Abstract:
:Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 × 1012 or 2 × 1013 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.
journal_name
Bloodjournal_title
Bloodauthors
Miesbach W,Meijer K,Coppens M,Kampmann P,Klamroth R,Schutgens R,Tangelder M,Castaman G,Schwäble J,Bonig H,Seifried E,Cattaneo F,Meyer C,Leebeek FWGdoi
10.1182/blood-2017-09-804419subject
Has Abstractpub_date
2018-03-01 00:00:00pages
1022-1031issue
9eissn
0006-4971issn
1528-0020pii
blood-2017-09-804419journal_volume
131pub_type
杂志文章,多中心研究相关文献
BLOOD文献大全abstract::Hydroxyurea, interferon, and HLA-identical sibling bone marrow transplantation are common therapies for chronic myelogenous leukemia (CML) in chronic phase. Which is best is controversial. The purpose of this study was to compare survival of patients with CML receiving HLA-identical sibling transplants versus hydroxyu...
journal_title:Blood
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1998-03-01 00:00:00
abstract::The efficacy of the addition of intensive therapy with daunorubicin (45 mg/m2 IV on days 1, 2, 3) to an otherwise identical induction program consisting of vincristine, prednisone, and L-asparaginase was assessed in 177 previously untreated adults (greater than or equal to 20 years of age) with acute lymphocytic leuke...
journal_title:Blood
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1984-07-01 00:00:00
abstract::The mechanisms by which hematopoietic progenitor cells become lineage-committed remain poorly understood. A cloned subline of the AML14 cell line (AML14.3D10) that spontaneously differentiates to eosinophilic myelocytes in the absence of cytokine stimulation was obtained by limiting dilution. This subline exhibits aug...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1995-11-15 00:00:00
abstract::Characterization of lymphocytes including B cells during early versus chronic HIV infection is important for understanding the impact of chronic viremia on immune cell function. In this setting, we investigated B cells before and after reduction of HIV plasma viremia by antiretroviral therapy (ART). At baseline, perip...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-05-285528
更新日期:2010-12-16 00:00:00
abstract::The interaction of thrombin with plasminogen activator inhibitor 1 (PAI-1) is shown to result in the simultaneous formation of both cleaved PAI-1 and a sodium dodecyl sulfate-stable thrombin-PAI-1 complex. The kinetics of this reaction can be described by a "suicide substrate" mechanism that includes a branched reacti...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract::Eosinophil accumulation has been associated with the pathogenesis of numerous allergic inflammatory disorders. Despite the great interest in this response, many aspects of eosinophil accumulation remain unknown. This is particularly true with respect to tissue-specific mechanisms that may regulate the accumulation of ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-11-15 00:00:00
abstract::The events that regulate engraftment and long-term repopulating ability of hematopoietic stem cells (HSCs) after transplantation are not well defined. We report for the first time that major histocompatibility complex (MHC) class I K plays a critical role in HSC engraftment via interaction with recipient natural kille...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2003-11-3910
更新日期:2004-08-01 00:00:00
abstract::It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:2000-02-01 00:00:00
abstract::Activated protein C is a potent anticoagulant and profibrinolytic enzyme that can be derived from the vitamin-K-dependent serine protease zymogen, protein C, by the action of thrombin. Protein C antigen concentration was determined in plasmas from normals (n = 40) and from 38 patients with intravascular coagulation as...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1982-07-01 00:00:00
abstract::Fc receptors play an important role in leukocyte activation and the modulation of ligand binding ("activation") is a critical point of regulation. Previous studies demonstrated that the Fc receptor for IgA (FcalphaRI/CD89) is regulated by cytokine stimulation, switching it to a high-binding state. To investigate the m...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood.v97.11.3478
更新日期:2001-06-01 00:00:00
abstract::Bcl-2 protein expression has been associated with poor prognosis in patients with noncutaneous diffuse large B-cell lymphomas. In primary cutaneous large B-cell lymphomas, the location on the leg, the round-cell morphology defined as the predominance of centroblasts and immunoblasts over large centrocytes, and multipl...
journal_title:Blood
pub_type: 杂志文章,多中心研究
doi:10.1182/blood-2003-08-2726
更新日期:2004-05-15 00:00:00
abstract::Relapse following remission induction chemotherapy remains a barrier to survival in approximately 20% of children suffering from acute lymphoblastic leukemia (ALL). To investigate the mechanism of relapse, 27 matched diagnosis and relapse ALL samples were analyzed for clonal populations using polymerase chain reaction...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-01-067785
更新日期:2007-07-15 00:00:00
abstract::Anti-CD22 moxetumomab pasudotox achieved 46% complete remissions (CRs) in previously reported phase 1 testing in relapsed/refractory hairy cell leukemia (HCL; n = 28). The importance of minimal residual disease (MRD) after CR in HCL is unknown. A 21-patient extension cohort received 50 µg/kg every other day for 3 dose...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2017-09-803072
更新日期:2018-05-24 00:00:00
abstract::Humans and mice with impaired perforin-dependent cytotoxic function may develop excessive T-cell activation and the fatal disorder hemophagocytic lymphohistiocytosis (HLH) after infection. Though cytotoxic lymphocytes can kill antigen-presenting cells, the physiological mechanism of perforin-mediated immune regulation...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2013-04-495309
更新日期:2013-06-27 00:00:00
abstract::Keeping track of individual cell identifications is imperative to the study of dynamic single-cell behavior over time. Highly motile hematopoietic stem and progenitor cells (HSPCs) migrate quickly and do not adhere, and thus must be imaged very frequently to keep cell identifications. Even worse, they are also flushed...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2017-07-794131
更新日期:2018-03-29 00:00:00
abstract::Heparin is a widely used anticoagulant. Because of its negative charge, it forms complexes with positively charged platelet factor 4 (PF4). This can induce anti-PF4/heparin IgG Abs. Resulting immune complexes activate platelets, leading to the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT)....
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2011-05-353391
更新日期:2012-02-02 00:00:00
abstract::Reestablishment of competent regulatory pathways has emerged as a strategy to reduce the severity of graft-versus-host disease (GVHD), and recalibrate the effector and regulatory arms of the immune system. However, clinically feasible, cost-effective strategies that do not require extensive ex vivo cellular manipulati...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2016-02-698241
更新日期:2016-10-20 00:00:00
abstract::Liver X receptors (LXRs) are nuclear receptors regulating lipid and cholesterol metabolism. Recent data revealed a cross talk between LXR and Toll-like receptor signaling in macrophages, indicating a role in immunity. Here, we show that LXRalpha is expressed in human myeloid dendritic cells (DCs) and induced during di...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2006-08-043422
更新日期:2007-05-15 00:00:00
abstract::We describe two assays to detect the action of colony-inhibiting cells. In the first assay, we used a simple density separation technique to remove dense neutrophils (PMN) from suspensions of blood and of bone marrow cells prior to culture in semisolid agar. Conditions were arranged to ensure that control suspensions ...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1976-03-01 00:00:00
abstract::Different biologic features have been associated with a more or less aggressive clinical course in chronic lymphocytic leukemia (CLL). In the present study, 20 patients with highly stable CLL observed at a single institution over a period of 10 to 23 years and who never required treatment were extensively characterize...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-12-3639
更新日期:2003-08-01 00:00:00
abstract::In childhood acute lymphoblastic leukemia (ALL), early response to treatment is a powerful prognostic indicator. To identify genes associated with this response, we analyzed gene expression of diagnostic lymphoblasts from 189 children with ALL and compared the findings with minimal residual disease (MRD) levels on day...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2006-01-0322
更新日期:2006-08-01 00:00:00
abstract::To define conditions for improved efficiency of retroviral-mediated gene transfer and expression in primate progenitor cells, four rhesus monkeys were treated with a 200 mg/kg intravenous bolus of 5-fluorouracil (5-FU). The kinetics of hematopoietic suppression and recovery were assessed in peripheral blood, bone marr...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1991-02-01 00:00:00
abstract::Delivery of biologically active peptides into human polymorphonuclear neutrophils (PMNs) has implications for studying cellular functions and may be therapeutically relevant. The transcription factor nuclear factor-kappaB (NF-kappaB) regulates the expression of multiple genes controlling inflammation, proliferation, a...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-09-2960
更新日期:2003-09-15 00:00:00
abstract::BMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib mesylate-resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)-exposed Ba/F3-p210(BCR-ABL) cells to compare incidence and types of KD mutants emerging in the p...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2006-02-004580
更新日期:2006-10-01 00:00:00
abstract::Interaction between human platelets and bacterial endotoxin was studied in vitro with transmission and scanning electron microscopy. Washed human platelets, whose aggregation was blocked with apyrase, were incubated in a plasma-free medium containing crude endotoxin that had previously been complexed with copper. Thir...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1978-03-01 00:00:00
abstract::Expression of the arterial marker molecule ephrinB2 in endothelial cells is a prerequisite for adequate remodeling processes of the developing or angiogenic vasculature. Although its role in these processes has been extensively studied, the impact of ephrinB2 on the remodeling of adult arteries is largely unknown. To ...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2007-12-128835
更新日期:2008-07-01 00:00:00
abstract::Many surface receptors and signaling molecules are thought to associate with unique membrane microdomains termed lipid rafts. We examined the involvement of lipid rafts in the activation of leukocyte function-associated antigen-1 (LFA-1). Depletion or sequestration of cholesterol with methyl-beta-cyclodextrin (MCD) or...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2002-10-3195
更新日期:2003-07-01 00:00:00
abstract::MicroRNAs (miRNAs) regulate cell physiology by altering protein expression, but the biology of platelet miRNAs is largely unexplored. We tested whether platelet miRNA levels were associated with platelet reactivity by genome-wide profiling using platelet RNA from 19 healthy subjects. We found that human platelets expr...
journal_title:Blood
pub_type: 杂志文章
doi:10.1182/blood-2010-09-299719
更新日期:2011-05-12 00:00:00
abstract::The synthetic cytokine (Synthokine) SC-55494 is a high-affinity interleukin-3 (IL-3) receptor ligand that stimulates greater in vitro multilineage hematopoietic activity than native IL-3, while inducing no significant increase in inflammatory activity relative to native IL-3. The aim of this study was to investigate t...
journal_title:Blood
pub_type: 杂志文章
doi:
更新日期:1996-01-15 00:00:00
abstract::NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3...
journal_title:Blood
pub_type: 杂志文章,随机对照试验
doi:10.1182/blood-2012-05-429282
更新日期:2013-01-17 00:00:00