ライフサイエンスコーパス: hemophilia A

1 and could represent a curative treatment for hemophilia A.

2 issense mutations lead to moderate to severe hemophilia A.

3 III (AAV5-hFVIII-SQ) in nine men with severe hemophilia A.

4 variability found among patients with severe hemophilia A.

5 ng previously untreated patients with severe hemophilia A.

6 nt impediment to the effective management of hemophilia A.

7 required to prevent bleeding associated with hemophilia A.

8 the importance of F8 genotyping in nonsevere hemophilia A.

9 ombinant) impair the effective management of hemophilia A.

10 the life-span among participants with severe hemophilia A.

11 outcomes with gene therapy in patients with hemophilia A.

12 152 patients (1-65 years of age) with severe hemophilia A.

13 he immune response to FVIII in patients with hemophilia A.

14 of F8 gene mutations in patients with severe hemophilia A.

15 al mechanisms and therapeutic development in hemophilia A.

16 on and less frequent dosing in patients with hemophilia A.

17 d by discrete cell populations would correct hemophilia A.

18 approach to reduce inhibitor development in hemophilia A.

19 factor VIII (FVIII) replacement therapy for hemophilia A.

20 l mechanism for secretion defects leading to hemophilia A.

21 rotein and gene transfer-based therapies for hemophilia A.

22 potential use of ADHLSCs in the treatment of hemophilia A.

23 r VIII (fVIII) results in moderate to severe hemophilia A.

24 improve treatment options for patients with hemophilia A.

25 n to factor VIII (FVIII) in a mouse model of hemophilia A.

26 us for on-demand treatment for patients with hemophilia A.

27 y and may deliver effective gene therapy for hemophilia A.

28 n preclinical studies of novel therapies for hemophilia A.

29 ically appropriate gene addition therapy for hemophilia A.

30 icity--toward successful treatment of murine hemophilia A.

31 auses the human congenital bleeding disorder hemophilia A.

32 offers a potential gene therapy strategy for hemophilia A.

33 other hemorrhages in young boys with severe hemophilia A.

34 fective in treating bleeding associated with hemophilia A.

35 factor VIII concentrates in the treatment of hemophilia A.

36 asma protein that is missing or deficient in hemophilia A.

37 as the potential to disrupt gene therapy for hemophilia A.

38 is a major complication in the treatment of hemophilia A.

39 II result in the inherited bleeding disorder hemophilia A.

40 lating this strategy to clinical therapy for hemophilia A.

41 es (inhibitors) is the major complication in hemophilia A.

42 sent in inhibitor plasmas from patients with hemophilia A.

43 of previously untreated patients with severe hemophilia A.

44 is clotting factor to treat individuals with hemophilia A.

45 FVIII inhibitors, and patients with acquired hemophilia A.

46 s is the basis of modern treatment of severe hemophilia A.

47 (LV)-mediated human platelet gene therapy of hemophilia A.

48 y treated males aged >/=12 years with severe hemophilia A.

49 elet-derived FVIII can improve hemostasis in hemophilia A.

50 VIII alloantibody formation in patients with hemophilia A.

51 obulin G1 (IgG1) in 165 patients with severe hemophilia A.

52 mice of 2 different strain backgrounds with hemophilia A.

53 pic variability is well recognized in severe hemophilia A.

54 lso arise spontaneously in cases of acquired hemophilia A.

55 iciency or dysfunction of factor VIII causes hemophilia A, a bleeding disorder.

56 Hemophilia A, a deficiency of functional coagulation fac

57 Defects or deficiency of FVIII cause Hemophilia A, a mild to severe bleeding disorder.

58 are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of pati

59 odies (inhibitors) in patients with acquired hemophilia A (AHA) and congenital hemophilia A (HA) are

60 Acquired hemophilia A (AHA) is an autoimmune disease caused by an

61 Acquired hemophilia A (AHA) is caused by autoantibodies against f

62 FVIII inhibitors, are the cause of acquired hemophilia A (AHA).

63 tabases detailing >2100 unique mutations for hemophilia A and >1100 mutations for hemophilia B, these

64 Hemophilia A and B are caused by deficiencies in coagula

65 Hemophilia A and B are inherited bleeding disorders char

66 and IX (hFVIII and hFIX) in mouse models of hemophilia A and B at therapeutic levels.

67 Vector delivery via the portal vein in hemophilia A and B dogs was well tolerated, and long-ter

68 Treatment of patients with hemophilia A and B has undergone significant advances du

69 ARC19499 corrects thrombin generation in hemophilia A and B plasma and restores clotting in FVIII

70 ) activity and accelerates clotting of human hemophilia A and B plasma.

71 mmonest severe inherited bleeding disorders, hemophilia A and B.

72 has shown great promise for the treatment of hemophilia A and B.

73 nt of inhibitory antibodies in patients with hemophilia A and discuss how these findings may be inter

74 Patients with severe hemophilia A and factor VIII inhibitors are at increased

75 ther bleeding events in patients with severe hemophilia A and factor VIII inhibitors.

76 elop this virus as a gene therapy vector for hemophilia A and familial hypercholesterolemia.

77 e tool, particularly in patients with severe hemophilia A and good risk profiles, and leads to a retu

78 New therapies for hemophilia A and hemophilia B will likely continue to ch

79 rtality did not differ significantly between hemophilia A and hemophilia B.

80 found in different cohorts of patients with hemophilia A and in healthy individuals.

81 II) antibodies that develop in patients with hemophilia A and in murine hemophilia A models, clinical

82 problems characteristic of individuals with hemophilias A and B suggest a link between specific defe

83 ents in intrinsic factor Xase function, i.e. hemophilias A and B, result in an impaired capacity to m

84 forts to extend AAV-mediated gene therapy to hemophilia A, and alternate approaches that may be usefu

85 ity criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor

86 on of AT levels in wild-type mice, mice with hemophilia A, and nonhuman primates (NHPs).

87 l for success in gene therapy strategies for hemophilia A as well as improve recombinant FVIII produc

88 acious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency.

89 de the most complete description of acquired hemophilia A available and are applicable to patients pr

90 tion and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled a

91 h sickle cell disease, beta-thalassemia, and hemophilia A/B or von Willebrand disease, respectively.

92 generate comparable curative fVIII levels in hemophilia A BALB/c mice after reduced-intensity total b

93 d in all United Kingdom patients with severe hemophilia A between 1990 and 2009.

94 normalize plasma FVIII level and activity in hemophilia A, but does not prevent the inhibitory effect

95 ns for the use of pFVIII in gene therapy for hemophilia A, but may also have physiologic consequences

96 Conversely, individuals with hemophilia A caused by F8 missense mutations are CRM-pos

97 In severe hemophilia A, clot stability increased by > 4-fold in th

98 Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and

99 Approximately 30% of patients with severe hemophilia A develop inhibitory anti-factor VIII (fVIII)

100 Approximately 25% of patients with hemophilia A develop inhibitory antibodies after treatme

101 Absence of either factor leads to hemophilia, a disabling disorder marked by excessive hem

102 icacy in 2 global tests of hemostasis in the hemophilia A dog model indicate that further evaluation

103 and safety of multiple AAV-cFVIII vectors in hemophilia A dogs and provides the basis for human clini

104 hallenges with cFVIII-BDD in young and adult hemophilia A dogs did not induce the formation of neutra

105 to AAV-FVIII dogs and treatment-naive severe hemophilia A dogs for a multiweek dose-escalating period

106 Infusion of cFVIII-BDD in hemophilia A dogs resulted in correction of the disease

107 Of importance, hemophilia A dogs that received AAV2-cFVIII, AAV6-cFVIII

108 BOECs isolated from hemophilia A dogs transduced with this lentiviral vector

109 All 3 hemophilia A dogs treated with FVIII-expressing autologo

110 ficacy and safety in dogs with hemophilia A (hemophilia A dogs) with minimally increased hemostasis a

111 ar between AAV2, AAV6, and AAV8 serotypes in hemophilia A dogs, in contrast to mice.

112 ine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs.

113 gene transfer and in treatment-naive severe hemophilia A dogs.

114 implanted into the omentum of 2 normal and 3 hemophilia A dogs.

115 Individuals with hemophilia A due to major deletions of the FVIII gene (F

116 cipants were >/=12 years of age, with severe hemophilia A (endogenous FVIII <1%).

117 ; plasma samples of 237 patients with severe hemophilia A enrolled in the SIPPET trial were collected

118 II in platelets has the potential to correct hemophilia A, even in the presence of inhibitory immune

119 icles can be adapted to hemophilic patients (hemophilia A (F-VIII deficient) and hemophilia B (F-IX d

120 bitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL).

121 aluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per millili

122 Black patients with hemophilia A (factor VIII deficiency) are twice as likel

123 The risk for inhibitor development in mild hemophilia A (factor VIII levels between 5 and 40 U/dL)

124 factor VIII (FVIII) is used in patients with hemophilia A for treatment of bleeding episodes or for p

125 eotide repeat expansions in diseases such as hemophilia A, fragile X syndrome, Hunter syndrome, and F

126 econstruct HCV incidence in White males with hemophilia A from 1940 through 1990.

127 ng without toxicity and translate success to hemophilia A gene therapy.

128 Up to 30% of patients with hemophilia A given therapeutic factor VIII (fVIII) can m

129 e can affect hemostasis in a canine model of hemophilia, a good predictor of efficacy of hemophilia t

130 h acquired hemophilia A (AHA) and congenital hemophilia A (HA) are primarily directed to the A2 and C

131 I (hFVIII) were systematically evaluated for hemophilia A (HA) gene therapy.

132 Hemophilia A (HA) is a bleeding disorder caused by facto

133 Injection of FVIII-RH protein in hemophilia A (HA) mice resulted in more efficacious hemo

134 In the naive FVIII null hemophilia A (HA) mouse, platelet-derived VIII prevents

135 African American hemophilia A (HA) patients experience a higher incidence

136 factor VIII (FVIII) inhibitors seen in black hemophilia A (HA) patients is not due to a mismatch betw

137 e, elicits unwanted anti-FVIII antibodies in hemophilia A (HA) patients.

138 stematic analysis of missense mutations from hemophilia A (HA) patients.

139 for failure of FVIII replacement therapy in hemophilia A (HA) patients.

140 e seen in 25% to 30% of patients with severe hemophilia A (HA).

141 dies ("inhibitors") are a serious problem in hemophilia A (HA).

142 iously untreated patients (PUPs) with severe hemophilia A (HA).

143 ed and novel approaches for the treatment of hemophilia A has expanded tremendously.

144 ors for replacement therapy of patients with hemophilia A has raised the life expectancy of these lif

145 vel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which ai

146 approximately 50% of individuals with severe hemophilia A) have been grouped with the former on the b

147 ansfer of a factor VIII (FVIII) plasmid into hemophilia A (HemA) mice achieved supraphysiologic FVIII

148 ately 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs.

149 In a murine model of human hemophilia A, hemarthrosis resulted in pathologic change

150 e potential efficacy and safety in dogs with hemophilia A (hemophilia A dogs) with minimally increase

151 ts with inherited bleeding disorders such as hemophilia A, hemophilia B, and von Willebrand disease.

152 in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment incre

153 ined FVIII gene delivery in a mouse model of hemophilia A if the immune response is prevented.

154 taneous administration of AV513 to mice with hemophilia A improved hemostasis.

155 e very early phenotypic expression of severe hemophilia A in 621 consecutively enrolled, well-charact

156 sing canine Factor VIII completely corrected hemophilia A in dogs, and that double-stranded adeno-ass

157 Novel approaches for hemophilia A in mice include expression of Factor VIII i

158 es and outcome of all patients with acquired hemophilia A in the United Kingdom.

159 a factor VIII concentrate for patients with hemophilia A including efficacy, availability, risk of t

160 inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multip

161 To apply this system to hemophilia A inhibitor formation, we created retroviral

162 mplified by a genotyping assay for the int22 hemophilia A inversion on Xq28.

163 y in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of

164 Hemophilia A is a bleeding disorder caused by a deficien

165 Hemophilia A is a clinically important coagulation disor

166 Hemophilia A is a lead candidate for treatment by gene t

167 Acquired hemophilia A is a rare bleeding disorder caused by autoa

168 Acquired hemophilia A is a severe bleeding disorder caused by an

169 Hemophilia A is caused by a variety of mutations in the

170 Hemophilia A is caused by mutations in the gene encoding

171 Hemophilia A is caused by mutations within the Factor VI

172 proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of facto

173 nsequences and result in a potential "cure." Hemophilia A is often complicated by the development of

174 t complication of treatment in patients with hemophilia A is the development of alloantibodies that i

175 n complication of treatment of patients with hemophilia A is the development of anti-factor VIII (fVI

176 with severe cases of congenital or acquired hemophilia A is the development of inhibitor antibodies

177 Inhibitor formation in hemophilia A is the most feared treatment-related compli

178 Hemophilia A is the X-linked bleeding disorder caused by

179 or previously untreated children with severe hemophilia A, it is unclear whether the type of factor V

180 actor VIII was administered i.v. to neonatal hemophilia A knockout mice.

181 ibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for repl

182 factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses

183 olerance to hFVIII in hFVIII plasmid-treated hemophilia A mice and allowed persistent, high-level FVI

184 vectors of serotypes 2, 5, 6, and 8 in both hemophilia A mice and dogs.

185 olerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodi

186 blood outgrowth endothelial cells (BOECs) to hemophilia A mice and showed that these cells remained s

187 ious times after transplantation (7-90 days) hemophilia A mice and their control mice counterparts we

188 wing naked DNA transfer into immunocompetent hemophilia A mice completely inhibits circulating FVIII

189 or VIII (fVIII) C2 domain immune response in hemophilia A mice consists of antibodies that can be div

190 Nontransplanted hemophilia A mice died within a few hours, whereas trans

191 lasma FVIII levels increased in transplanted hemophilia A mice during this period to 8% to 12% of wil

192 -type mice through 50 weeks, while untreated hemophilia A mice exhibited no detectable FVIII activity

193 tion conferred sustained FVIII expression in hemophilia A mice for several months without the generat

194 derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearanc

195 r 8 (F8) in platelets improves hemostasis in hemophilia A mice in several injury models.

196 in vivo clearance and hemostatic efficacy in hemophilia A mice of the R484A/R489A/P492A mutant were i

197 ower expression levels relative to mFVIIa in hemophilia A mice or in hemophilia B mice with inhibitor

198 f HSCs into myeloablated and nonmyeloablated hemophilia A mice resulted in high-level fVIII expressio

199 urther, plasma FVIII activity in the treated hemophilia A mice was nearly identical to that in wild-t

200 tg+/-) BM cells still improved hemostasis in hemophilia A mice with inhibitors.

201 responses against coagulation factor VIII in hemophilia A mice, even in animals previously sensitized

202 2bF8) gene therapy can improve hemostasis in hemophilia A mice, even in the presence of inhibitory an

203 MAbs were injected into hemophilia A mice, followed by injection of human B doma

204 ssion in platelets can restore hemostasis in hemophilia A mice, this approach has not been studied in

205 FVIII by transplanting healthy mouse BM into hemophilia A mice.

206 apsules and injected them intravenously into hemophilia A mice.

207 existing anti-FVIII inhibitory antibodies in hemophilia A mice.

208 jected directly into the liver of irradiated hemophilia A mice.

209 ody formation, and improved the phenotype of hemophilia A mice.

210 m, we sought to recapitulate its efficacy in hemophilia A mice.

211 c levels of FVIII gene expression in treated hemophilia A mice.

212 ysiologic levels of plasma FVIII activity in hemophilia A mice.

213 splantation into genetically immunocompetent hemophilia A mice.

214 prevents or decreases existing antibodies in hemophilia A mice.

215 -O-phospho-l-serine complex was evaluated in hemophilia A mice.

216 hospho-l-serine retained in vivo activity in hemophilia A mice.

217 4A/R489A or R484A/R489A/P492A was studied in hemophilia A mice.

218 acute and prolonged vascular injury model in hemophilia A mice.

219 2 monoclonal Abs (mAbs) produced in a murine hemophilia A model.

220 in patients with hemophilia A and in murine hemophilia A models, clinically termed "inhibitors," bin

221 equences provides curative fVIII levels in a hemophilia A mouse model.

222 tocytes and correcting FVIII deficiency in a hemophilia A mouse model.

223 ease fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model.

224 therapy can be lifesaving for patients with hemophilia A, neutralizing alloantibodies to FVIII, know

225 arch 25, 1999, for bleeding in patients with hemophilia A or B and inhibitors to factors VIII or IX.

226 study presents mortality in 6018 people with hemophilia A or B in the United Kingdom during 1977 to 1

227 d 4 through 18 years with moderate or severe hemophilia A or B were monitored for bleeds for up to 1

228 and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibo

229 sed thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibo

230 in phase 1 clinical testing in subjects with hemophilia A or B.

231 s, and the wave did not form in plasmas from hemophilia A or C patients who lack factors VIII and XI,

232 potency of ADHLSCs to control bleeding in a hemophilia A patient and assess the biodistribution of t

233 I-binding antibodies in different cohorts of hemophilia A patients and in healthy individuals.

234 The presence of antibodies (Abs) in hemophilia A patients can potentially influence the ther

235 This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Aust

236 ompetence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that w

237 evaluation of AV513 as a hemostatic agent in hemophilia A patients is warranted.

238 ve and 174 inhibitor-negative Italian severe hemophilia A patients using a TaqMan genotyping assay.

239 on that affects approximately one-quarter of hemophilia A patients who have access to replacement the

240 creased incidence of anti-drug antibodies in hemophilia A patients with haplotypes H3 and H4.

241 approach for future tolerogenic treatment of hemophilia A patients with inhibitors.

242 However, hemophilia A patients with the missense mutation Arg372

243 A major problem in treating hemophilia A patients with therapeutic factor VIII (FVII

244 o FVIII is a serious problem in treatment of hemophilia A patients, we investigated the potential of

245 r complication in the replacement therapy of hemophilia A patients.

246 ctor VIII replacement therapy for congenital hemophilia A patients.

247 inhibitors and could improve the outcomes of hemophilia A patients.

248 7 to 13 days (at 35 IU/kg rFVIII) in severe hemophilia A patients.

249 may be useful for therapeutic management of hemophilia A patients.

250 antibodies against factor VIII in 15-30% of hemophilia A patients.

251 specific IgG to FVIII half-life reduction in hemophilia A patients.

252 responses, including inhibitor responses in hemophilia A patients.

253 anti-FVIII inhibitory antibody formation in hemophilia A patients.

254 to 8% to 12% of wild type and corrected the hemophilia A phenotype.

255 property likely reflects the severity of the hemophilia A phenotype.

256 ependent prolongation of clot lysis times in hemophilia A plasma and loss of TM-stimulated conversion

257 bin generation measurements in platelet-rich hemophilia A plasma revealed competition for TF, which p

258 ects were compared with 4 inhibitor-positive hemophilia A plasma samples with inhibitor titers of 1 B

259 lot lysis assay on TM-expressing cells using hemophilia A plasma, NAc-Hep prevented PF4-mediated inhi

260 untreated or minimally treated patients with hemophilia A; plasma samples of 237 patients with severe

261 velopment was investigated in all 407 severe hemophilia A previously untreated patients born in the U

262 Among 235 randomized patients with severe hemophilia A previously untreated with FVIII concentrate

263 different categories of patients with severe hemophilia A: previously untreated patients, multiply tr

264 VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding patter

265 ne tolerance induction(ITI) in patients with hemophilia A refractory to replacement therapy after the

266 Patients with hemophilia A rely on exogenous factor VIII to prevent bl

267 ver, corrections of the propagation phase in hemophilia A required rFVIIa concentrations above the ra

268 r prophylaxis and treatment of patients with hemophilia A. rFVIIIFc is a recombinant fusion protein c

269 c epitope in FVIII were isolated from a mild hemophilia A subject (the proband) 19 weeks and 21 month

270 recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human

271 binant T-cell receptor (TCR) isolated from a hemophilia A subject's T-cell clone.

272 purified human anti-fVIIIAb, isolated from a hemophilia A subject, was used as a calibrator with a de

273 150 healthy donors and 39 inhibitor-negative hemophilia A subjects were compared with 4 inhibitor-pos

274 M, whereas 13 (33%) of the 39 inhibitor-free hemophilia A subjects were positive for anti-fVIIIAb in

275 115 "good-risk," severe high-titer inhibitor hemophilia A subjects.

276 the FVIII variant K1967I is associated with hemophilia A, suggests that these residues contribute to

277 man use of a new nonsubstitutive therapy for hemophilia A that can potentially be disruptive to the w

278 In a mouse model of hemophilia A, the complex normalized hemostasis upon vas

279 In hemophilia A, the most severe complication of factor VII

280 eas substitution of FVIII is the mainstay of hemophilia A therapy, treatment of patients with inhibit

281 minates how inhibitory antibodies complicate hemophilia A therapy.

282 Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and

283 actor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being

284 factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the bac

285 We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor

286 actor VIII (FVIII), the protein deficient in hemophilia A, to elucidate the relationship between prot

287 its by diminishing bleeding complications in hemophilia A via restoration of TAFIa-mediated protectio

288 A patient suffering from hemophilia A was injected with repeated doses of ADHLSCs

289 nhibitor development in patients with severe hemophilia A, we applied whole-exome sequencing (WES) an

290 g this strategy into the canine (c) model of hemophilia A, we increased cFVIII transgene expression b

291 ciation study (GWAS) involving patients with hemophilia A who were exposed to but uninfected with hum

292 e of anti-FVIII NNAs in patients with severe hemophilia A who were not previously exposed to FVIII co

293 We enrolled patients with hemophilia A who were older than 2 years of age, had hig

294 Clinical success for gene therapy of hemophilia A will be judged by achievement of sustained,

295 ealthy individuals, patients with congenital hemophilia A with and without FVIII inhibitors, and pati

296 roved thrombin generation in an NHP model of hemophilia A with anti-factor VIII inhibitors.

297 epopulation of the livers of mice that model hemophilia A with healthy endothelial cells restored pla

298 f 42 adult patients with severe and moderate hemophilia A without inhibitors.

299 Gene therapy for hemophilia A would be facilitated by development of smal

300 or VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment optio