Article
Biotechnology & Applied Microbiology
Britta Handyside, Ashrafali Mohamed Ismail, Lening Zhang, Bridget Yates, Lin Xie, Choong-Ryoul Sihn, Ryan Murphy, Taren Bouwman, Chan Kyu Kim, Rolando De Angelis, Omair A. Karim, Nicole L. McIntosh, Michael Xavier Doss, Shilpa Shroff, Erno Pungor, Vikas S. Bhat, Sherry Bullens, Stuart Bunting, Sylvia Fong
Summary: This study compared expression profiles of rAAV vectors produced in different cell lines and found that genome loss and epigenetic regulation are the main factors contributing to the decline in transgene protein expression.
Article
Immunology
Glaivy Batsuli, Jasmine Ito, Elizabeth S. York, Courtney Cox, Wallace Baldwin, Surinder Gill, Pete Lollar, Shannon L. Meeks
Summary: This study analyzed the internalization of FVIII complexed with epitope-mapped FVIII-specific IgG monoclonal antibodies by murine bone marrow-derived dendritic cells (BMDCs) in vitro, as well as the antibody development in hemophilia A (FVIII-/-) mice injected with FVIII-IC over time. The results showed that certain FVIII-IC subsets modulate the humoral response to FVIII in an epitope-dependent manner.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Hematology
Amber Vander Kooi, Shuaishuai Wang, Meng-Ni Fan, Alex Chen, Junping Zhang, Chun-Yu Chen, Xiaohe Cai, Barbara A. Konkle, Weidong Xiao, Lei Li, Carol H. Miao
Summary: The N-glycosylation of FVIII has a significant impact on its immunogenicity, as shown in this study. Gene mutations were introduced to eliminate glycosylation at potential sites, and it was found that FVIII activity remained stable while immune responses varied. A specific glycopeptide epitope surrounding one of the glycosylation sites was identified and characterized for its activation of T cells.
Review
Hematology
Mikhail V. Ovanesov, Joseph W. Jackson, Basil Golding, Timothy K. Lee
Summary: This article discusses the factors to consider when choosing an assay for potency assignment and postadministration monitoring of new factor products, including the validity of the assay calibrated with the IS, the meaning of potency values in IU, standards of care for patients, clinical relevance between the assigned potency value and recovery value from clinical laboratories, and patient safety.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Biochemistry & Molecular Biology
Stamatia Papoutsopoulou, Lorna Morris, Andrew Bayliff, Thomas Mair, Hazel England, Massimiliano Stagi, Francois Bergey, Mohammad Tauqeer Alam, Raheleh Sheibani-Tezerji, Philip Rosenstiel, Werner Muller, Vitor A. P. Martins Dos Santos, Barry J. Campbell
Summary: The NF kappa B transcription factors play a crucial role in innate immune responses and their dysregulation is associated with inflammatory diseases. In this study, the introduction of human RelA protein into mouse cells was shown to impact murine gene transcription, affecting both NF kappa B and non-NF kappa B target genes, and interfering with interferon and cytokine signaling pathways.
Article
Multidisciplinary Sciences
Tiago J. S. Lopes, Ricardo Rios, Tatiane Nogueira, Rodrigo F. Mello
Summary: This study investigated the pathogenesis of hemophilia A by creating a residue interaction network, revealing important properties related to disease severity. The properties derived from the network were found to be in close agreement with in vitro and clinical reports, indicating that the detailed map of the FVIII protein accurately captures its biological properties.
SCIENTIFIC REPORTS
(2021)
Article
Immunology
Jacob C. Zbesko, Jennifer Beischel Frye, Danielle A. Becktel, Diana K. Gerardo, Jessica Stokes, Kylie Calderon, Thuy-Vi V. Nguyen, Deepta Bhattacharya, Kristian P. Doyle
Summary: The text explores the activation of B-lymphocytes following stroke and their involvement in cognitive decline. The study found that B-lymphocytes, T-lymphocytes, and plasma cells progressively infiltrate the infarct between 2 and 7 weeks after stroke. Additionally, a population of IgA + plasma cells develop independently of CD4 + helper T-lymphocytes and MyD88 signaling, producing natural antibodies.
BRAIN BEHAVIOR AND IMMUNITY
(2021)
Review
Biotechnology & Applied Microbiology
Manish Muhuri, Daniel Levy, Martin Schulz, Douglas McCarty, Guangping Gao
Summary: Recombinant adeno-associated virus (rAAV) gene therapy has the potential to improve the lives of patients with genetic disorders. However, it is uncertain how long the therapeutic effect will last. This review explores the non-immunological and immunological factors that may affect durability, as well as strategies to increase the duration of the therapeutic effect.
Article
Hematology
Josse van Galen, Nadia Freato, Malgorzata A. Przeradzka, Eduard H. T. M. Ebberink, Mariette Boon-Spijker, Carmen van der Zwaan, Maartje van den Biggelaar, Alexander B. Meijer
Summary: HDX-MS analysis showed how FIXa alters the structure of the Leu631-Tyr637 region in FVIIIa, thereby regulating the cofactor function of FVIII.
THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Hematology
Viola J. F. Strijbis, Lorenzo G. R. Romano, Ka Lei Cheung, Jeroen Eikenboom, Ying Poi Liu, Andrew C. McCreary, Frank W. G. Leebeek, Mettine H. A. Bos
Summary: This study aimed to evaluate the efficacy of FIX-FIAV in plasma from HA patients. The results showed that FIX-FIAV could increase the FVIII-equivalent activity and coagulation activity in HA patient plasma, mitigating the HA phenotype. Therefore, FIX-FIAV could serve as a potential treatment for HA patients.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
James R. Fuller, Kevin E. Knockenhauer, Nina C. Leksa, Robert T. Peters, Joseph D. Batchelor
Summary: The interaction between FVIII and VWF is crucial for hemostasis, and mutations affecting this interaction can lead to von Willebrand disease type 2N. Understanding the structural basis of this interaction is important for developing therapies for bleeding disorders like hemophilia A. The structure of the bioengineered FVIII molecule BIVV001 provides insights into the FVIII-VWF complex formation and sheds light on mutations associated with hemophilia A and VWD type 2N.
Article
Hematology
Joseph S. Gish, Lexi Jarvis, Kenneth C. Childers, Shaun C. Peters, Connor S. Garrels, Ian W. Smith, H. Trent Spencer, Christopher B. Doering, Pete Lollar, P. Clint Spiegel
Summary: The study reveals the structure of a therapeutically active fVIII construct complexed with an anti-C1 domain inhibitor, shedding light on the interaction between the antibody and fVIII, which may lead to the development of more effective and safe fVIII replacement therapies.
Review
Chemistry, Multidisciplinary
Tahereh Zadeh Mehrizi, Kamran Mousavi Hosseini
Summary: This review summarizes the applications of nanotechnology in improving the stability and function of antibodies and coagulation factor VIII (FVIII) over the past decade. Studies show that nanomaterials can not only effectively protect the structure of proteins, but also enhance their functions in some cases. PEGylation has shown to have the most impact on the stability of FVIII.
NANOSCALE ADVANCES
(2021)
Article
Hematology
Yuto Nakajima, Hiroaki Minami, Keiji Nogami
Summary: Studies suggest that certain residues in the A3 acidic region of FVIII play a role in thrombin activation through cleavage at Arg (1689).
THROMBOSIS AND HAEMOSTASIS
(2021)
Review
Hematology
Gordon Lowe, Olivia Wu, Astrid van Hylckama Vlieg, Aaron Folsom, Frits Rosendaal, Mark Woodward
Summary: This study conducted a systematic review and meta-analysis to investigate the associations between plasma factor VIII (FVIII) and factor IX (FIX) levels and the risk of venous thromboembolism (VTE). The results showed significant correlations between elevated FVIII and FIX levels in the population and increased risk of VTE. Levels above the 90th percentile had two times the risk for FIX, three times the risk for FVIII, and almost five times the risk for both elevated FVIII and FIX levels.
THROMBOSIS RESEARCH
(2023)
Article
Medicine, Research & Experimental
Brian R. Long, Krystal Sandia, Jennifer Holcomb, Lucy Crockett, Gregory M. Hayes, Jeremy Arens, Carlos Fonck, Laurie S. Tsuruda, Becky Schweighardt, Charles A. O'Neill, Stephen Zoog, Christian Vettermann
MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT
(2019)
Article
Hematology
Ashok Roy, Sophia Stanford, Sean Nunn, Sue Alves, Nigel Sargant, Savita Rangarajan, Emily Arbuthnot Smith, John Bell, Sanjeev Dayal, Tom Cecil, Alexios Tzivanakis, Irina Kruzhkova, Cristina Solomon, Sigurd Knaub, Brendan Moran, Faheez Mohamed
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2020)
Article
Biochemistry & Molecular Biology
Fan Yang, Kathryn Patton, Theresa Kasprzyk, Brian Long, Soumi Gupta, Stephen J. Zoog, Kristin Tracy, Christian Vettermann
Summary: The study successfully validated the IFN-gamma-based ELISpot assay for measuring T cell responses against viral antigens in cynomolgus monkeys, but monitoring peripheral T cell responses in non-clinical AAV5 gene therapy studies was found to have limited value for interpreting safety or efficacy.
Article
Biotechnology & Applied Microbiology
Brian R. Long, Philippe Veron, Klaudia Kuranda, Romain Hardet, Nina Mitchell, Gregory M. Hayes, Wing Yen Wong, Kelly Lau, Mingjin Li, M. Benjamin Hock, Stephen J. Zoog, Christian Vettermann, Federico Mingozzi, Becky Schweighardt
Summary: The evaluation of immune responses before and after AAV-mediated gene therapy plays a key role in determining therapeutic safety and efficacy. This study found that administration of BMN 270 mainly led to antibodies against the AAV5 capsid, with no FVIII inhibitor responses observed within 3 years of treatment.
Article
Hematology
Peter L. Turecek, Rachel C. Peck, Savita Rangarajan, Christopher Reilly-Stitt, Michael A. Laffan, Rashid Kazmi, Izabela James, Ahilanandan Dushianthan, Gerald Schrenk, Herbert Gritsch, Bruce M. Ewenstein, Bjorn Mellgard, Wolfhard Erdlenbruch, Nisha Jain, Nikolaus B. Binder, Andrew D. Mumford
Summary: Thrombosis is common in severe COVID-19 patients, with an imbalance of VWF/ADAMTS13 implicated in its pathogenesis. Correction of this imbalance through rADAMTS13 may help restore hemostatic balance and potentially serve as a therapeutic approach in severe COVID-19 cases.
THROMBOSIS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Krystal Sandza, Annie Clark, Elli Koziol, Hassibullah Akeefe, Fan Yang, Jennifer Holcomb, Kathryn Patton, Kevin Hammon, Nina Mitchell, Wing Y. Wong, Stephen J. Zoog, Benjamin Kim, Joshua Henshaw, Christian Vettermann
Summary: A new method iqPCR was developed to monitor the presence and shedding kinetics of intact vector capsids following AAV gene therapy, with validated accuracy and specificity. Clinical studies showed that AAV5-FVIII-SQ capsids were detectable in plasma and semen but became undetectable within nine weeks after dose administration.
Article
Biochemistry & Molecular Biology
Sylvia Fong, Bridget Yates, Choong-Ryoul Sihn, Aras N. Mattis, Nina Mitchell, Su Liu, Chris B. Russell, Benjamin Kim, Adebayo Lawal, Savita Rangarajan, Will Lester, Stuart Bunting, Glenn F. Pierce, K. John Pasi, Wing Yen Wong
Summary: Factor VIII gene transfer using valoctocogene roxaparvovec (AAV5-hFVIII-SQ) through a single intravenous infusion has shown clinical benefits lasting 5 years in patients with severe hemophilia A. This study investigated the molecular mechanisms underlying the sustained expression of AAV5-hFVIII-SQ-derived FVIII in the liver. The results demonstrated persistent episomal vector structures and provided insights into potential mechanisms mediating interindividual variability in transgene expression.
Article
Hematology
Nirmalkumar Choraria, Savita Rangarajan, M. Joseph John, Shashikant Apte, Pritam Gupta, Seema Pai, Rohit Chand, Shyam Parvatini, G. S. H. Ramakanth, Jeremy Rupon, Amit Chhabra, Hitesh Bhaskarrao Muley, Damien Simoneau
Summary: This study evaluated the safety and efficacy of moroctocog alfa in Indian patients with moderate or severe congenital hemophilia A. The results showed that the treatment was safe, effective, and well-tolerated, with no development of FVIII inhibitors.
INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION
(2023)
Article
Hematology
Nirmalkumar Choraria, Savita Rangarajan, M. Joseph John, Shashikant Apte, Pritam Gupta, Seema Pai, Rohit Chand, Shyam Parvatini, G. S. H. Ramakanth, Jeremy Rupon, Amit Chhabra, Hitesh Bhaskarrao Muley, Damien Simoneau
Summary: This study evaluated the safety and efficacy of nonacog alfa in Indian patients with hemophilia B. The results demonstrate that nonacog alfa is a safe and effective treatment for preventing bleeding episodes, with no significant adverse events or thrombotic events reported.
INDIAN JOURNAL OF HEMATOLOGY AND BLOOD TRANSFUSION
(2023)
Article
Medicine, General & Internal
Guy Young, Alok Srivastava, Kaan Kavakli, Cecil Ross, Jameela Sathar, Chur-Woo You, Huyen Tran, Jing Sun, Runhui Wu, Stacey Poloskey, Zhiying Qiu, Salim Kichou, Shauna Andersson, Baisong Mei, Savita Rangarajan
Summary: This study evaluated the efficacy and safety of Fitusiran prophylaxis in patients with hemophilia A or B and inhibitors. The results showed that Fitusiran prophylaxis significantly reduced the annualized bleeding rate, with two-thirds of the participants experiencing no bleeds. Therefore, Fitusiran may have the potential to improve hemostatic efficacy in patients with hemophilia A or B and inhibitors.
Article
Hematology
Alok Srivastava, Savita Rangarajan, Kaan Kavakli, Robert Klamroth, Gili Kenet, Liane Khoo, Chur-Woo You, Weiqun Xu, Niel Malan, Laurent Frenzel, Catherine N. Bagot, Oleksandra Stasyshyn, Chia-Yau Chang, Stacey Poloskey, Zhiying Qiu, Shauna Andersson, Baisong Mei, Steven W. Pipe
Summary: Fitusiran, an investigational siRNA therapeutic, has shown efficacy in reducing bleeding rate in severe hemophilia patients without inhibitors. The prophylactic use of Fitusiran has the potential to transform the management of hemophilia.
LANCET HAEMATOLOGY
(2023)
Article
Medicine, General & Internal
Ahilanandan Dushianthan, Nabil Abdul, Josh Dmochowski, Izabela James, Lesley Heesom, Jennifer Westwood, Judith Effney, Sarah Bruty, Kordo Saeed, Savita Rangarajan, Rashid Kazmi
Summary: The study found that peak D-dimer and vWF-ADAMTS13-platelet axis are associated with ICU severity and outcome in severe COVID-19 patients admitted to ICU.
CUREUS JOURNAL OF MEDICAL SCIENCE
(2021)
Article
Medicine, General & Internal
K. John Pasi, Savita Rangarajan, Nina Mitchell, Will Lester, Emily Symington, Bella Madan, Michael Laffan, Chris B. Russell, Mingjin Li, Glenn F. Pierce, Wing Y. Wong
NEW ENGLAND JOURNAL OF MEDICINE
(2020)
