IPC분류정보
국가/구분 |
United States(US) Patent
등록
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국제특허분류(IPC7판) |
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출원번호 |
US-0007315
(2004-12-09)
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등록번호 |
US-7256182
(2007-08-14)
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발명자
/ 주소 |
- Lawrence, III,John H.
- Donahue,J. Kevin
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출원인 / 주소 |
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대리인 / 주소 |
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인용정보 |
피인용 횟수 :
2 인용 특허 :
21 |
초록
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The present provides methods and compositions that enable effective delivery of nucleic acids to desired cells, including to a solid organ such as a mammalian heart. The methods and compositions enable effective gene transfer and subsequent expression to a majority of cells throughout a solid organ
The present provides methods and compositions that enable effective delivery of nucleic acids to desired cells, including to a solid organ such as a mammalian heart. The methods and compositions enable effective gene transfer and subsequent expression to a majority of cells throughout a solid organ such as the heart. Methods and compositions of the invention preferably provide enhanced vascular permeability that enables increased gene transfer to targeted cells, but without significant degradation or injury to endothelial cell layers. Global delivery of nucleic acid to an intact heart has been achieved with as little as 2 minutes of intracoronary exposure to the administered nucleic acid.
대표청구항
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What is claimed is: 1. A method for delivering nucleic acid to cells in a tissue of interest, comprising: contacting the tissue with a plurality of agents which increase vascular permeability to an exogenous nucleic acid, said agents selected from the group consisting of serotonin, bradykinin, plat
What is claimed is: 1. A method for delivering nucleic acid to cells in a tissue of interest, comprising: contacting the tissue with a plurality of agents which increase vascular permeability to an exogenous nucleic acid, said agents selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and administering to the tissue the exogenous nucleic acid under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar, whereby transfer efficiency of the exogenous nucleic acid by the cells in the tissue is increased. 2. A method for delivering nucleic acid to cells in a tissue of interest, comprising: contacting the tissue with an agent which increases vascular permeability to an exogenous nucleic acid, said agent selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and administering to the tissue the exogenous nucleic acid in a viral vector under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar, whereby transfer efficiency of the exogenous nucleic acid by the cells in the tissue is increased. 3. A method for delivering an exogenous nucleic acid to cells of a tissue of interest, comprising: contacting the tissue with a plurality of vascular permeability increasing agents under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar to increase vascular permeability to an exogenous nucleic acid, said agents selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and administering the exogenous nucleic acid to the tissue, whereby transfer efficiency of the exogenous nucleic acid to the cells of the tissue of interest is increased. 4. A method for delivering an exogenous nucleic acid to cells of a tissue of interest, comprising: contacting the tissue with a vascular permeability increasing agent under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar to increase vascular permeability to an exogenous nucleic acid, said agent selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and administering the exogenous nucleic acid in a viral vector to the tissue, whereby transfer efficiency of the exogenous nucleic acid to the cells of the tissue of interest is increased. 5. A method for delivering a nucleic acid to malignant cells in a tissue, comprising: treating the tissue with a plurality of vascular permeability increasing agents to increase delivery of an exogenous nucleic acid to the malignant cells in the tissue, said agents selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and administering to the tissue the exogenous nucleic acid under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar. 6. A method for delivering a nucleic acid to malignant cells in a tissue, comprising: treating the tissue with a vascular permeability increasing agent to increase delivery of an exogenous nucleic acid to the malignant cells in the tissue, said agent selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and administering to the tissue the exogenous nucleic acid in a viral vector under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar. 7. A method of providing to a recipient subject donor cells that comprise nucleic acid exogenous to the cells, comprising: contacting a tissue comprising the donor cells with a plurality of agents that increase vascular permeability to increase transfer efficiency of an exogenous nucleic acid to the donor cells, said agents selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); administering to the tissue comprising the donor cells nucleic acid under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar; and introducing the donor cells into the recipient subject to express a gene product encoded by the nucleic acid. 8. A method of providing to a recipient subject donor cells that comprise nucleic acid exogenous to the cells, comprising: contacting a tissue comprising the donor cells with an agent that increases vascular permeability to increase transfer efficiency of an exogenous nucleic acid to the donor cells, said agent selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); administering to the tissue comprising the donor cells nucleic acid in a viral vector under an effective amount of low calcium ion concentration of less than or equal to 500 micromolar; and introducing the donor cells into the recipient subject to express a gene product encoded by the nucleic acid. 9. The method of claim 7 wherein an organ comprising the donor cells is transplanted into the recipient subject. 10. The method of claim 8 wherein an organ comprising the donor cells is transplanted into the recipient subject. 11. The method of claim 7 wherein the donor cells are swine cells or primate cells. 12. The method of claim 8 wherein the donor cells are swine cells or primate cells. 13. A pharmaceutical kit comprising: a plurality of permeability agents that can increase vascular permeability to a nucleic acid in a subject, said agents selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME), a solution having a calcium ion concentration of from about 40 μmol/L to about 500 μmol/L; and a nucleic acid for administration to a subject. 14. A pharmaceutical kit comprising: a permeability agent that can increase vascular permeability to a nucleic acid in a subject, said agent selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); a solution having a calcium ion concentration of from about 40 μmol/L to about 500 μmol/L; and a nucleic acid in a viral vector for administration to a subject. 15. A treatment solution which has a calcium ion concentration of from about 40 μmol/L to about 500 μmol/L, comprising: a) a plurality of permeability agents that can increase vascular permeability to a nucleic acid, said agents selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and b) a nucleic acid. 16. A treatment solution which has a calcium ion concentration of from about 40 μmol/L to about 500 μmol/L, comprising: a) a permeability agent that can increases vascular permeability to a nucleic acid, said agent selected from the group consisting of serotonin, bradykinin, platelet-activating factor (PAF), prostaglandin E1 (PGE1 ), histamine, vascular endothelium growth factor (VEGF), zona occludens toxin (ZOT), interleukin-2, L-N-monomethyl arginine (L-NMMA), and L-N-nitro-arginine methyl ester (L-NAME); and b) a nucleic acid in a viral vector. 17. A treatment solution comprising a nucleic acid in a viral vector in a fluid carrier and having a calcium ion concentration of from about 40 μmol/L to about 500 μmol/L. 18. A method for delivering nucleic acid to cells in tissue of interest, comprising: administering to the cells an exogenous nucleic acid in a viral vector under an effective amount of low calcium ion concentration of about from about 40 μM/L to about 500 μmol/L. 19. The method of claim 18 wherein the nucleic acid is administered by perfusion. 20. The method of claim 18 wherein a perfusate of nucleic acid is recirculated and then readministered to the cells. 21. The method of claim 18 wherein a fluid having a calcium ion concentration of from about 40 μmol/L to about 500 μmol/L is used as a perfusate of the tissue. 22. The method of claim 18 wherein the cells are in a solid cell mass. 23. The method of claim 18 wherein the cells are in a solid organ. 24. The method of claim 18 wherein the cells are of an organ selected from the group consisting of heart, lung, kidney, testes, ovaries, skeletal muscle, kidneys, brain or spleen. 25. The method of claim 18 wherein the tissue is cardiac tissue. 26. The method of claim 18 wherein the tissue comprises malignant cells. 27. The method of claim 18 wherein the cells are in a solid tumor. 28. The method of claim 18 wherein the tissue is mammalian. 29. The method of claim 18 wherein the nucleic acid is administered ex vivo. 30. The method of claim 18 wherein the nucleic acid is administered in vivo. 31. The method of claim 18 wherein the nucleic acid is administered to livestock, poultry, dog or cat. 32. The method of claim 1 wherein the plurality of agents comprise VEGF. 33. The method of claim 2 wherein the viral vector is an adenovirus. 34. The method of claim 3 wherein the plurality of agents comprise VEGF. 35. The method of claim 4 wherein the viral vector is an adenovirus. 36. The method of claim 5 wherein the plurality of agents comprise VEGF. 37. The method of claim 6 wherein the viral vector is an adenovirus. 38. The method of claim 7 wherein the plurality of agents comprise VEGF. 39. The method of claim 8 wherein the viral vector is an adenovirus. 40. The pharmaceutical kit of claim 13 wherein the plurality of agents comprise VEGF. 41. The pharmaceutical kit of claim 14 wherein the viral vector is an adenovirus. 42. The treatment solution of claim 15 wherein the plurality of agents comprise VEGF. 43. The treatment solution of claim 16 wherein the viral vector is an adenovirus. 44. The treatment solution of claim 17 wherein the viral vector is an adenovirus. 45. The method of claim 18 wherein the viral vector is an adenovirus. 46. The method of claim 19 wherein the viral vector is an adenovirus. 47. The method of claim 20 wherein the viral vector is an adenovirus. 48. The method of claim 21 wherein the viral vector is an adenovirus. 49. The method of claim 32 wherein the exogenous nucleic acid is in a viral vector. 50. The method of claim 34 wherein the exogenous nucleic acid is in a viral vector. 51. The method of claim 36 wherein the exogenous nucleic acid is in a viral vector. 52. The method of claim 38 wherein the exogenous nucleic acid is in a viral vector. 53. The method of claim 32 wherein the exogenous nucleic acid is in a adenoviral vector. 54. The method of claim 34 wherein the exogenous nucleic acid is in a adenoviral vector. 55. The method of claim 36 wherein the exogenous nucleic acid is in a adenoviral vector. 56. The method of claim 38 wherein the exogenous nucleic acid is in a adenoviral vector. 57. The pharmaceutical kit of claim 40 wherein the nucleic acid is in a viral vector. 58. The pharmaceutical kit of claim 40 wherein the nucleic acid is in adenoviral vector. 59. The treatment solution of claim 42 wherein the nucleic acid is in a viral vector. 60. The treatment solution of claim 42 wherein the nucleic acid is in adenoviral vector.
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