ライフサイエンスコーパス: hemophilia B

1 IXa variants that are associated with severe hemophilia B.

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

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

4 es of hemophilia B, and 1.1 cases for severe hemophilia B.

5 actor IX antibody development in humans with hemophilia B.

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

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

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

9 es of hemophilia B, and 1.5 cases for severe hemophilia B.

10 achieve hemostatic correction in a dog with hemophilia B.

11 for treatment of inherited disorders such as hemophilia B.

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

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

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

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

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

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

18 luation of novel gene therapy strategies for hemophilia B.

19 rated to develop gene therapy strategies for hemophilia B.

20 correct the bleeding diathesis of mice with hemophilia B.

21 ible strategy for treatment of patients with hemophilia B.

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

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

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

25 apy has emerged as a promising treatment for hemophilia B.

26 hemophilia A or moderately severe to severe hemophilia B.

27 normalize factor IX levels in patients with hemophilia B.

28 A, 24% for hemophilia B, and 27% for severe hemophilia B.

29 ent and prophylaxis for patients with severe hemophilia B.

30 ) vector-based gene therapy in patients with hemophilia B.

31 uccess, particularly in patients with severe hemophilia B.

32 IX activity results in the bleeding disorder hemophilia B.

33 cy and safety of AAV gene therapy for severe hemophilia B.

34 nificantly improve therapy for patients with hemophilia B.

35 sed FIX Padua gene therapy, in patients with hemophilia B.

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

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

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

39 w annualized bleeding rates in patients with hemophilia B.

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

41 2 (AAV-2)-injected muscles of a patient with hemophilia B.

42 r prophylaxis and treatment in patients with hemophilia B.

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

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

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

46 basis for evaluating rFIXFc in patients with hemophilia B.

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

48 iffer significantly between hemophilia A and hemophilia B.

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

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

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

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

53 ge infiltration was significantly delayed in hemophilia B.

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

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

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

57 Gene therapy for hemophilia B aims to establish sustained factor IX activ

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

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

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

61 Men 18 to 65 years of age with hemophilia B and a factor IX level of 2% or less were el

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

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

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

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

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

67 cytes and achieved therapeutic thresholds in hemophilia B and phenylketonuria.

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

69 emophilia A, 3.8 cases for all severities of hemophilia B, and 1.1 cases for severe hemophilia B.

70 emophilia A, 5.0 cases for all severities of hemophilia B, and 1.5 cases for severe hemophilia B.

71 ilia A, 37% for severe hemophilia A, 24% for hemophilia B, and 27% for severe hemophilia B.

72 hyperactive form of FIX improved efficacy in hemophilia B, and superior engineered variants of FVIII

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

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

75 Hemophilia A (HA) and hemophilia B are due to inherited deficiencies in the ac

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

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

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

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

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

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

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

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

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

85 ting factor IX (FIX) levels in patients with hemophilia B by delivering a functional human F9 gene in

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

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

88 pproval of two products for the treatment of hemophilia B (coagulation factor IX deficiency) and one

89 sociated virus (AAV) gene-therapy vector for hemophilia B containing a high-activity human factor IX

90 , circulate in the majority of patients with hemophilia B (CRM(+)).

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

92 The results in this mouse model of CRM(+) hemophilia B demonstrate that the endogenous expression

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

94 72-777 was found when hepatocyte cDNA from a hemophilia B dog was sequenced.

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

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

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

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

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

100 Three newborn hemophilia B dogs that were injected intravenously with

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

102 2/8 vector in both naive and AAV2-pretreated hemophilia B dogs.

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

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

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

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

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

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

109 per kilogram of body weight) to 54 men with hemophilia B (factor IX activity <=2% of the normal valu

110 ion of etranacogene dezaparvovec in men with hemophilia B (factor IX activity level, <=2 IU per decil

111 articipants with severe or moderately severe hemophilia B (factor IX coagulant activity, <=2% of the

112 of hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) have now been achiev

113 in patients with severe or moderately severe hemophilia B (factor IX level, <=2% of normal value).

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

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

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

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

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

119 Hemophilia B gene therapy treatments have not addressed

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

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

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

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

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

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

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

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

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

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

130 Hemophilia A (HA) and hemophilia B (HB) are the most common severe bleeding di

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

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

133 Hemophilia B (HB) is a life-threatening inherited diseas

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

135 hepatocytes to assess the differentiation of hemophilia B (HB) patient's induced pluripotent stem cel

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

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

138 The efficacy of hemophilia B (HB) replacement therapy is evaluated by co

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

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

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

142 of the intrinsic Xase complex, resulting in hemophilia B (HB).

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

144 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an

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

146 Coagulation factor IX deficiency causes hemophilia B in humans.

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

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

149 -Padua gene therapy for patients with severe hemophilia B in the United States vs on-demand FIX repla

150 Hemophilia B is a bleeding disorder caused by a deficien

151 Hemophilia B is a bleeding disorder resulting from facto

152 Hemophilia B is a leading target for gene therapy becaus

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

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

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

156 Hemophilia B is caused by the absence of functional coag

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

158 Hemophilia B is treated by replacement of the missing fa

159 Moderate-to-severe hemophilia B is treated with lifelong, continuous coagul

160 laxis for the treatment of participants with hemophilia B, leading to reduced bleeding and stable fac

161 (AAV) vector developed for the treatment of hemophilia B, led to sustained expression of the high-ac

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

163 Hemophilia B management would benefit from a FIX protein

164 of hF9 transgene in both adult and neonatal hemophilia B mice (mF9 -/-), yielding high levels of cir

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

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

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

168 ciated with mild hemophilia, which protected hemophilia B mice from major bleeding episodes for 50 da

169 Studies using hemophilia B mice have shown that delayed FIXa inhibitio

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

171 l (cross-reactive material negative, CRM(-)) hemophilia B mice suggest the concentration of Col4 read

172 Neonatal hemophilia B mice that received different amounts of RV

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

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

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

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

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

178 In bleeding CRM(-) hemophilia B mice, the times to first clot at a saphenou

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

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

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

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

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

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

185 corrected abnormal hemostatic parameters in hemophilia B mice.

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

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

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

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

190 In a hemophilia B mouse model, antihepsin preconditioning enh

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

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

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

194 dosis I (MPS I) (n = 3), MPS II (n = 9), and hemophilia B (n = 1).

195 (ABR ratio 0.05 [hemophilia A, n=40]; 0.13 [hemophilia B, n=8]).

196 Prophylactic treatment for hemophilia B necessitates lifelong, regular intravenous

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

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

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

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

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

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

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

204 icacy following AAV-directed gene therapy in hemophilia B patients than what is currently achievable

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

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

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

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

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

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

211 Ten men with severe hemophilia B received a single intravenous infusion of t

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

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

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

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

216 The hemophilia B subject was not able to decrease use of fac

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

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

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

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

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

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

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

224 In hemophilia B, this FIX-Col4 interaction reduces the plas

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

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

227 al to address significant unmet needs in the hemophilia B treatment paradigm.

228 irected gene therapy in patients with severe hemophilia B were reported in 2011, many gene therapy st

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

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

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

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