The composition of  claim 38  wherein the lysosomal acid lipase has more than six N-linked acetylglycosylation residues.  
   
   
       45 ) The composition of  claim 43  wherein the N-acetylglycosylation residue is oligosaccharide-terminated.  
   
   
       46 ) The composition of  claim 45  wherein the oligosaccharide terminating residue is a mannose residue.  
   
   
       47 ) The composition of  claim 44  wherein the N-acetylglycosylation residue is oligosaccharide-terminated.  
   
   
       48 ) The composition of  claim 47  wherein the oligosaccharide terminating residue is a mannose residue.  
   
   
       49 ) A composition comprising a safe and effective amount of lysosomal acid lipase in a pharmaceutically acceptable carrier.  
   
   
       50 ) A composition comprising a safe and effective amount of a lipid hydrolyzing protein showing at least 85% sequence homology to lysosomal acid lipase in a pharmaceutically acceptable carrier.  
   
   
       51 ) A method for providing biologically active lipid hydrolyzing protein or polypeptide, or mixtures thereof, to cells of a mammal having deficiency in biologically active lipid hydrolyzing protein or polypeptide, said method comprising administration into cells a vector comprising and expressing a DNA sequence encoding biologically active lipid hydrolyzing protein or polypeptide, and expressing the DNA sequence in said cells to produce biologically active lipid hydrolyzing protein or polypeptide.  
   
   
       52 ) The method of  claim 51  wherein the cells harboring the vector secrete the biologically active lipid hydrolyzing protein or polypeptide which is taken up by other cells deficient in the lipid hydrolyzing protein or polypeptide.  
   
   
       53 ) The method of  claim 51  wherein the biologically active human lipid hydrolyzing protein or polypeptide is lysosomal acid lipase.  
   
   
       54 ) The method of  claim 51  wherein the biologically active human lipid hydrolyzing protein or polypeptide is a protein having at least 85% sequence homology to lysosomal acid lipase.  
   
   
       55 ) The method of  claim 51  wherein the biologically active human lipid hydrolyzing protein or polypeptide is a polymorphic variant protein of lysosomal acid lipase with substitution of amino acid Pro(−6) to Thr and Gly2 to Arg.  
   
   
       56 ) A method for providing biologically active lysosomal acid lipase to cells of a mammal having deficiency in biologically active lysosomal acid lipase, said method comprising administration into cells a vector comprising and expressing a DNA sequence encoding biologically active lysosomal acid lipase and expressing the DNA sequence in said cells to produce biologically active lysosomal acid lipase.  
   
   
       57 ) The method of  claim 56  wherein the cells harboring the vector secrete biologically active lysosomal acid lipase which is taken up by other cells deficient in lysosomal acid lipase.  
   
   
       58 ) The method of  claim 56  wherein the vector is a viral vector.  
   
   
       59 ) The method of  claim 58  wherein the viral vector is selected from the group consisting of a lentivirus, adenovirus, adeno-associated virus and virus-like vectors.  
   
   
       60 ) The method of  claim 56  wherein the vector is a plasmid.  
   
   
       61 ) The method of  claim 56  wherein the vector is a lipid vesicle.  
   
   
       62 ) A method for providing biologically active lysosomal acid lipase to cells of a mammal with atherosclerosis, comprising administration into the cells of said mammal an amount of a vector comprising and expressing a DNA sequence encoding lysosomal acid lipase and which is effective to transfect and sustain expression of biologically active lysosomal acid lipase in cells deficient therein.  
   
   
       63 ) The method of  claim 62  wherein the expressed lysosomal acid lipase is secreted from the infected cells and is taken up by other cells deficient therein.  
   
   
       64 ) A method for treatment of Wolman's Disease in a mammal comprising administering to said mammal a safe and effective amount of lysosomal acid lipase sufficient to treat said condition.  
   
   
       65 ) A method for treatment of Cholesteryl Ester Storage Disease in a mammal comprising administering to said mammal a safe and effective amount of lysosomal acid lipase sufficient to treat said condition.  
   
   
       66 ) A method for treatment of atherosclerosis in a mammal comprising administering to said mammal a safe and effective amount of exogenously produced lysosomal acid lipase sufficient to treat said condition.  
   
   
       67 ) The method of  claim 66  wherein the lysosomal acid lipase is in a suitable pharmaceutically acceptable carrier.  
   
   
       68 ) The method of  claim 67  wherein the lysosomal acid lipase is administered by intravenous infusion.  
   
   
       1 - 63 . (canceled)  
   
   
       64 ) A method for treatment of Wolman's Disease in a mammal comprising administering to said mammal a safe and effective amount of lysosomal acid lipase sufficient to treat said condition.  
   
   
       65 ) A method for treatment of Cholesteryl Ester Storage Disease in a mammal comprising administering to said mammal a safe and effective amount of lysosomal acid lipase sufficient to treat said condition.  
   
   
       65 - 68 . (canceled)

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