ライフサイエンスコーパス: hemophilia B

1 t a Factor IX (FIX)-deficient mouse model of hemophilia B.

2 ed strategies for factor IX gene transfer in hemophilia B.

3 a safe and effective treatment for PUPs with hemophilia B.

4 the safety of this approach in patients with hemophilia B.

5 achieve hemostatic correction in a dog with hemophilia B.

6 for treatment of inherited disorders such as hemophilia B.

7 X is safe and effective for the treatment of hemophilia B.

8 e or moderate (< 5 IU/dL factor IX activity) hemophilia B.

9 IX infusions in a minority of patients with hemophilia B.

10 on of the bleeding diathesis in animals with hemophilia B.

11 ucts, heralds a new era for the treatment of hemophilia B.

12 use for the development of gene therapy for hemophilia B.

13 luation of novel gene therapy strategies for hemophilia B.

14 rated to develop gene therapy strategies for hemophilia B.

15 correct the bleeding diathesis of mice with hemophilia B.

16 ible strategy for treatment of patients with hemophilia B.

17 and shown to exhibit a phenotype similar to hemophilia B.

18 ful animal model for gene therapy studies of hemophilia B.

19 ions which result in mild to severe forms of hemophilia B.

20 ector dose shown to be safe in subjects with hemophilia B.

21 w annualized bleeding rates in patients with hemophilia B.

22 vels of human factor IX in a murine model of hemophilia B.

23 2 (AAV-2)-injected muscles of a patient with hemophilia B.

24 r prophylaxis and treatment in patients with hemophilia B.

25 on and less frequent dosing in patients with hemophilia B.

26 AAV) into skeletal muscle of men with severe hemophilia B.

27 ets could be a new gene therapy strategy for hemophilia B.

28 basis for evaluating rFIXFc in patients with hemophilia B.

29 ciated virus (AAV)-mediated gene therapy for hemophilia B.

30 uccess, particularly in patients with severe hemophilia B.

31 iffer significantly between hemophilia A and hemophilia B.

32 erapeutic levels of F.IX in dogs with severe hemophilia B.

33 ypal ubiquitous promoter in a mouse model of hemophilia B.

34 city in a recent human gene therapy trial of hemophilia B.

35 and histology of wound healing is altered in hemophilia B.

36 ge infiltration was significantly delayed in hemophilia B.

37 ted in nonhuman primates for gene therapy of hemophilia B.

38 on long-term FIX expression in patients with hemophilia B.

39 actor IX antibody development in humans with hemophilia B.

40 udies of this delivery method in humans with hemophilia B.

41 long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an ini

42 iated, muscle-directed approach for treating hemophilia B, a detailed biochemical analysis of F.IX sy

43 Gene therapy for hemophilia B aims to ameliorate bleeding risk and provid

44 Hemophilia B, also known as Christmas disease, arises fr

45 es are routinely used to treat patients with hemophilia B, an X-linked bleeding disorder that affects

46 Hemophilia B, an X-linked disorder, is ideally suited fo

47 s and limitations of this clinical trial for hemophilia B and approaches to advance beyond this miles

48 have been used as gene delivery vehicles for hemophilia B and for muscular dystrophies in experimenta

49 ct estimate of the overall mutation rate for hemophilia B and information on the mutations present in

50 the relevance of these data for treatment of hemophilia B and other genetic diseases.

51 t of AAV pseudotype-based gene therapies for hemophilia B and other liver-related diseases.

52 e highly compatible with those obtained from hemophilia B and showed higher mutation rates in the mal

53 ted bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease.

54 mplement the use of other (mouse and canine) hemophilia B animal models in current use for the develo

55 The majority of cases of human hemophilia B are the result of missense mutations in the

56 coding sequences indicates that our recent, hemophilia B-based estimate of the rate of deleterious m

57 sed the maximum thrombin level in "acquired" hemophilia B blood from 120 to 480 nM.

58 congenital hemophilia A blood and "acquired" hemophilia B blood in vitro, addition of 10 to 50 nM fac

59 rmal thrombin generation in hemophilia A and hemophilia B blood in vitro.

60 anti-factor IX antibody-induced ("acquired") hemophilia B blood was investigated.

61 Ia to both hemophilia A blood and "acquired" hemophilia B blood.

62 e) reproduce the bleeding phenotype of human hemophilia B, but because the models produce no factor I

63 herapy has been successful in a patient with hemophilia B, but expression was unstable due to an immu

64 , this study was undertaken using the severe hemophilia B canines of the Chapel Hill strain.

65 In hemophilia B (coagulation factor IX [F.IX] deficiency),

66 enetic disease such as the bleeding disorder hemophilia B [deficiency in blood coagulation factor IX

67 inhibitors appearing in patients with severe hemophilia B display specificity against restricted func

68 72-777 was found when hepatocyte cDNA from a hemophilia B dog was sequenced.

69 In an AAV2-pretreated hemophilia B dog, cFIX expression increased from less th

70 In an 8-year study, inhibitor-prone hemophilia B dogs (n = 2) treated with liver-directed AA

71 -associated viral (AAV) vector into mice and hemophilia B dogs results in vector dose-dependent, long

72 rFIX and pdFIX products, in vivo testing in hemophilia B dogs showed the functional behavior of thes

73 Two naive hemophilia B dogs that received a single intraportal adm

74 Three newborn hemophilia B dogs that were injected intravenously with

75 The five hemophilia B dogs treated showed stable, vector dose-dep

76 2/8 vector in both naive and AAV2-pretreated hemophilia B dogs.

77 were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of </=2 IU per

78 al in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of

79 eric Factor IX, when infused into a dog with hemophilia B, exhibits a greater than threefold increase

80 atients (hemophilia A (F-VIII deficient) and hemophilia B (F-IX deficient)) with a risk of bleeding,

81 dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were

82 human factor IX protein from a patient with hemophilia B (factor IX activity <1%; factor IX antigen

83 trial in 25 previously treated subjects with hemophilia B (FIX </= 2 IU/dL) examined the safety and p

84 al, open-label study included 10 adults with hemophilia B (FIX </=2% of normal) and severe-bleeding p

85 ents (PUPs) with severe or moderately severe hemophilia B (FIX activity, < or = 3 IU/dL).

86 peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values).

87 available mouse factor IX knockout models of hemophilia B (FIXKO mouse) reproduce the bleeding phenot

88 rvations may have important implications for hemophilia B gene therapy with rAAV vectors.

89 l vector represents an important advance for hemophilia B gene therapy.

90 In patients with severe hemophilia B, gene therapy that is mediated by a novel s

91 In contrast, FIX(-/-) mice, a model of hemophilia B, had normal hearts.

92 Although hemophilia B has been described in many dog breeds, this

93 been established and the molecular basis of hemophilia B has been determined.

94 lysis of the factor IX gene in patients with hemophilia B has provided insights into the human germli

95 A recent clinical trial in patients with hemophilia B has suggested that adeno-associated virus (

96 Long-term cures of hemophilia B have been achieved using AAV2 delivering th

97 Mice with hemophilia B have been engineered using gene targeting t

98 ced immune tolerance to factor IX (FIX) in a hemophilia B (HB) dog with previously formed anti-FIX in

99 For AAV-mediated hemophilia B (HB) gene therapy, we have overcome this ob

100 Healing of skin wounds is delayed in hemophilia B (HB) mice.

101 mutations in the factor IX (FIX) genes of 88 hemophilia B (HB) patients and 7 wild-type controls.

102 sense mutations, present in 70% (324/469) of hemophilia B (HB) patients with PTCs.

103 sing adeno-associated viral (AAV) vector for hemophilia B (HB) showed that the risk of cellular immun

104 gene transfer of the factor IX (FIX) gene in hemophilia B (HB) subjects with advanced liver disease.

105 Studies on gene therapy for hemophilia B (HB) using adeno-associated viral (AAV) vec

106 hylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent inj

107 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an

108 hilia and used it to improve gene therapy of hemophilia B in dogs, and Cantore et al have shown simil

109 Coagulation factor IX deficiency causes hemophilia B in humans.

110 patic gene therapy is effective for treating hemophilia B in mice and dogs, although the immune syste

111 d expression after neonatal gene therapy for hemophilia B in mice or dogs.

112 Hemophilia B is a bleeding disorder caused by a deficien

113 Hemophilia B is a bleeding disorder resulting from facto

114 Hemophilia B is a leading target for gene therapy becaus

115 Hemophilia B is a severe X-linked bleeding diathesis cau

116 Hemophilia B is an X-linked coagulopathy caused by absen

117 Hemophilia B is an X-linked coagulopathy caused by absen

118 Hemophilia B is caused by the absence of functional coag

119 A deficiency of current murine models of hemophilia B is that they are all due to gene deletions,

120 In a trial for hemophilia B, long-term expression of human FIX has been

121 Hemophilia B management would benefit from a FIX protein

122 Fc (Alprolix) and wild-type FIX (BeneFIX) in hemophilia B mice 7 days postinfusion.

123 We delivered these transgenes to hemophilia B mice by hepatocyte-targeted integration-com

124 ression, as well as phenotypic correction of hemophilia B mice following gene transfer of the murine

125 This high-responder strain of hemophilia B mice represents a new animal model to study

126 Neonatal hemophilia B mice that received different amounts of RV

127 elative to mFVIIa in hemophilia A mice or in hemophilia B mice with inhibitors to factor IX.

128 In summary, 7 days postinfusion into hemophilia B mice, BeneFIX and Alprolix are hemostatical

129 In hemophilia B mice, factor IX replacement reduced the ave

130 successfully cured the bleeding disorder of hemophilia B mice, proving the feasibility of using AAV-

131 t around 9%, 13%, and 16% of normal in the 3 hemophilia B mice, respectively, until the last measurem

132 n (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice.

133 with FVIIa (EGF2 and catalytic domain) into hemophilia B mice.

134 ociated virus serotype 9 (scAAV9) vectors in hemophilia B mice.

135 ve as mouse FVIIa in controlling bleeding in hemophilia B mice.

136 ed FIX can correct the bleeding phenotype in hemophilia B mice.

137 corrected abnormal hemostatic parameters in hemophilia B mice.

138 human F.IX-specific CD4(+) T-cell epitope in hemophilia B mice.

139 ition in an intravital laser injury model in hemophilia B mice.

140 loped a prophylactic protocol using a murine hemophilia B model.

141 from hemophilic synovitis, we established a hemophilia B mouse model of synovitis.

142 We developed 2bF9 transgenic mice in a hemophilia B mouse model with the expression of human fa

143 let-derived FIX normalizes hemostasis in the hemophilia B mouse model.

144 Since the effective target for hemophilia B mutations is only 1.05% of the factor IX ge

145 with C(6)PS and allow us to correlate known hemophilia B mutations of factor IX at Lys5 or Phe9 with

146 ny human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, ca

147 patients who fail to respond to ITI or have hemophilia B, new and improved tools are needed.

148 the severe form of hemophilia, also known as hemophilia B or Christmas disease.

149 Hemophilia B, or factor IX deficiency, is an X-linked re

150 In humans, one hemophilia B patient achieved 10% of normal activity aft

151 imilar to the plasma levels reported for the hemophilia B patients carrying the same mutations.

152 xtending this success to a greater number of hemophilia B patients remains a major goal of the field,

153 IXWT, eight point mutants mostly based on hemophilia B patients, and a replacement mutant (IXhelix

154 r and closely resemble the phenotype seen in hemophilia B patients.

155 factor IX which causes a warfarin-sensitive hemophilia B phenotype.

156 telet alpha-granules and corrects the murine hemophilia B phenotype.

157 ave created a human factor IX mouse model of hemophilia B (R333Q-hFIX mouse) by homologous recombinat

158 o extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was in

159 als, most notably for those in patients with hemophilia B (ref.

160 Treatment of hemophilia B requires frequent infusions of factor IX (F

161 to the livers of murine and canine models of hemophilia B, respectively.

162 ion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in ci

163 tic transfer of the Factor IX gene (F9) into hemophilia B subjects suggests that CTL responses agains

164 has been limited in vivo testing of rFIX in hemophilia B subjects, this study was undertaken using t

165 for evaluating novel strategies for treating hemophilia B such as gene therapy.

166 In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vect

167 transfer has been reported in patients with hemophilia B, the large size of the factor VIII coding r

168 y process recombinant factor IX (rFIX) limit hemophilia B therapy to <20% of the world's population.

169 ons for hemophilia A and >1100 mutations for hemophilia B, these diseases are among the most extensiv

170 demonstrated successful conversion of severe hemophilia B to mild or moderate disease in 6 adult male

171 in (rIX-FP) has been developed to facilitate hemophilia B treatment by less frequent FIX dosing.

172 s per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2%

173 New therapies for hemophilia A and hemophilia B will likely continue to change clinical pra

174 s well as those reported year by year in the hemophilia B world database.

175 inical trials including gene replacement for Hemophilia B, X-linked Severe Combined Immunodeficiency,