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Cohesin connects CTCF-binding sites and other genomic loci in cis to form chromatin loops and replicated DNA molecules in trans to mediate sister chromatid cohesion. Whether cohesin uses distinct or related mechanisms to perform these functions is unknown. Here, we describe a cohesin hinge mutant that can extrude DNA into loops but is unable to mediate cohesion in human cells. Our results suggest that the latter defect arises during cohesion establishment. The observation that cohesin's cohesion and loop extrusion activities can be partially separated indicates that cohesin uses distinct mechanisms to perform these two functions. Unexpectedly, the same hinge mutant can also not be stopped by CTCF boundaries as well as wild-type cohesin. This suggests that cohesion establishment and cohesin's interaction with CTCF boundaries depend on related mechanisms and raises the possibility that both require transient hinge opening to entrap DNA inside the cohesin ring.
Assuntos
Proteínas de Ciclo Celular , Cromátides , Humanos , Cromátides/genética , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , CoesinasRESUMO
Dividing eukaryotic cells package extremely long chromosomal DNA molecules into discrete bodies to enable microtubule-mediated transport of one genome copy to each of the newly forming daughter cells1-3. Assembly of mitotic chromosomes involves DNA looping by condensin4-8 and chromatin compaction by global histone deacetylation9-13. Although condensin confers mechanical resistance to spindle pulling forces14-16, it is not known how histone deacetylation affects material properties and, as a consequence, segregation mechanics of mitotic chromosomes. Here we show how global histone deacetylation at the onset of mitosis induces a chromatin-intrinsic phase transition that endows chromosomes with the physical characteristics necessary for their precise movement during cell division. Deacetylation-mediated compaction of chromatin forms a structure dense in negative charge and allows mitotic chromosomes to resist perforation by microtubules as they are pushed to the metaphase plate. By contrast, hyperacetylated mitotic chromosomes lack a defined surface boundary, are frequently perforated by microtubules and are prone to missegregation. Our study highlights the different contributions of DNA loop formation and chromatin phase separation to genome segregation in dividing cells.
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Cromatina , Microtúbulos , Mitose , Acetilação , Cromatina/metabolismo , Segregação de Cromossomos , DNA/metabolismo , Histonas/metabolismo , Microtúbulos/metabolismo , Transição de Fase , Fuso Acromático/metabolismoRESUMO
Genetic information is stored in linear DNA molecules, which are highly folded inside cells. DNA replication along the folded template path yields two sister chromatids that initially occupy the same nuclear region in an intertwined arrangement. Dividing cells must disentangle and condense the sister chromatids into separate bodies such that a microtubule-based spindle can move them to opposite poles. While the spindle-mediated transport of sister chromatids has been studied in detail, the chromosome-intrinsic mechanics presegregating sister chromatids have remained elusive. Here, we show that human sister chromatids resolve extensively already during interphase, in a process dependent on the loop-extruding activity of cohesin, but not that of condensins. Increasing cohesin's looping capability increases sister DNA resolution in interphase nuclei to an extent normally seen only during mitosis, despite the presence of abundant arm cohesion. That cohesin can resolve sister chromatids so extensively in the absence of mitosis-specific activities indicates that DNA loop extrusion is a generic mechanism for segregating replicated genomes, shared across different Structural Maintenance of Chromosomes (SMC) protein complexes in all kingdoms of life.
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Cromátides , Proteínas Cromossômicas não Histona , Humanos , Cromátides/genética , Cromátides/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Mitose , DNA , Fase G2 , CoesinasRESUMO
ABSTRACT: Gene therapy using adeno-associated virus (AAV) vectors is a promising approach for the treatment of monogenic disorders. Long-term multiyear transgene expression has been demonstrated in animal models and clinical studies. Nevertheless, uncertainties remain concerning the nature of AAV vector persistence and whether there is a potential for genotoxicity. Here, we describe the mechanisms of AAV vector persistence in the liver of a severe hemophilia A dog model (male = 4, hemizygous; and female = 4, homozygous), more than a decade after portal vein delivery. The predominant vector form was nonintegrated episomal structures with levels correlating with long-term transgene expression. Random integration was seen in all samples (median frequency, 9.3e-4 sites per cell), with small numbers of nonrandom common integration sites associated with open chromatin. No full-length integrated vectors were found, supporting predominant episomal vector-mediated long-term transgene expression. Despite integration, this was not associated with oncogene upregulation or histopathological evidence of tumorigenesis. These findings support the long-term safety of this therapeutic modality.
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Dependovirus , Fator VIII , Terapia Genética , Vetores Genéticos , Hemofilia A , Fígado , Animais , Cães , Dependovirus/genética , Hemofilia A/genética , Hemofilia A/terapia , Vetores Genéticos/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Terapia Genética/métodos , Feminino , Fator VIII/genética , Técnicas de Transferência de Genes , Integração Viral , Transgenes , Modelos Animais de DoençasRESUMO
Sister chromatid cohesion conferred by entrapment of sister DNAs within a tripartite ring formed between cohesin's Scc1, Smc1, and Smc3 subunits is created during S and destroyed at anaphase through Scc1 cleavage by separase. Cohesin's association with chromosomes is controlled by opposing activities: loading by Scc2/4 complex and release by a separase-independent releasing activity as well as by cleavage. Coentrapment of sister DNAs at replication is accompanied by acetylation of Smc3 by Eco1, which blocks releasing activity and ensures that sisters remain connected. Because fusion of Smc3 to Scc1 prevents release and bypasses the requirement for Eco1, we suggested that release is mediated by disengagement of the Smc3/Scc1 interface. We show that mutations capable of bypassing Eco1 in Smc1, Smc3, Scc1, Wapl, Pds5, and Scc3 subunits reduce dissociation of N-terminal cleavage fragments of Scc1 (NScc1) from Smc3. This process involves interaction between Smc ATPase heads and is inhibited by Smc3 acetylation.
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Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Acetilação , Sítios de Ligação , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/genética , DNA Fúngico/metabolismo , Modelos Moleculares , Mutação , Estrutura Terciária de Proteína , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , CoesinasRESUMO
Hemophilia is an X-linked inherited bleeding disorder, resulting from defects in the F8 (hemophilia A) or F9 (hemophilia B) genes. Persons with hemophilia have bleeding episodes into the soft tissues and joints, which are treated with self-infusion of factor VIII or IX concentrates. Hemophilia provides an attractive target for gene therapy studies, due to the monogenic nature of these disorders and easily measurable endpoints (factor levels and bleed rates). All successful, pre-clinical and clinical studies to date have utilized recombinant adeno-associated viral (AAV) vectors for factor VIII or IX hepatocyte transduction. Recent clinical data have presented normalization of factor levels in some patients with improvements in bleed rate and quality of life. The main toxicity seen within these studies has been early transient elevation in liver enzymes, with variable effect on transgene expression. Although long-term data are awaited, durable expression has been seen within the hemophilia dog model with no late-toxicity or oncogenesis. There are a number of phase III studies currently recruiting; however, there may be some limitations in translating these data to clinical practice, due to inclusion/exclusion criteria. AAV-based gene therapy is one of a number of novel approaches for treatment of hemophilia with other gene therapy (in vivo and ex vivo) and non-replacement therapies progressing through clinical trials. Availability of these high-cost novel therapeutics will require evolution of both clinical and financial healthcare services to allow equitable personalization of care for persons with hemophilia.
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Fator IX/genética , Fator VIII/genética , Terapia Genética , Hemofilia A/genética , Hemofilia A/terapia , Hemofilia B/genética , Hemofilia B/terapia , Animais , Estudos Clínicos como Assunto , Terapia Combinada , Regulação da Expressão Gênica , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/efeitos adversos , Vetores Genéticos/genética , Humanos , Isoanticorpos/imunologia , Especificidade de Órgãos , Transdução Genética , Transgenes , Resultado do TratamentoRESUMO
INTRODUCTION: Inhibitor formation is the greatest challenge facing persons with haemophilia treated with factor concentrates. The gold standard testing methodologies are the Nijmegen-Bethesda assay (NBA) for FVIII and Bethesda assay (BA) for FIX inhibitors, which are affected by pre-analytical and inter-laboratory variability. AIMS: To evaluate inhibitor testing methodology and assess correlation between self-reported and actual methodology. METHODS: Methodology was evaluated using a survey distributed alongside a UK National External Quality Assessment Service Blood Coagulation external quality assurance (EQA) exercise for FVIII and FIX inhibitor testing. RESULTS: Seventy four survey and EQA exercise responses were received (response rate 63.2%), with 50 paired survey/EQA results. 47.1% (33/70) reported using the NBA and 42.9% (30/70) the BA for FVIII inhibitor testing. Review of FVIII inhibitor assay methodology demonstrated discrepancy (self-reported to actual) in 64.3% (BA reporting) and 27.6% (NBA reporting). Pre-analytical heat treatment was used by 32.4%, most commonly 56°C for 30 minutes. Assay cut-offs of 0.1-1.0 BU/mL were reported. EQA samples (acquired FVIII and congenital FIX) demonstrated titres and coefficients of variation (CV) of 3.1 BU/mL (0.7-15.4 BU/mL; CV = 43%) and 18.0 BU/mL (0-117 BU/mL; CV = 33%), respectively. No significant assay or laboratory factors were found to explain this variance, which could have resulted in change in management for 6 patients (5 misclassified high-titre FVIII inhibitors and 1 false negative for a FIX inhibitor). CONCLUSIONS: Heterogeneity was seen at each stage of assay methodology. No assay-related factors were found to explain variation in inhibitor titres. Further standardization is required to improve inhibitor quantification to guide patient care.
Assuntos
Fator VIII , Hemofilia A , Inibidores dos Fatores de Coagulação Sanguínea , Testes de Coagulação Sanguínea , Hemofilia A/diagnóstico , Hemofilia A/tratamento farmacológico , Humanos , Reino UnidoRESUMO
Anti-drug antibody formation following factor VIII (FVIII) replacement therapy is the most important treatment-related complication in patients with severe haemophilia A. A significant number of these antibodies show neutralising activity against FVIII and are referred to as FVIII inhibitors. Alloimmunity to FVIII, given the absence of endogenous circulating FVIII protein, may be predictable to some extent; however, only 30% of patients develop inhibitors. Genetic and environmental risk factors have been identified, contributing to the likelihood of inhibitor development. Multiple immunological theories have been proposed which in part explain the outcomes of many epidemiological studies. Significant differences exist among replacement therapies, including the source, FVIII sequence, glycosylation, formulation components, impurities and aggregation potential, which significantly complicate interpretation of the results from these studies. In this review, we present recent advances in the understanding of the cellular mechanisms of inhibitor formation and highlight some areas of uncertainty requiring further investigation.
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Autoanticorpos , Inibidores dos Fatores de Coagulação Sanguínea , Fator VIII , Autoanticorpos/genética , Autoanticorpos/imunologia , Inibidores dos Fatores de Coagulação Sanguínea/genética , Inibidores dos Fatores de Coagulação Sanguínea/imunologia , Fator VIII/genética , Fator VIII/imunologia , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Hemofilia A/genética , Hemofilia A/imunologia , Hemofilia A/patologia , Humanos , Masculino , Fatores de RiscoRESUMO
Inhibitor formation in non-severe haemophilia A is a life-long risk and associated with morbidity and mortality. There is a paucity of data to understand real-world inhibitor screening practice. We evaluated the treatment burden, haemostatic strategies, F8 genotyping and inhibitor screening practices in non-severe haemophilia A in seven London haemophilia centres. In the 2-year study period, 44% (377/853) patients received at least one haemostatic treatment. Seventy-nine percent of those treated (296/377) received factor VIII (FVIII) concentrate. F8 genotype was known in 88% (331/377) of individuals. Eighteen per cent (58/331) had 'high-risk' F8 genotypes. In patients with 'standard-risk' F8 genotypes treated on-demand with FVIII concentrate, 51·3% episodes (243/474) were screened within 1 year. However, poor screening compliance was observed after 'high-risk' treatment episodes. In patients with 'standard-risk' F8 genotypes, 12·3% (28/227) of treatment episodes were screened in the subsequent 6 weeks after surgery or a bleed requiring ≥5 exposure days. Similarly, in the context of 'high-risk' F8 genotypes after any FVIII exposure, only 13·6% (12/88) of episodes were screened within 6 weeks. Further study is required to assess optimal practice of inhibitor screening in non-severe haemophilia A to inform subsequent clinical decisions and provide more robust prevalence data to further understand the underlying immunological mechanism.
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Fator VIII/genética , Genótipo , Hemofilia A/imunologia , Hemofilia A/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Hemofilia A/genética , Hemostáticos/uso terapêutico , Humanos , Lactente , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Adulto JovemAssuntos
Ácidos Indolacéticos/farmacologia , Linfócitos/efeitos dos fármacos , Piridinas/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Agregação Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Humanos , Imunidade Inata/efeitos dos fármacos , Linfócitos/fisiologiaRESUMO
Adeno-associated viral vector (AAV) gene therapy provides a promising platform for treatment of monogenic inherited disorders. Clinical studies have demonstrated long-term expression with reduction in bleeding using this approach for the treatment of hemophilia. Despite these advances, there are unknowns surrounding the natural history of recombinant AAV (rAAV) vectors and the cellular mechanisms mediating vector persistence. These unknowns underpin questions regarding long-term efficacy and safety. The predominant mechanism via which AAV is proposed to persist is in circular double-stranded extrachromosomal DNA structures (episomes) within the nucleus. Studies of wild-type (WT-AAV) and rAAV have demonstrated that AAV also persists via integration into a host cell's DNA. It is important to determine whether these integration events can mediate expression or could result in any long-term safety concerns. WT-AAV infection affects a large proportion of the general population, which is thought to have no long-term sequelae. Recent studies have highlighted that this WT-AAV has been detected in cases of acute hepatitis in children and in a minority of cases of hepatocellular carcinoma. Integration following treatment using rAAV has also been reported in preclinical and clinical studies. There have been variable reports on the potential implications of integration for rAAV vectors with data in some murine studies demonstrating recurrent integration with development of hepatocellular carcinoma. These findings have not been seen in other pre-clinical or clinical studies. In this review, we will summarize current understanding of the natural history of AAV (wild-type and recombinant) with a focus on genomic integration and the cellular implications.
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Antifibrinolytic drugs are used extensively for on-demand treatment of severe acute bleeding. Controlling fibrinolysis may also be an effective strategy to prevent or lessen chronic recurring bleeding in bleeding disorders such as hemophilia A (HA), but current antifibrinolytics have unfavorable pharmacokinetic profiles. Here, we developed a long-lasting antifibrinolytic using small interfering RNA (siRNA) targeting plasminogen packaged in clinically used lipid nanoparticles (LNPs) and tested it to determine whether reducing plasmin activity in animal models of HA could decrease bleeding frequency and severity. Treatment with the siRNA-carrying LNPs reduced circulating plasminogen and suppressed fibrinolysis in wild-type and HA mice and dogs. In HA mice, hemostatic efficacy depended on the injury model; plasminogen knockdown improved hemostasis after a saphenous vein injury but not tail vein transection injury, suggesting that saphenous vein injury is a murine bleeding model sensitive to the contribution of fibrinolysis. In dogs with HA, LNPs carrying siRNA targeting plasminogen were as effective at stabilizing clots as tranexamic acid, a clinical antifibrinolytic, and in a pilot study of two dogs with HA, the incidence of spontaneous or excess bleeding was reduced during 4 months of prolonged knockdown. Collectively, these data demonstrate that long-acting antifibrinolytic therapy can be achieved and that it provides hemostatic benefit in animal models of HA.
Assuntos
Antifibrinolíticos , Hemofilia A , Hemostáticos , Lipossomos , Nanopartículas , Cães , Animais , Camundongos , Fibrinólise/genética , Antifibrinolíticos/farmacologia , Plasminogênio/farmacologia , Hemofilia A/tratamento farmacológico , RNA Interferente Pequeno , Projetos Piloto , Hemorragia/tratamento farmacológico , Hemostáticos/farmacologiaRESUMO
Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy, with no standard treatment other than splenectomy. Rituximab has shown encouraging results. We therefore retrospectively assessed 43 patients from two centres, who received rituximab, either alone or with chemotherapy. All patients responded, 34/43 (79%) achieving a complete response (CR), compared with 3/10 (30%) after chemotherapy without rituximab (P = 0·005). Of these 10 patients, 9 (90%) subsequently achieved a CR after rituximab (P = 0·02). Rituximab monotherapy appeared equally as effective as rituximab combination therapy (90% vs. 79% CR, P = 0·7) with significantly less toxicity (12·5% vs. 83%, P = 0·002). Splenectomized patients were more likely to obtain a CR with rituximab (16/16, 100%) than unsplenectomized patients (18/27, 67%, P = 0·008). Disease-free survival (DFS) at 3 years was better after rituximab than after splenectomy alone [79% (95% confidence interval 60-89) vs. 29% (8-54), Hazard ratio (HR) 0·28 (0·12-0·68), P = 0·003] and better than after chemotherapy without rituximab [25% (4-55), HR 0·21 (0·08-0·51), P = 0·0004]. Survival at 3 years after rituximab was 98%. In summary, the CR and DFS rates after rituximab, given alone or with chemotherapy, were significantly better than after chemotherapy without rituximab in the same patients, with manageable toxicity. Rituximab, with or without splenectomy, should be considered for the treatment of SMZL.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Neoplasias Esplênicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Progressão da Doença , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Rituximab , Neoplasias Esplênicas/mortalidade , Resultado do TratamentoRESUMO
Recombinant adeno-associated virus (AAV) is an effective platform for therapeutic gene transfer; however, tissue-tropism differences between species are a challenge for successful translation of preclinical results to humans. We evaluated the use of in vitro primary hepatocyte cultures to predict in vivo liver-directed AAV expression in different species. We assessed whether in vitro AAV transduction assays in cultured primary hepatocytes from mice, nonhuman primates (NHPs), and humans could model in vivo liver-directed AAV expression of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), an experimental gene therapy for hemophilia A with a hepatocyte-selective promoter. Relative levels of DNA and RNA in hepatocytes grown in vitro correlated with in vivo liver transduction across species. Expression in NHP hepatocytes more closely reflected expression in human hepatocytes than in mouse hepatocytes. We used this hepatocyte culture model to assess transduction efficacy of a novel liver-directed AAV capsid across species and identified which of 3 different canine factor VIII vectors produced the most transgene expression. Results were confirmed in vivo. Further, we determined mechanisms mediating inhibition of AAV5-hFVIII-SQ expression by concomitant isotretinoin using primary human hepatocytes. These studies support using in vitro primary hepatocyte models to predict species translatability of liver-directed AAV gene therapy and improve mechanistic understanding of drug-drug interactions.
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The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women's health, arterial thrombosis, pediatrics, COVID-related thrombosis, vaccine-induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self-explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.
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Since the cloning and characterization of the factor VIII (FVIII) and factor IX genes in the mid-1980s, gene therapy has been perceived as having significant potential for the treatment of severe hemophilia. Now, some 35 years later, these proposals are close to being realized through the licensing of the first clinical gene therapy product. Adeno-associated viral vector-mediated gene therapy for hemophilia A and B has been extensively investigated in preclinical models over the past 20 years, and since 2011, there has been increasing evidence in early phase clinical trials that this therapeutic strategy can provide safe and effective rescue of the hemostatic phenotype in severe hemophilia. As the uptake of hemophilia gene therapy progresses, it is clear that many aspects of the gene therapy process require crucial laboratory support to ensure safe and effective outcomes from his new therapeutic paradigm. These laboratory contributions extend from evaluations of the gene therapy vehicle, assessments of the patient immune status for the vector, and ultimately the performance of assays to determine the hemostatic benefit of the gene therapy and potentially of its long-term safety on the host genome. As with many aspects of past hemophilia care, the safe and effective delivery of gene therapy will require an informed and coordinated contribution from laboratory science.
Assuntos
Terapia Genética , Hemofilia A/terapia , Hemofilia B/terapia , Animais , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Ensaios Clínicos como Assunto , Dependovirus/genética , Fator IX/genética , Fator VIII/genética , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/efeitos adversos , Vetores Genéticos/genética , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemofilia A/genética , Hemofilia B/sangue , Hemofilia B/diagnóstico , Hemofilia B/genética , Humanos , Mutação , Fenótipo , Resultado do TratamentoRESUMO
The clinical potential of hemophilia gene therapy has now been pursued for the past 30 years, and there is a realistic expectation that this goal will be achieved within the next couple of years with the licensing of a gene therapy product. While recent late phase clinical trials of hemophilia gene therapy have shown promising results, there remain a number of issues that require further attention with regard to both efficacy and safety of this therapeutic approach. In this review, we present information relating to the current status of the field and focus attention on the unanswered questions for hemophilia gene therapy and the future challenges that need to be overcome to enable the widespread application of this treatment paradigm.
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: Women with inherited bleeding disorders (IBDs) are reported to have higher rates of primary and secondary postpartum haemorrhage (PPH), even with optimal haemostatic management. We evaluated whether women with IBD have higher odds of PPH compared with those without, when controlled for mode of delivery with a control group of women without IBDs. The obstetric experiences and outcomes of all women with IBD delivering at a tertiary centre between 2008 and 2017, were compared with matched controls (1â:â1). Obstetric care was provided according to national guidelines to both women with IBD and controls. Primary PPH was defined as estimated blood loss at least 500âml. There were 46 completed pregnancies in women with IBD: 16 haemophilia A carriers, eight haemophilia B carriers, eight factor XI deficiency patients and 14 von Willebrand disease patients (type 1â=â6; type 2â=â8). No peripartum haemostatic treatment was received by carriers of haemophilia A or B. There were 74 control pregnancies. Women with IBD had higher odds of primary PPH, in a model controlling for mode of anaesthesia (adjusted odds ratio 5.30, 95% confidence interval 1.02-27.59, Pâ=â0.048). Carriers of haemophilia A had a higher, statistically nonsignificant, odds for primary PPH than controls (adjusted odds ratio 6.85, confidence interval 0.77-60.73, Pâ=â0.084). An increase in primary PPH was observed in women with IBD, particularly in haemophilia A, despite management according to guidelines. These results warrant further investigation and consideration should be given as to which factor levels to target.