Article
Medicine, General & Internal
Lindsey A. George, Paul E. Monahan, M. Elaine Eyster, Spencer K. Sullivan, Margaret Ragni, Stacy E. Croteau, John E. J. Rasko, Michael Recht, Benjamin J. Samelson-Jones, Amy MacDougall, Kristen Jaworski, Robert Noble, Marla Curran, Klaudia Kuranda, Federico Mingozzi, Tiffany Chang, Kathleen Z. Reape, Xavier M. Anguela, Katherine A. High
Summary: A gene therapy trial using an AAV vector (SPK-8011) for factor VIII expression in 18 men with hemophilia A showed sustained expression in most participants, leading to reduced bleeding events and discontinuation of prophylaxis.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Hematology
Anne-Fleur Zwagemaker, Fabienne R. Kloosterman, Samantha C. Gouw, Sara Boyce, Paul Brons, Marjon H. Cnossen, Peter W. Collins, Jeroen Eikenboom, Charles Hay, Rutger C. C. Hengeveld, Shannon Jackson, Caroline A. M. Klopper-Tol, Marieke J. H. A. Kruip, Britta Laros-van Gorkom, Christoph Male, Laurens Nieuwenhuizen, Susan Shapiro, Karin Fijnvandraat, Michiel Copens
Summary: This study investigated the discrepancy between one-stage and chromogenic assays of coagulation factor activity in moderate and mild hemophilia A and B patients. The results showed that only a small number of patients exhibited a discrepancy between the two assays, and this discrepancy was largely determined by laboratory variables.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
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
Hematology
Paolo Simioni, Stefano Cagnin, Francesca Sartorello, Gabriele Sales, Luca Pagani, Cristiana Bulato, Sabrina Gavasso, Francesca Nuzzo, Francesco Chemello, Claudia M. Radu, Daniela Tormene, Luca Spiezia, Tilman M. Hackeng, Elena Campello, Elisabetta Castoldi
Summary: This study identified the molecular basis of high FVIII levels leading to severe thrombophilia in two Italian families, involving a tandem duplication of the proximal portion of the F8 gene. This rearrangement led to upregulation of F8 messenger RNA and transcriptional enhancement, potentially mediating the severe thrombophilia observed in carriers of the duplication.
Article
Hematology
Julia H. Joo, Xuefeng Wang, Swati Singh, Chun -Yu Chen, Chong Li, Jennifer E. Adair, Hans -Peter Kiem, David J. Rawlings, Carol H. Miao
Summary: This study demonstrates the long-term safety and efficacy of intraosseous delivery of lentiviral vector for factor VIII in treating hemophilia A in a humanized model. The successful transduction of self-regenerating hematopoietic stem and progenitor cells was confirmed, indicating potential for long-term transgene expression. The study also evaluated the safety and efficacy of gene transfer therapy into human HSPCs, showing megakaryocyte-specific gene expression and polyclonal integration pattern. Overall, the results support the feasibility of translating this method for clinical applications.
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
Biotechnology & Applied Microbiology
Binbin Li, Zhihan Wu, Wenjue Xu, Wenwen Han, Jiayu Liu, Dawei Wang, Guowei Zhang
Summary: Targeting FIX Padua expression in platelets has been shown to effectively improve bleeding symptoms in hemophilia B mice without increasing the risk of thrombosis. However, limitations such as the inability to overcome the presence of inhibitors exist with FIX Padua. Therefore, targeting FIX Padua expression in platelets may be a safe and effective gene therapy strategy for hemophilia B.
HUMAN GENE THERAPY
(2021)
Article
Biochemistry & Molecular Biology
Junzheng Wu, Hang Zhang, Tong Lian, Yaling Ding, Chunlei Song, Dekuan Li, Liheng Wu, Tao Lei, Hong Liang
Summary: A novel B-domain-deleted recombinant FVIII was developed in this study without the use of animal or human serum-derived components. rFVIII promoted the generation of activated factor X and downstream thrombin, and exhibited ideal binding affinity to human von Willebrand factor. In vitro and in vivo experiments demonstrated the satisfactory efficacy and potency of rFVIII, suggesting its potential as an effective treatment strategy for FVIII deficiency.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Hematology
Amelia R. Wilhelm, Nicole A. Parsons, Benjamin J. Samelson-Jones, Robert J. Davidson, Charles T. Esmon, Rodney M. Camire, Lindsey A. George
Summary: This study compared an APC-resistant FVIII variant with wild-type FVIII, and found that APC plays an important role in the in vivo regulation of FVIIIa, which could be exploited for developing novel treatments for hemophilia A.
Article
Biology
Jeong Pil Han, Dong Woo Song, Jeong Hyeon Lee, Geon Seong Lee, Su Cheong Yeom
Summary: Innovative gene therapy is advancing towards functional restoration, with hemophilia being a representative genetic disorder. A novel mouse model of hemophilia A has been developed in this study, which could be utilized for future gene correction preclinical trials.
Article
Biochemistry & Molecular Biology
Jie Gong, Rui Yang, Min Zhou, Lung-Ji Chang
Summary: This study developed advanced lentiviral vectors for targeted expression of factor VIII (FVIII) and conducted functional experiments in human endothelial and megakaryocytic cell lines. In a mouse model, one of the vectors showed excellent packaging and delivery efficiencies, with endothelial specificity and low immunogenicity, suggesting its potential for clinical applications.
MOLECULAR MEDICINE
(2023)
Editorial Material
Hematology
Lindsey A. George
Summary: The study suggests that in patients with hemophilia B, gene therapy using AAV vectors may not maintain expression despite steroid intervention, possibly due to the CpG motifs in the vector stimulating the immune system. This provides insights into the mechanisms of the immune response to AAV vectors and has implications for future vector design.
Review
Biotechnology & Applied Microbiology
Dries De Wolf, Kshitiz Singh, Marinee K. Chuah, Thierry Vandendriessche
Summary: Extensive preclinical research has led to the recent regulatory approval of gene therapy products for hemophilia. Roctavian and Hemgenix have shown significant efficacy and safety in clinical trials, resulting in increased levels of clotting factors and reduced bleeding episodes for patients. However, there is variability in patient response and short-term liver inflammation was observed. Longer follow-up studies are needed to determine if lifelong expression of clotting factors can be achieved. Next-generation gene editing technologies offer new prospects for a sustained cure for hemophilia.
HUMAN GENE THERAPY
(2023)
Review
Hematology
Robert F. Sidonio Jr, Steven W. Pipe, Michael U. Callaghan, Leonard A. Valentino, Paul E. Monahan, Stacy E. Croteau
Summary: This article discusses the potential of gene therapy in treating hemophilia and important aspects of clinical trials, including the influence of treatment method differences on practical application and how to select appropriate clinical trial participants. In addition, infographic summaries are provided to assist healthcare providers in conducting informed consultations.
Article
Cardiac & Cardiovascular Systems
Brandon Tse, Rosane Nisenbaum, Georgina Floros, Aziz Jiwajee, Jerome Teitel, Michelle Sholzberg
Summary: Continuous factor VIII (FVIII) or factor IX (FIX) infusions are commonly used for patients with hemophilia A (HA) or B (HB) undergoing surgery. This study found differences in initial recovery and subsequent FIX and FVIII levels, as well as clinical outcomes, among HB and HA patients receiving perioperative continuous infusion (CI) of recombinant FVIII and FIX concentrates. HB patients had higher initial bolus dose and longer length of hospital stay, suggesting a need for a higher CI rate for adequate surgical hemostatic coverage.
JOURNAL OF THROMBOSIS AND THROMBOLYSIS
(2023)
Article
Biochemistry & Molecular Biology
Warut Tulalamba, Jonas Weinmann, Quang Hong Pham, Jihad El Andari, Thierry VandenDriessche, Marinee K. Chuah, Dirk Grimm
Editorial Material
Biotechnology & Applied Microbiology
David M. Markusic, Ashley T. Martino, Christopher D. Porada, Thierry VandenDriessche
Article
Medicine, Research & Experimental
Jaitip Tipanee, Mario Di Matteo, Warut Tulalamba, Ermira Samara-Kuko, Jiri Keirsse, Jo A. Van Ginderachter, Marinee Khim Chuah, Thierry Vanden Driessche
MOLECULAR THERAPY-NUCLEIC ACIDS
(2020)
Article
Hematology
Glenn F. Pierce, K. John Pasi, Donna Coffin, Radoslaw Kaczmarek, David Lillicrap, Johnny Mahlangu, Dawn Rottellini, Thomas Sannie, Alok Srivastava, Thierry VandenDriessche, Alain Weill
Article
Genetics & Heredity
Jennifer Bolleyn, Matthias Rombaut, Nisha Nair, Steven Branson, Anja Heymans, Marinee Chuah, Thierry VandenDriessche, Vera Rogiers, Joery De Kock, Tamara Vanhaecke
Article
Hematology
Nisha Nair, Dries De Wolf, Phuong Anh Nguyen, Quang Hong Pham, Ermira Samara-Kuko, Jeff Landau, Grant E. Blouse, Marinee K. Chuah, Thierry VandenDriessche
Summary: The novel FIX variant CB 2679d-GT showed significantly improved clotting activity and hemostatic correction in hemophilic mice compared to the current standard R338L-Padua variant following AAV-directed gene therapy. This study highlights the potential of CB 2679d-GT to achieve higher FIX activity levels and superior hemostatic efficacy in hemophilia B patients.
Article
Biotechnology & Applied Microbiology
Alberto Malerba, Chiara Sidoli, Ngoc Lu-Nguyen, Shan Herath, Anita Le Heron, Hayder Abdul-Razak, Susan Jarmin, Thierry VandenDriessche, Marinee K. Chuah, George Dickson, Linda Popplewell
Summary: Duchenne muscular dystrophy (DMD) is a genetic disease affecting male individuals, with no cure currently available. Gene therapy, particularly using AAV vectors, shows promise in improving expression levels and relieving symptoms in patients.
HUMAN GENE THERAPY
(2021)
Article
Biotechnology & Applied Microbiology
Jaitip Tipanee, Ermira Samara-Kuko, Thierry Gevaert, Marinee K. Chuah, Thierry VandenDriessche
Summary: This study developed a non-viral platform based on Sleeping Beauty transposons and minicircles for genetic modification, allowing efficient expression of CD19-28z.CAR and inactivation of allogeneic TCRs using CRISPR-Cas9. The resulting CAR T cells showed anti-tumor activity against CD19+ tumor cells and induced complete tumor remission in a mouse model, while minimizing TCR alloreactivity and GvHD. This non-viral approach provides an alternative method for generating next-generation CD19-specific CAR T cells, reducing GvHD risk and manufacturing constraints associated with viral vectors.
Editorial Material
Biotechnology & Applied Microbiology
Thierry VandenDriessche, Steven W. Pipe, Glenn F. Pierce, Radoslaw Kaczmarek
Editorial Material
Biotechnology & Applied Microbiology
Thierry VandenDriessche, Marinee K. Chuah
Review
Biotechnology & Applied Microbiology
Dries De Wolf, Kshitiz Singh, Marinee K. Chuah, Thierry Vandendriessche
Summary: Extensive preclinical research has led to the recent regulatory approval of gene therapy products for hemophilia. Roctavian and Hemgenix have shown significant efficacy and safety in clinical trials, resulting in increased levels of clotting factors and reduced bleeding episodes for patients. However, there is variability in patient response and short-term liver inflammation was observed. Longer follow-up studies are needed to determine if lifelong expression of clotting factors can be achieved. Next-generation gene editing technologies offer new prospects for a sustained cure for hemophilia.
HUMAN GENE THERAPY
(2023)
Article
Multidisciplinary Sciences
Jonas Weinmann, Sabrina Weis, Josefine Sippel, Warut Tulalamba, Anca Remes, Jihad El Andari, Anne-Kathrin Herrmann, Quang H. Pham, Christopher Borowski, Susanne Hille, Tanja Schoenberger, Norbert Frey, Martin Lenter, Thierry VandenDriessche, Oliver J. Mueller, Marinee K. Chuah, Thorsten Lamla, Dirk Grimm
NATURE COMMUNICATIONS
(2020)
Article
Hematology
Flora Peyvandi, David Lillicrap, Johnny Mahlangu, Claire McLintock, K. John Pasi, Steven W. Pipe, Wendy Scales, Alok Srivastava, Thierry VandenDriessche
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2020)