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1. (WO1997015330) HYALURONIC ACID AS DNA CARRIER FOR GENE THERAPY AND VEGF ANTISENSE DNA TO TREAT ABNORMAL RETINAL VASCULARIZATION
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CLAIMS

1. A composition comprising a nucleic acid and a hyaluronic acid or a derivative thereof, together with a pharmaceutically-acceptable carrier.
2. A composition according to Claim 1, in which the nucleic acid iβ a nucleotide βequence which is in the antisense orientation to a target sequence.
3. A composition according to Claim 2, in which the target nucleic acid βequence iβ a genomic DNA, a cDNA, a messenger RNA or an oligonucleotide.
4. A composition according to Claim 1, in which the nucleic acid is present in a vector comprising a nucleic acid βequence to be transferred into a target cell.
5. A composition according to Claim 4, in which the nucleic acid sequence to be transferred is a genomic DNA, a cDNA, a messenger RNA or an oligonucleotide.
6. A composition according to Claim 5, wherein the vector comprises a senβe sequence to be provided to a target cell in order to exert a function.
7. A composition according to Claim 6, in which the vector comprises an anti-senβe sequence to be provided to a target cell in order to inhibit the functioning of a nucleic acid present in the target cell.
8. A composition according to any one of Claims 1 to

7, in which the vector is a liposome.
9. A composition according to any one of Claims 1 to

8, in which the vector iβ a viruβ.
10. A compoβition according to any one of Claims 1 to

9, in which the viruβ iβ an adenovirus, an adeno-associated virus, a herpes virus or a retrovirus.
11. A composition according to Claim 9, in which the virus is a replication-defective adenovirus.
12. A composition according to Claim 11, where the virus is a replication-defective adenovirus comprising a promoter selected from the group consisting of respiratory syncytial virus promoter, cytomegalovirus promoter, adenovirus major late protein (MLP) , VAl pol III euid β-actin promoters .
13. A compoβition according to Claim 11, wherein the vector iβ pAd.RSV, pAd.MLP or pAd.VAl.
14. A compoβition according o Claim 11, wherein the vector iβ Ad.RSV.aVEGF or Ad .VAl . aVEGF .
15. A compoβition according to any one of Claimβ 10 to 14, wherein the vector alβo compriβeβ a polyandenylation signal sequence.
16. A composition according to Claim 15, wherein the polyadenylation βignal sequence is the SV40 βignal
βequence .
17. A method of treatment of a pathological condition in a subject in need of such treatment, comprising the step of administering an effective dose of a compoβition
according to any one of Claime 1 to 16 to βaid subject.
18. A method according to Claim 17, in which the composition iβ adminiβtered systemically by injection.
19. A method according to Claim 17 , in which the composition is adminiβtered topically.
20. A method according to Claim 17, in which the compoβition iβ adminiβtered directly into the tissue to be treated.
21. A method of preparing a compoβition according to any one of Claimβ 1 to 16, comprising the step of binding a nucleic acid or vector to a hyaluronic acid or a derivative thereof, and isolating the thus-formed complex.
22. A composition for treatment of a retinal disease mediated by abnormal vascularization comprising
a) an anti-βenβe nucleic acid βequence
directed against vascular endothelial growth factor (VEGF) , and
b) hyaluronic acid,
together with a pharmaceutically-acceptable carrier.
23. A composition according to Claim 22, in which the anti-senβe nucleic acid sequence is present in a vector compriβing a nucleic acid βequence to be tranβferred into a target cell.
24. A compoβition according to Claim 23, in which the vector iβ a viruβ.
25. A composition according to Claim 24, in which the virus is an adenovirus, an adeno-asβociated viruβ, a herpeβ virus or a retrovirus.
26. A composition according to Claim 24 or Claim 25, in which the viral vector is a replication-defective recombinant virue .
27. A compoβition according to Claim 26, where the virus is a replication-defective adenovirus comprising a promoter selected from the group consisting of respiratory syncytial viruβ promoter, cytomegalovirus promoter, adenovirus major late protein (MLP), VAl pol III and β-actin promotera.
28. A composition according to Claim 27, wherein the vector is pAd.RSV, pAd.MLP or pAd.VAl.
29. A composition according to Claim 27, wherein the vector is Ad.RSV.aVEGF or Ad.VAl .OCVEGF.
30. A composition according to any one of Claims 1 to 29, wherein the vector also comprises a polyadenylation signal sequence.
31. A compoβition according to Claim 30, wherein the polyadenylation signal βequence iβ the SV40 βignal
sequence.
32. A compoβition for treatment of a retinal disease mediated by abnormal vascularization, comprising an antisense nucleic acid sequence corresponding to at least a part of the sequence encoding VEGF, and optionally further comprising one or more adjuvants for increasing cellular uptake, together with a pharmaceutically-acceptable carrier.
33. A composition according to Claim 32, wherein the anti-βenβe βequence has 100% complementarity to a
corresponding region of the gene encoding VEGF.

34. A composition for short-term treatment according to Claim 32 or Claim 33, wherein the anti-sense βequence ie 16 to 50 nucleotideβ long.
35. A compoβition for short-term treatment according to Claim 34, wherein the anti-sense sequence iβ 16 to 22 nucleotideβ long.
36. A composition for short-term treatment according to Claim 35, wherein the anti-sense sequence is 16 to 19 nucleotides long.
37. A composition according to Claim 33, wherein a modified oligonucleotide as herein defined is used, and the anti-sense sequence is 7 to 50 nucleotides long.
38. A composition according to any one of Claims 32 to 37 wherein the adjuvant is hyaluronic acid or a
derivative thereof .
39. A composition for long-term treatment of a retinal diseaβe mediated by abnormal vascularization, comprising a recombinant viruβ compriβing an anti-βenβe nucleic acid βequence correeponding to at leaet part of the βequence encoding VEGF, together with a pharmaceutically-acceptable carrier, wherein the anti-βenβe βequence iβ between 20 nucleotideβ in length and the full length βequence encoding VEGF.
40. A compoβition according to Claim 39, wherein the anti-βenβe βequence iβ between 50 nucleotides long and the full length sequence of VEGF.
41. A composition according to any one of Claims 1 to 40, wherein the VEGF sequence is that of VEGF from human retinal pigment epithelial cells or choroidal endothelial cells.
42. A composition for treatment of a retinal disease mediated by abnormal vascularization, wherein βaid
treatment iβ effective for an indefinite period, comprising a virus compriβing an anti-βenβe DNA correeponding to at leaet part of the βequence encoding VEGF, together with a pharmaceutically-acceptable carrier, wherein βaid virus is one capable of integrating the anti-sense sequence into the genome of the target cell.
43. A composition according to Claim 42, wherein the virus iβ an adeno-associated virus .
44. A compoβition according to Claim 42 or Claim 43, wherein the anti-sense sequence is between 20 nucleotides long and the full length βequence of VEGF.
45. A compoβition according to Claim 44, wherein the anti-sense sequence is between 50 nucleotides long and the full length sequence of VEGF.
46. A method of treatment of a retinal diseaβe mediated by abnormal neovascularization, comprising the step of administering an effective amount of an anti-sense nucleic acid sequence corresponding to at leaet part of the βequence encoding VEGF into the eye(β) of a βubject in need of βuch treatment, thereby to inhibit neovascularization.

47. A method according to Claim 46, wherein the antisense sequence is 16 to 50 nucleotides long.
48. A method according to Claim 46, wherein the antisense sequence is 16 to 22 nucleotides long.
49. A method according to Claim 46, wherein the anti-βenβe βequence iβ 16 to 19 nucleotideβ long.
50. A method according to Claim 46, wherein a
modified oligonucleotide ae herein defined ie uβed, and the anti-βenβe βequence iβ 7 to 50 nucleotideβ long.
51. A method of treatment of a retinal disease mediated by abnormal neovascularization, comprising the step of administering an effective amount of a composition according to any one of Claims 22 to 45 to a subject in need of such treatment .
52. A method of treatment of a retinal diseaβe mediated by abnormal neovascularization, comprising the step of administering a composition according to any one of Claims 39 to 41 to the eye(s) of a subject in need of such treatment, thereby to inhibit neovascularization in the long term.
53. A method of treatment of a retinal diseaβe mediated by abnormal neovaβcularization, comprising the etep of administering an effective amount of a composition according to Claimβ 42 to 45 into the eye(β) of a subject in need of such treatment, thereby to inhibit
neovascularization for an indefinite period.
54. A method according to any one of Claimβ 46 to 53, wherein the retinal disease is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, branch or central retinal vein occlusion, retinopathy of prematurity, rubeosis iridis and corneal neovascularization.
55. A method of promoting uptake of an exogenous nucleic acid sequence by a target cell, comprising the step of exposing the cell to the nucleic acid, or to a virus or vector comprising the nucleic acid, in the presence of a hyaluronic acid or a derivative thereof.
56. A method according to Claim 55, in which the target cell is a phagocytic cell .
57. A method according to Claim 55 or Claim 56, in which the nucleic acid and hyaluronic acid are administered together in vitro.
58. A method according to Claim 55 or Claim 56, in which the nucleic acid and hyaluronic acid are adminiβtered together in vivo.