Methods for Treating or Preventing Vascular Graft Failure

1 . A method for treating failure of a vascular graft in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide of amino sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof, and a pharmaceutically acceptable carrier.

2 . The method according to claim 1 , wherein the step of administering is by implanting a biomedical device, wherein the device is a vascular graft, and wherein the composition is disposed on or in the graft.

3 . The method according to claim 1 , wherein the step of administering occurs parenterally.

4 . The method according to claim 1 , wherein the step of administering occurs topically.

5 . The method according to claim 1 , wherein the vascular graft is an autologous graft.

6 . The method according to claim 1 , wherein the vascular graft is a syngeneic graft.

7 . The method according to claim 1 , wherein the vascular graft is an allogeneic graft.

8 . The method according to claim 1 , wherein the vascular graft is a xenograft.

9 . The method according to claim 1 , wherein the vascular graft is a synthetic graft.

10 . The method according to claim 1 , wherein the vascular graft is a prosthetic graft.

11 . The method according to claim 1 , wherein the vascular graft is a tissue engineered graft.

12 . The method according to claim 1 , wherein the vascular graft is a vascular access graft.

13 . The method according to claim 1 , wherein the vascular graft is an arteriovenous graft.

14 . The method according to claim 1 , wherein the vascular graft is a coronary artery bypass graft.

15 . The method according to claim 1 , wherein the step of administering occurs at one time as a single dose, wherein the one time is during vascular graft surgery.

16 . The method according to claim 1 , wherein the step of administering is performed as a plurality of doses over a period of time.

17 . The method according to claim 16 , wherein the period of time is a day, a week, a month, a year, or multiples thereof.

18 . The method according to claim 1 , wherein the step of administering is performed at least once daily.

19 . The method according to claim 1 , wherein the step of administering is performed at least once daily for a period of at least one week.

20 . The method according to claim 1 , wherein the step of administering is performed at least once weekly.

21 . The method according to claim 1 , wherein the step of administering is performed weekly for a period of at least one month.

22 . The method according to claim 1 , wherein the step of administering is performed at least once monthly.

23 . The method according to claim 1 , wherein the method reduces stenosis of the vascular graft.

24 . The method according to claim 1 , wherein the method reduces vasospasm of at least one blood vessel related to the vascular graft.

25 . The method according to claim 1 , wherein the method reduces intimal hyperplasia of at least one blood vessel related to the vascular graft.

26 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has a substantial sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

27 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 70 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

28 . The method according to claim 1 wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 80 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

29 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 90 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

30 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 95 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

31 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence WLRRIKAWLRRIKALNRQLGVAA (SEQ ID NO: 3).

32 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence FAKLAARLYRKALARQLGVAA (SEQ ID NO: 4).

33 . The method according to claim 1 , the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence KAFAKLAARLYRKALARQLGVAA (SEQ ID NO: 5).

34 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALNRQLGVAA (SEQ ID NO: 6).

35 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALARQLAVA (SEQ ID NO: 7).

36 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALARQLGVA (SEQ ID NO: 8).

37 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALNRQLAVA (SEQ ID NO: 9).

38 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALNRQLGVA (SEQ ID NO: 10).

39 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALNRQLGVAA (SEQ ID NO: 11).

40 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a polypeptide of amino acid sequence YARAAARQARAKALNRQLAVAA (SEQ ID NO: 12)

41 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a fusion protein comprising a first polypeptide operatively linked to a second polypeptide, wherein the first polypeptide is of amino acid sequence YARAAARQARA (SEQ ID NO: 26), and wherein the second polypeptide comprises a therapeutic domain that has a substantial identity to amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

42 . The method according to claim 41 , wherein the second polypeptide has at least 70 percent sequence identity to amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

43 . The method according to claim 41 , wherein the second polypeptide has at least 80 percent sequence identity to amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

44 . The method according to claim 41 , wherein the second polypeptide has at least 90 percent sequence identity to amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

45 . The method according to claim 41 , wherein the second polypeptide has at least 95 percent sequence identity to amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

46 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALARQLAVA (SEQ ID NO: 13).

47 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALARQLGVA (SEQ ID NO: 14).

48 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALARQLGVAA (SEQ ID NO: 15).

49 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRQLGVAA (SEQ ID NO: 16).

50 . The method according to claim 41 , wherein the second polypeptide is of the amino acid sequence KAANRQLGVAA (SEQ ID NO: 17).

51 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNAQLGVAA (SEQ ID NO: 18).

52 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRALGVAA (SEQ ID NO: 19).

53 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRQAGVAA (SEQ ID NO: 20).

54 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRQLAVA (SEQ ID NO: 21)

55 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRQLAVAA (SEQ ID NO: 22).

56 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRQLGAAA (SEQ ID NO: 23).

57 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KALNRQLGVA (SEQ ID NO: 24).

58 . The method according to claim 41 , wherein the second polypeptide is of amino acid sequence KKKALNRQLGVAA (SEQ ID NO: 25).

59 . The method according to claim 1 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a fusion protein comprising a first polypeptide operatively linked to a second polypeptide, wherein the first polypeptide comprises a protein transduction domain functionally equivalent to amino acid sequence YARAAARQARA (SEQ ID NO: 26), and wherein the second polypeptide is of amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

60 . The method according to claim 59 , wherein the first polypeptide is of amino acid sequence WLRRIKAWLRRIKA (SEQ ID NO: 27).

61 . The method according to claim 59 , wherein the first polypeptide is of amino acid sequence WLRRIKA (SEQ ID NO: 28).

62 . The method according to claim 59 , wherein the first polypeptide is of amino acid sequence YGRKKRRQRRR (SEQ ID NO: 29).

63 . The method according to claim 59 , wherein the first polypeptide is of amino acid sequence WLRRIKAWLRRI (SEQ ID NO: 30).

64 . The method according to claim 59 , wherein the first polypeptide is of amino acid sequence FAKLAARLYR (SEQ ID NO: 31).

65 . The method according to claim 59 wherein the first polypeptide is of amino acid sequence KAFAKLAARLYR (SEQ ID NO: 32).

66 . A method for treating a vascular disease comprising intimal hyperplasia in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a polypeptide of amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) or a functional equivalent thereof, and a pharmaceutically acceptable carrier.

67 . The method according to claim 66 , wherein the vascular disease is a pre-atherosclerotic intimal hyperplasia.

68 . The method according to claim 66 , wherein the vascular disease is an atherosclerosis.

69 . The method according to claim 66 , wherein the step of administering is by implanting a biomedical device, wherein the pharmaceutical composition is disposed on or in the device.

70 . The method according to claim 66 , wherein the step of administering occurs parenterally.

71 . The method according to claim 66 , wherein the step of administering occurs topically.

72 . The method according to claim 66 , wherein the step of administering occurs at one time as single dose, wherein the one time is during vascular graft surgery.

73 . The method according to claim 66 , wherein the step of administering is performed as a plurality of doses over a period of time.

74 . The method according to claim 73 , wherein the period of time is a day, a week, a month, a year, or multiples thereof.

75 . The method according to claim 66 , wherein the step of administering is performed at least once daily.

76 . The method according to claim 66 , wherein the step of administering is performed at least once daily for a period of at least one week.

77 . The method according to claim 66 , wherein the step of administering is performed at least once weekly.

78 . The method according to claim 66 , wherein the step of administering is performed weekly for a period of at least one month.

79 . The method according to claim 66 , wherein the step of administering is performed at least once monthly.

80 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has a substantial sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

81 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 70 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

82 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 80 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

83 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 90 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

84 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) has at least 95 percent sequence identity to amino acid sequence YARAAARQARAKALARQLGVAA (SEQ ID NO: 1).

85 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence WLRRIKAWLRRIKALNRQLGVAA (SEQ ID NO: 3).

86 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence FAKLAARLYRKALARQLGVAA (SEQ ID NO: 4).

87 . The method according to claim 66 , the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence KAFAKLAARLYRKALARQLGVAA (SEQ ID NO: 5).

88 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALNRQLGVAA (SEQ ID NO: 6).

89 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALARQLAVA (SEQ ID NO: 7).

90 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALARQLGVA (SEQ ID NO: 8).

91 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALNRQLAVA (SEQ ID NO: 9).

92 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALNRQLGVA (SEQ ID NO: 10).

93 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALNRQLGVAA (SEQ ID NO: 11).

94 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is of amino acid sequence YARAAARQARAKALNRQLAVAA (SEQ ID NO: 12)

95 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a fusion protein comprising a first polypeptide operatively linked to a second polypeptide, wherein the first polypeptide is of amino acid sequence YARAAARQARA (SEQ ID NO: 26), and wherein the second polypeptide comprises a therapeutic domain that has a substantial identity to amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

96 . The method according to claim 95 , wherein the second polypeptide has at least 70 percent sequence identity to KALARQLGVAA (SEQ ID NO: 2).

97 . The method according to claim 95 , wherein the second polypeptide has at least 80 percent sequence identity to KALARQLGVAA (SEQ ID NO: 2).

98 . The method according to claim 95 , wherein the second polypeptide has at least 90 percent sequence identity to KALARQLGVAA (SEQ ID NO: 2).

99 . The method according to claim 95 , wherein the second polypeptide has at least 95 percent sequence identity to KALARQLGVAA (SEQ ID NO: 2).

100 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALARQLAVA (SEQ ID NO: 13).

101 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALARQLGVA (SEQ ID NO: 14).

102 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALARQLGVAA (SEQ ID NO: 15).

103 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRQLGVAA (SEQ ID NO: 16).

104 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KAANRQLGVAA (SEQ ID NO: 17).

105 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNAQLGVAA (SEQ ID NO: 18).

106 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRALGVAA (SEQ ID NO: 19).

107 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRQAGVAA (SEQ ID NO: 20).

108 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRQLAVA (SEQ ID NO: 21).

109 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRQLAVAA (SEQ ID NO: 22).

110 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRQLGAAA (SEQ ID NO: 23).

111 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KALNRQLGVA (SEQ ID NO: 24).

112 . The method according to claim 95 , wherein the second polypeptide is of amino acid sequence KKKALNRQLGVAA (SEQ ID NO: 25).

113 . The method according to claim 66 , wherein the functional equivalent of the polypeptide YARAAARQARAKALARQLGVAA (SEQ ID NO: 1) is a fusion protein comprising a first polypeptide operatively linked to a second polypeptide, wherein the first polypeptide comprises a protein transduction domain functionally equivalent to amino acid sequence YARAAARQARA (SEQ ID NO: 26), and wherein the second polypeptide is of amino acid sequence KALARQLGVAA (SEQ ID NO: 2).

114 . The method according to claim 113 , wherein the first polypeptide is of amino acid sequence WLRRIKAWLRRIKA (SEQ ID NO: 27).

115 . The method according to claim 113 , wherein the first polypeptide is of amino acid sequence WLRRIKA (SEQ ID NO: 28).

116 . The method according to claim 113 , wherein the first polypeptide is of amino acid sequence YGRKKRRQRRR (SEQ ID NO: 29).

117 . The method according to claim 113 , wherein the first polypeptide is of amino acid sequence WLRRIKAWLRRI (SEQ ID NO: 30).

118 . The method according to claim 113 , wherein the first polypeptide is of amino acid sequence FAKLAARLYR (SEQ ID NO: 31).

119 . The method according to claim 113 , wherein the first polypeptide is of amino acid sequence KAFAKLAARLYR (SEQ ID NO: 32).