Molecular evolution of the vertebrate blood coagulation network

Davidson, Courtney; Hirt, Robert P.; Lal, Kalpana; Snell, Philip; Elgar, Greg; Tuddenham, Edward G. D.; McVey, John H.

doi:10.1055/s-0037-1613369

Cited by 88 publications

(64 citation statements)

References 26 publications

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“…An important consideration in this development was that even though the B domains from different species are not highly conserved, the 6 Nlinked glycosylation consensus sequences (N-X-T/S) dispersed across the proximal 226 aa of this region are maintained, suggesting that they play an important biological role. 38 Therefore, to reduce the size of rAAV-HLP-codop-hFVIII-N6, the 226-aa B domain spacer was replaced with a 17-aa V3 peptide in which the 6 N-linked glycosylation triplets were placed adjacent to each other.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant

McIntosh

Lenting

Rosales

et al. 2013

Blood

241

271

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• Novel, more potent codonoptimized human FVIII variant (codop-hFVIII-V3).• Codop-hFVIII-V3 is safe and efficacious in mice and nonhuman primates, thus improving the prospects of gene therapy for hemophilia A.Recombinant adeno-associated virus (rAAV) vectors encoding human factor VIII (hFVIII) were systematically evaluated for hemophilia A (HA) gene therapy. A 5.7-kb rAAVexpression cassette (rAAV-HLP-codop-hFVIII-N6) containing a codon-optimized hFVIII cDNA in which a 226 amino acid (aa) B-domain spacer replaced the entire B domain and a hybrid liver-specific promoter (HLP) mediated 10-fold higher hFVIII levels in mice compared with non-codon-optimized variants. A further twofold improvement in potency was achieved by replacing the 226-aa N6 spacer with a novel 17-aa peptide (V3) in which 6 glycosylation triplets from the B domain were juxtaposed. The resulting 5.2-kb rAAV-HLP-codop-hFVIII-V3 cassette was more efficiently packaged within AAV virions and mediated supraphysiologic hFVIII expression (732 6 162% of normal) in HA knockout mice following administration of 2 3 10 12 vector genomes/kg, a vector dose shown to be safe in subjects with hemophilia B. Stable hFVIII expression at 15 6 4% of normal was observed at this dose in a nonhuman primate. hFVIII expression above 100% was observed in 3 macaques that received a higher dose of either this vector or the N6 variant. These animals developed neutralizing anti-FVIII antibodies that were abrogated with transient immunosuppression. Therefore, rAAV-HLP-codop-hFVIII-V3 substantially improves the prospects of effective HA gene therapy. (Blood. 2013;121(17):3335-3344) Introduction Hemophilia A (HA), the most common inherited bleeding disorder, caused by a deficiency of factor VIII (FVIII) is well suited for a gene replacement approach, primarily because a modest increase in the level of FVIII (.1% of normal) can ameliorate the severe bleeding phenotype.1 Several gene transfer strategies for FVIII replacement have been evaluated. 2 However, adeno-associated viral (AAV) vectors currently show the greatest promise because of their excellent safety profile and ability to direct long-term transgene expression from postmitotic tissues such as the liver.3-5 Indeed, our ongoing gene therapy clinical trial for hemophilia B, a related bleeding diathesis, has demonstrated that a single peripheral vein administration of AAV vector leads to stable (.30 months) expression of human factor IX (FIX) at levels between 1% to 6% of normal. This is sufficient for conversion of the hemophilia phenotype from severe to moderate or mild.5 Two-thirds of the participants in this study have discontinued prophylaxis and remain free of spontaneous hemorrhage. The other participants have increased the interval between FIX prophylaxes. The use of AAV vectors for HA gene therapy, however, poses new challenges because of the distinct molecular and biochemical properties of human FVIII (hFVIII). Compared with other proteins of similar size, expression of hFVIII is highly inefficient.6 Bioengineeri...

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Section: Discussionmentioning

confidence: 99%

Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant

McIntosh

Lenting

Rosales

et al. 2013

Blood

241

271

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“…Such a rudimentary system could then have acquired regulatory complexity as well as the potential for rapid spatially restricted amplification by addition of upstream Gla domain-and EGF domain-containing proteases (factors VII, IX, and X). These proteases are likely to have arisen from a prototypical Gla-EGF 2 -serine protease structure through successive gene and͞or global genome duplications (43,44).…”

Section: Discussionmentioning

confidence: 99%

Vitamin K-dependent proteins in Ciona intestinalis , a basal chordate lacking a blood coagulation cascade

Kulman

Harris

Nakazawa

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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We have isolated and sequenced several cDNAs derived from the sea squirt Ciona intestinalis that encode vitamin K-dependent proteins. Four of these encode ␥-carboxyglutamic acid (Gla) domain-containing proteins, which we have named Ci-Gla1 through Ci-Gla4. Two additional cDNAs encode the apparent orthologs of ␥-glutamyl carboxylase and vitamin K epoxide reductase. Ci-Gla1 undergoes ␥-glutamyl carboxylation when expressed in CHO cells and is homologous to Gla-RTK, a putative receptor tyrosine kinase previously identified in a related ascidian. The remaining three Gla domain proteins are similar to proteins that participate in fundamental developmental processes, complement regulation, and blood coagulation. These proteins are generally expressed at low levels throughout development and exhibit either relatively constant expression (Ci-Gla1, ␥-glutamyl carboxylase, and vitamin K epoxide reductase) or spatiotemporal regulation (Ci-Gla2, -3, and -4). These results demonstrate the evolutionary emergence of the vitamin K-dependent Gla domain before the divergence of vertebrates and urochordates and suggest novel functions for Gla domain proteins distinct from their roles in vertebrate hemostasis. In addition, these findings highlight the usefulness of C. intestinalis as a model organism for investigating vitamin K-dependent physiological phenomena, which may be conserved among the chordate subphyla.ascidian ͉ ␥-carboxyglutamic acid ͉ urochordate ͉ warfarin

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“…[9][10][11][12] Zebrafish (Danio rerio) have been widely used to study hemostasis, demonstrating conservation and function of the structural components of coagulation, including fibrinogen 13,14 and von Willebrand factor, 15,16 and the ability to develop thrombosis in response to a laser-induced injury. 14,17 Embryonic development is external, rapid, and transparent, allowing unfettered access to studies of the circulatory system.…”

Section: Introductionmentioning

confidence: 99%

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

Liu¹,

Kretz

Maeder

et al. 2014

Blood

108

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Molecular evolution of the vertebrate blood coagulation network

Cited by 88 publications

References 26 publications

Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant

Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant

Vitamin K-dependent proteins in Ciona intestinalis , a basal chordate lacking a blood coagulation cascade

Targeted mutagenesis of zebrafish antithrombin III triggers disseminated intravascular coagulation and thrombosis, revealing insight into function

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