Evidence map›Paper›PMID 41658978›Full record

ArticleResearch and practice in thrombosis and haemostasis2026

Mutations of six amino acid residues in a B domain-deleted blood coagulation factor VIII have a cumulative effect on increasing its secretion.

Bo Shi, Philip Olivares, Leonid A Parunov, Yideng Liang, Haarin Chun, Wells W Wu, Vijaya L Simhadri, Pratima Bajgain, Wojciech Jankowski, Margarita Krivega and 7 more

Abstract read
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In one paragraph

Article in Research and practice in thrombosis and haemostasis, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Bo ShiU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Philip OlivaresU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Leonid A ParunovU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Yideng LiangU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Haarin ChunU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Wells W WuU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Vijaya L SimhadriU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Pratima BajgainU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Wojciech JankowskiU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Margarita KrivegaSonoThera, Inc, South San Francisco, California, USA.
Julia PoniatowskiSonoThera, Inc, South San Francisco, California, USA.
Elizabeth Del GrecoSonoThera, Inc, South San Francisco, California, USA.
Ivan KrivegaSonoThera, Inc, South San Francisco, California, USA.
Svetlana A ShestopalU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Abu Hasanat Md ZulfikerU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Zuben E SaunaU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.
Andrey G SarafanovU.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Office of Therapeutic Products, Office of Plasma Protein Therapeutics, Division of Hemostasis, Silver Spring, Maryland, USA.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Background: High levels of factor VIII (FVIII) expression are needed for various applications to treat Hemophilia A. Besides deletion of the B-domain (BDD) and codon-optimization, F309S mutation, and other 5 mutations (X5) in FVIII were previously described to increase its expression. Objectives: To investigate whether combining the 6 aforementioned mutations (X6) results in a further increase of FVIII expression. Methods: The 5 (X5) and 6 (X6) mutations were introduced into a BDD-FVIII (wild-type [WT]), and proteins were expressed in cell cultures with different transgene copy numbers, purified, and tested for specific activity, binding to von Willebrand factor and a low-density lipoprotein receptor-related protein fragment, tyrosine sulfation levels and immunogenicity in silico and in human T-cell culture. The 6 mutations were also reproduced in full-length FVIII (FL-FVIII) and tested for secretion levels. Results: From the single-copy transgene cell lines, secretion levels of X5 and X6 increased 1.6-fold and 2.3-fold, respectively, compared with WT. These levels increased proportionally with increasing transgene copy number, approaching saturation. The specific activity, binding to von Willebrand factor and lipoprotein receptor-related protein fragment, and assessments of immunogenicity of X6 in model systems were similar to WT, while tyrosine sulfation levels, were moderately lower at the highest gene dose. However, the 6 mutations reproduced in FL-FVIII did not result in increased secretion. Conclusion: Combining the 6 mutations in BDD-FVIII improved its expression and did not affect general protein properties, making it promising for future product development. The data also indicate that BDD-FVIII and FL-FVIII have different expression mechanisms.

Indexed as

blood coagulationfactor VIIIgene expressionhemophilia Amutagenesis

Identifiers

PMID41658978
PMCPMC12876599

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.