Engineered coagulation factor VIII with enhanced secretion and coagulation potential for hemophilia A gene therapy.

Gene Therapy with BMN 270 Results in Therapeutic Levels of FVIII in Mice and Primates and Normalization of Bleeding in Hemophilic Mice.

Phenotypic Correction of Hemophilia A by Ectopic Expression of Activated Factor VII in Platelets

In vivo dose threshold effect of adenovirus-mediated factor VIII gene therapy in hemophiliac mice.

A Novel Deletion in the Fviii B-Domain That Reduces Transgene Size While Preserving FVIII Activity.

Phenotype Correction of Hemophilia A Mice with Adeno-Associated Virus (AAV) Vectors Carrying the B Domain Deleted Canine Factor VIII Gene.

The possible consequences of the long intermittent fasting schedule during Ramadan (one month of food and water intake limited to night hours, a practice that is followed by the majority of the Muslims worldwide) on certain biochemical constituents or coagulation variables have not been extensively documented. During the month of Ramadan and two months after, we monitored the concentration of different plasma lipoproteins, lipoprotein (a) [Lp(a)], apoproteins A(1) and B, fibrinogen, factor VII activity and some selected hematological factors in 50 healthy subjects who were employees of institutes related to the Isfahan University of Medical Sciences and aged between 30 and 45 years. The effect of fasting in Ramadan on the relationship between biochemical and coagulation variables was also investigated. The values of apoprotein B, Lp(a) and low-density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL-C) ratio were significantly decreased during Ramadan (P<0.05), while total cholesterol (Tot-C), triglycerides (TG), LDL-C, HDL-C and fasting blood glucose did not change during that month. Among coagulation and hematological factors, fibrinogen level and factor VII activity were significantly decreased during the month (P<0.05). Results also indicated a significant positive association between fibrinogen level and Lp(a), factor VII activity and Tot-C, LDL-C, TG and Apo B during Ramadan. Our findings contribute to a better understanding of previous reports, as the metabolic and coagulation changes that are considered as atherosclerosis risk factors are counterbalanced during Ramadan.

Novel mutation in coagulation factor VII (Carmel mutation): Identification and characterization

GO-8: Preliminary Results of a Phase I/II Dose Escalation Trial of Gene Therapy for Haemophilia a Using a Novel Human Factor VIII Variant

Updated Results of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (PF-07055480/SB-525) Gene Therapy in Adults with Severe Hemophilia Α

Relationship between Endogenous, Transgene FVIII Expression and Bleeding Events Following Valoctocogene Roxaparvovec Gene Transfer for Severe Hemophilia A: A Post-Hoc Analysis of the GENEr8-1 Phase 3 Trial

Founder haplotype associated with the factor VIII Asp1241Glu polymorphism in a cohort of mild hemophilia A patients.

First-in-Human Dose-Finding Study of AAVhu37 Vector-Based Gene Therapy: BAY 2599023 Has Stable and Sustained Expression of FVIII over 2 Years

Objective To study the effect of the promoter methylation of coagulation factor VII (FVII) on the coagulation factor VII activity (FVIIa) in traumatic brain injury (TBI) patients, and the correlation between the promoter methylation in FVII and intracranial progressive hemorrhagic injury (PHI). Methods A prospective analysis was conducted on 79 patients with moderate-severe TBI admitted to emergency department from August 2010 to August 2014. The peripheral venous blood samples were collected at admission and then were delivered for measurement of FVIIa. Genomic DNA was isolated from patient blood, and the promoter methylation in FVII (CpG2, CpG3, CpG4, CpG5, and CpG6) were analyzed. According to the level of plasma FVIIa, the patients were divided into FVIIa≥90% group and FVIIa<90% group. Based on the presence of PHI, the patients were divided into PHI group and non-PHI group. The FVII promoter methylation, age, gender, systolic blood pressure, Glasgow Coma Scale (GCS), length of stay and mortality between FVIIa≥90% group and FVIIa<90% group, PHI group and non-PHI group were compared. Results There were no significant differences in age, gender, systolic blood pressure, GCS, LOS, and mortality between FVIIa ≥90% group and FVIIa 0.05). The methylation of CpG3 in FVIIa ≥90% group was less than that in FVIIa 0.05). No significant differences in all of methylation levels of the CpG sites between PHI group and non-PHI group were found (P>0.05). Conclusions The promoter methylation of FVII affects plasma FVIIa concentrations, and higher methylation results in lower FVIIa. The promoter methylation of FVII is not associated with PHI in TBI patients. Key words: Brain injuries; Factor VII; Methylation; Progressive hemorrhagic injury

Inhibiting Activated Protein C Cleavage of Factor VIII for Hemophilia a Gene Therapy

Factor VII (FVII) coagulant activity has been proven to be associated with the risk of future fatal coronary heart disease (CHD) in middle-aged men. Recent studies have emphasized the role of triglyceride-rich lipoproteins and FVII genotype in determining plasma levels of FVII protein and activity. The present study was undertaken to examine whether FVII activity state and protein concentration in fasting plasma are altered in young men with proven myocardial infarction (MI) and examined the relations of FVII to subfractions of apo B-containing lipoproteins and the Arg-->Gln polymorphism in the FVII gene. Activated FVII (FVIIa) was determined by a clotting assay using soluble, recombinant, truncated tissue factor. A total of 94 men with a first MI before the age of 45 (mean age +/- SD, 39.6 +/- 4.5 years) were included in the study along with 99 population-based, age-matched control subjects. In addition to FVIIa and FVII antigen (FVII:Ag), a panel of FVII activity assays were included for comparison with previous work in this field. The plasma level of FVII:Ag was higher in patients than in control subjects when the entire groups were compared (537 +/- 128 versus 479 +/- 93 ng/mL, P < .001), the differences being accounted for by patients with hypertriglyceridemic lipoprotein phenotypes. In contrast, FVIIa was similar in patients and control subjects (4.6 +/- 1.4 versus 4.3 +/- 1.3 ng/mL, NS), which means that the proportion of FVIIa molecules was unaltered or even lower in the patients. As expected, the Arg-->Gln polymorphism significantly influenced both FVII mass and activity levels. In addition, presence of the Gln allele appeared to be associated with a lower proportion of fully active FVII molecules. The polymorphism also affected the relation between the plasma concentration of VLDL and FVII:Ag. The triglyceride content and particle number of all VLDL subfractions, irrespective of particle size, correlated fairly strongly with FVII mass determinations but not at all with FVIIa. HDL cholesterol concentration, on the other hand, presumably reflecting the efficiency of lipoprotein lipase-mediated lipolysis of VLDL, related significantly to the FVIIa level. The Arg-->Gln polymorphism, independent of lipoprotein effects, explained 5% to 10% of the variation in FVII mass and activity. In conclusion, the present findings speak against a role of FVII as a risk factor for CHD, because a significantly increased potential for activation of coagulation (ie, raised basal concentration of FVIIa) was not observed among young postinfarction patients.(ABSTRACT TRUNCATED AT 400 WORDS)