US2006019914A1PendingUtilityA1

Inhibition of tumor growth and invasion by anti-matrix metalloproteinase DNAzymes

42
Assignee: UNIV TENNESSEE RES FOUNDATIONPriority: Feb 11, 2004Filed: Feb 11, 2005Published: Jan 26, 2006
Est. expiryFeb 11, 2024(expired)· nominal 20-yr term from priority
Inventors:Tayebeh PourmotabbedHisashi HasegawaChad Batson
C12N 15/1137C12N 9/6489C07K 14/8146A61K 38/00C12N 2310/12
42
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Claims

Abstract

The presently disclosed subject matter provides DNA molecules designed to down regulate the expression of MMP genes in a cell. Also provided are compositions comprising the DNA molecules. The presently disclosed subject matter further provides methods of using the DNA molecules to inhibit metastasis of a cancer cell. The presently disclosed subject matter also provides methods of using the DNA molecules to modulate tumor growth in a subject.

Claims

exact text as granted — not AI-modified
1 . A method of modulating cellular expression of at least one matrix metalloproteinase protein, the method comprising introducing into a cell at least one DNA oligonucleotide having binding specificity for a target region of a messenger ribonucleotide (mRNA) encoding a matrix metalloproteinase protein.  
     
     
         2 . The method of  claim 1 , wherein modulating cellular expression of the matrix metalloproteinase protein comprises inhibiting expression of the matrix metalloproteinase protein.  
     
     
         3 . The method of  claim 1 , wherein the DNA oligonucleotide is a DNAzyme.  
     
     
         4 . The method of  claim 3 , wherein the DNAzyme comprises a catalytic domain flanked on each side by substrate binding domains each having binding specificity for a distinct nucleotide sequence of the target region.  
     
     
         5 . The method of  claim 4 , wherein the DNA oligonucleotide has a nucleotide sequence comprising the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:22, or SEQ ID NO:29.  
     
     
         6 . The method of  claim 4 , wherein the DNA oligonucleotide comprises a modification that increases the stability of the DNA oligonucleotide.  
     
     
         7 . The method of  claim 6 , wherein the modification comprises an inverted deoxythymidine at the 3′ end of the DNA oligonucleotide.  
     
     
         8 . The method of  claim 1 , wherein the at least one matrix metalloproteinase protein is MMP-2, MMP-9, or both MMP-2 and MMP-9.  
     
     
         9 . A method of inhibiting metastasis of a cancer cell, the method comprising introducing into a cancer cell at least one DNA oligonucleotide having binding specificity for a target region of a messenger ribonucleotide (mRNA) encoding a protein which contributes to metastasis.  
     
     
         10 . The method of  claim 9 , wherein inhibiting metastasis of the cancer cell comprises inhibiting expression of the protein which contributes to metastasis.  
     
     
         11 . The method of  claim 10 , wherein the protein is an enzyme that degrades extracellular matrix components.  
     
     
         12 . The method of  claim 11 , wherein the enzyme is a matrix metalloproteinase protein.  
     
     
         13 . The method of  claim 12 , wherein the at least one matrix metalloproteinase protein is MMP-2, MMP-9, or both MMP-2 and MMP-9.  
     
     
         14 . The method of  claim 9 , wherein the DNA oligonucleotide is a DNAzyme.  
     
     
         15 . The method of  claim 14 , wherein the DNAzyme comprises a catalytic domain flanked on each side by substrate binding domains each having binding specificity for a distinct nucleotide sequence of the target region.  
     
     
         16 . The method of  claim 15 , wherein the DNA oligonucleotide has a nucleotide sequence comprising the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:22, OR SEQ ID NO:29.  
     
     
         17 . The method of  claim 15 , wherein the DNA oligonucleotide comprises a modification that increases the stability of the oligonucleotide.  
     
     
         18 . The method of  claim 17 , wherein the modification comprises an inverted deoxythymidine at the 3′ end of the oligonucleotide.  
     
     
         19 . The method of  claim 9 , wherein the cancer cell is a cell from a cancerous tissue selected from the group consisting of glioma, melanoma, fibrosarcoma, and adenosarcoma.  
     
     
         20 . A method of modulating tumor growth in a subject, the method comprising administering to a subject a composition comprising at least one DNA oligonucleotide having binding specificity for a target region of a messenger ribonucleotide (mRNA) encoding a matrix metalloproteinase protein.  
     
     
         21 . The method of  claim 20 , wherein modulating tumor growth comprises inhibiting tumor growth.  
     
     
         22 . The method of  claim 20 , wherein the DNA oligonucleotide is a DNAzyme.  
     
     
         23 . The method of  claim 22 , wherein the DNAzyme comprises a catalytic domain flanked on each side by substrate binding domains each having binding specificity for a distinct nucleotide sequence of the target region.  
     
     
         24 . The method of  claim 23 , wherein the DNA oligonucleotide has a nucleotide sequence comprising the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:22, OR SEQ ID NO:29.  
     
     
         25 . The method of  claim 23 , wherein the DNA oligonucleotide further comprises a modification that increases the stability of the oligonucleotide.  
     
     
         26 . The method of  claim 25 , wherein the modification comprises an inverted deoxythymidine at the 3′ end of the oligonucleotide.  
     
     
         27 . The method of  claim 20 , wherein the at least one matrix metalloproteinase protein is MMP-2, MMP-9, or both MMP-2 and MMP-9.  
     
     
         28 . An isolated enzymatic DNA molecule comprising a polynucleotide sequence having binding specificity for a target region of a messenger ribonucleotide (mRNA) encoding a matrix metalloproteinase protein.  
     
     
         29 . The DNA molecule of  claim 28 , wherein the DNA molecule is a DNAzyme.  
     
     
         30 . The DNA molecule of  claim 29 , wherein the DNAzyme comprises a catalytic domain flanked on each side by substrate binding domains each having binding specificity for a distinct nucleotide sequence of the target region.  
     
     
         31 . The DNA molecule of  claim 30 , wherein the polynucleotide sequence comprises the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:22, OR SEQ ID NO:29.  
     
     
         32 . The DNA molecule of  claim 30 , wherein the DNA molecule comprises a modification that increases the stability of the DNA molecule.  
     
     
         33 . The DNA molecule of  claim 32 , wherein the modification comprises an inverted deoxythymidine at the 3′ end of the DNA molecule.  
     
     
         34 . The DNA molecule of  claim 28 , wherein the at least one matrix metalloproteinase protein is MMP-2, MMP-9, or both MMP-2 and MMP-9.  
     
     
         35 . A composition comprising at least one DNA oligonucleotide having binding specificity for a target region of a messenger ribonucleotide (mRNA) encoding a matrix metalloproteinase protein.  
     
     
         36 . The composition of  claim 35 , wherein the DNA oligonucleotide is a DNAzyme.  
     
     
         37 . The composition of  claim 36 , wherein the DNAzyme comprises a catalytic domain flanked on each side by substrate binding domains each having binding specificity for a distinct nucleotide sequence of the target region.  
     
     
         38 . The composition of  claim 37 , wherein the DNA oligonucleotide comprises the sequence of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:22, OR SEQ ID NO:29.  
     
     
         39 . The composition of  claim 37 , wherein the DNA oligonucleotide comprises a modification that increases the stability of the DNA oligonucleotide.  
     
     
         40 . The composition of  claim 39 , wherein the modification comprises an inverted deoxythymidine at the 3′ end of the DNA oligonucleotide.  
     
     
         41 . The composition of  claim 35 , wherein the matrix metalloproteinase protein is MMP-2, MMP-9, or both MMP-2 and MMP-9.  
     
     
         42 . The composition of  claim 35 , further comprising a carrier.

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