Article
Multidisciplinary Sciences
Qiang Wang, Lin Zhang, Guo-Wei Zhang, Jian-Hua Mao, Xiao-Dong Xi, Lu Jiang, Gang Lv, Jing Lu, Yan Shen, Zhu Chen, Jiang Zhu, Sai-Juan Chen
Summary: The study demonstrates that a single DNA cutting-mediated long-range replacement can restore the FIX-encoding function of a mutant F9 (mF9) carrying both regulatory and coding defects in a severe mouse HB model. It establishes an AAV/CRISPR-mediated gene-editing protocol applicable to complicated monogenetic disorders, underscoring the potentiality of improving therapeutic benefits through managing inflammation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Microbiology
Jakob Shoti, Keyun Qing, Arun Srivastava
Summary: Recombinant MV serotype vectors and their variants are being used in clinical trials for gene therapy for hemophilia. However, traditional liver-directed AAV gene therapy does not work in children with hemophilia. This study describes the development of an optimized human Factor IX gene expression cassette for potential gene therapy for hemophilia in children.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Immunology
Thais B. Bertolini, Jamie L. Shirley, Irene Zolotukhin, Xin Li, Tsuneyasu Kaisho, Weidong Xiao, Sandeep R. P. Kumar, Roland W. Herzog
Summary: AAV vectors are promising for gene therapy, but immune responses can occur due to CpG motifs in the vector genome, leading to CD8(+) T cell activation. Depletion of CpG motifs can reduce such immune responses.
FRONTIERS IN IMMUNOLOGY
(2021)
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
Biotechnology & Applied Microbiology
Robert Klamroth, Gregory Hayes, Tatiana Andreeva, Keith Gregg, Takashi Suzuki, Ismail Haroon Mitha, Brandon Hardesty, Midori Shima, Toni Pollock, Patricia Slev, Johannes Oldenburg, Margareth C. Ozelo, Natalie Stieltjes, Sabine-Marie Castet, Johnny Mahlangu, Flora Peyvandi, Rashid Kazmi, Jean-Francois Schved, Andrew D. Leavitt, Michael Callaghan, Brigitte Pan-Petesch, Doris Quon, Jayson Andrews, Alex Trinh, Mingjin Li, Wing Yen Wong
Summary: This global study investigated the prevalence of pre-existing immunity against five AAV serotypes in patients with hemophilia A, and found significant variability between different countries and regions. AAV5 consistently had the lowest seroprevalence across the countries studied. These data are important for clinical trials of AAV-mediated gene therapy.
HUMAN GENE THERAPY
(2022)
Article
Biotechnology & Applied Microbiology
Jenny A. Greig, Kelly M. Martins, Camilo Breton, R. Jason Lamontagne, Yanqing Zhu, Zhenning He, John White, Jing-Xu Zhu, Jessica A. Chichester, Qi Zheng, Zhe Zhang, Peter Bell, Lili Wang, James M. Wilson
Summary: Through studying nonhuman primates, we discovered limitations in gene therapy for the liver due to the mechanism of transduction affecting performance. Although transgene expression declines and stabilizes over time, high transduction of non-immunogenic transgenes is still possible. AAV-mediated transgene expression in primate hepatocytes occurs in two phases: high but short-lived expression from episomal genomes, followed by lower but stable expression from integrated vectors.
NATURE BIOTECHNOLOGY
(2023)
Review
Genetics & Heredity
Xiangjun He, Brian Anugerah Urip, Zhenjie Zhang, Chun Christopher Ngan, Bo Feng
Summary: In recent years, gene therapy has entered a new era with AAV emerging as a potent vector for gene transfer in vivo. AAV-based gene therapy products have been approved by FDA and EMA for the treatment of previously incurable diseases, marking significant progress in the field. The combination of AAV vectors with genome editing tools has introduced new therapeutic modalities, expanding treatment options for untreatable diseases.
JOURNAL OF MOLECULAR MEDICINE-JMM
(2021)
Review
Cell Biology
Shaza S. Issa, Alisa A. Shaimardanova, Valeriya V. Solovyeva, Albert A. Rizvanov
Summary: Despite the advancements in gene and cell therapy, some diseases still lack effective treatment. Adeno-associated viruses (AAVs) have enabled the development of effective gene therapy methods for various diseases. Numerous AAV-based gene therapy medications are undergoing trials and entering the market. This article provides a review of AAV discovery, properties, serotypes, tropism, and their applications in gene therapy for different diseases of organs and systems.
Article
Immunology
David Brown, Michael Altermatt, Tatyana Dobreva, Sisi Chen, Alexander Wang, Matt Thomson, Viviana Gradinaru
Summary: Engineered variants of recombinant adeno-associated viruses are rapidly being developed to meet the demand for gene therapy delivery vehicles with specific cell-type and tissue tropisms. An experimental and computational single-cell RNA sequencing pipeline has been developed to characterize barcoded rAAV pools at high resolution, revealing both confirmed and unidentified AAV capsid targeting biases.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Biotechnology & Applied Microbiology
Dongsheng Duan
Summary: This mini-review summarizes clinical findings of lethal immunotoxicity induced by high-dose systemic AAV gene therapy and calls for collaborative efforts to better understand the underlying mechanisms and develop effective prevention/treatment strategies.
Review
Pharmacology & Pharmacy
Paul Young
Summary: Advanced therapy medicinal products have extended the treatment paradigm to gene therapy, which modifies genes for therapeutic effect. Gene therapy has strong growth potential, especially using adeno-associated viruses (AAVs) for targeted delivery. However, manufacturing challenges exist in generating high-quality and efficacious viral vectors. Learning from established processes like monoclonal antibody production and embracing innovative approaches are crucial for scalable and cost-effective solutions. Ultimately, the goal is to turn treatment into a cure.
DRUG DISCOVERY TODAY
(2023)
Review
Pharmacology & Pharmacy
Paul Young
Summary: Advanced therapy medicinal products have expanded the treatment options in the pharmaceutical industry by enabling gene therapy for potentially curative approaches, primarily using adeno-associated viruses (AAVs) for targeted delivery. However, manufacturing challenges exist in ensuring high quality and efficacy of AAV-based gene therapy products. Learning from established manufacturing processes like monoclonal antibodies (mAbs) can help develop scalable and cost-effective solutions. Future innovation and collaboration with regulatory agencies are essential for further advancements in gene therapy manufacturing and achieving the ultimate goal of cure.
DRUG DISCOVERY TODAY
(2023)
Review
Hematology
Leonard A. Valentino, Radoslaw Kaczmarek, Glenn F. Pierce, Declan Noone, Brian O'Mahony, David Page, Dawn Rotellini, Mark W. Skinner
Summary: The introduction of adeno-associated virus-mediated, liver-directed gene therapy brings both promise and uncertainty to the hemophilia community. Despite significant advances in treatment, challenges remain and health equity has not been achieved. Informed, holistic, and shared decision-making is crucial for individuals considering gene therapy. Addressing bias among healthcare professionals and patients is essential for optimal outcomes.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Immunology
Bradley A. Hamilton, J. Fraser Wright
Summary: This article discusses the host immune responses that limit durable therapeutic gene expression in AAV-based human gene therapies. A strategy of removing pathogen-associated molecular patterns in AAV vector genomes to overcome immunological barriers is proposed.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Immunology
Thomas Weber
Summary: AAV vector-based gene therapy is currently the only approved in vivo gene therapy in the US and Europe, but the presence of pre-existing anti-AAV antibodies presents a formidable challenge to its successful clinical use. Establishing protocols to determine relevant titers of these antibodies and methods to deplete them is now more urgent than ever to ensure the efficacy of AAV gene transfer therapy.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Hematology
Joseph H. Oved, Andrew J. Paris, Kandace Gollomp, Ning Dai, Kathryn Rubey, Ping Wang, Lynn A. Spruce, Steven H. Seeholzer, Mortimer Poncz, G. Scott Worthen
Summary: Neutrophils play a critical role in sterile inflammation, engulfing and degrading extracellular DNA fragments to facilitate optimal organ repair.
Letter
Hematology
Bhavya S. Doshi, Char M. Witmer
Article
Medicine, Research & Experimental
Bhavya S. Doshi, Jyoti Rana, Giancarlo Castaman, Mostafa A. Shaheen, Radoslaw Kaczmarek, John S. S. Butterfield, Shannon L. Meeks, Cindy Leissinger, Moanaro Biswas, Valder R. Arruda
Summary: Inhibitors of factor VIII (FVIII) in hemophilia A are a challenging complication of FVIII protein replacement therapy. Research suggests that BAFF may play a role in regulating the generation and maintenance of FVIII inhibitors, and anti-BAFF therapy could prevent the formation of inhibitors. Combination therapy with anti-CD20 and anti-BAFF antibodies shows promise in significantly reducing FVIII inhibitors.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Review
Emergency Medicine
Bhavya S. Doshi, Angela M. Ellison
Summary: The incidence of venous thromboembolism (VTE) is increasing in pediatric patients. Current treatment guidelines are largely expert opinion-based, but emerging direct-acting oral anticoagulants are being investigated in pediatric VTE.
PEDIATRIC EMERGENCY CARE
(2021)
Meeting Abstract
Hematology
Bhavya S. Doshi, Mostafa A. Shaheen, Juliana C. Small, Paris Margaritis, Valder R. Arruda
Meeting Abstract
Hematology
Robert Chen, Bhavya S. Doshi, Timothy C. Nichols, Michael C. Milone, Ben J. Samelson-Jones, Valder R. Arruda, Vijay Bhoj, Don L. Siegel
Article
Ophthalmology
Zujaja Tauqeer, Kandace L. Gollomp, Peter Bracha, Albert M. Maguire
Summary: We report a case of a 14-year-old boy with atypical hemolytic uremic syndrome presenting with new-onset complications in the eye. The patient had a history of retinal problems and developed a new retinal detachment in the left eye. Despite surgical intervention, the patient experienced progressive retinal and optic nerve ischemia.
Article
Oncology
Bhavya S. Doshi, Aditi Kamdar, Michele P. Lambert, Amrom E. Obstfeld
Summary: Hemolysis in glucose-6-phosphate dehydrogenase (G6PD) deficiency varies depending on the mutation status and oxidative stressor. The classification of hemolysis risk by the percentage of enzymatic deficiency is complicated by the variability in normal G6PD values. This study retrospectively assessed the risk of medication-induced hemolysis in G6PD deficient patients and found that only patients with very low enzymatic activity experienced hemolytic episodes. No hemolytic events occurred when G6PD levels were above 7 units/g hemoglobin. The correlation between G6PD levels and mutation status may improve the predictive capacity for hemolysis in G6PD deficiency.
JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY
(2022)
Review
Hematology
Allyson M. Pishko, Bhavya S. Doshi
Summary: Acquired hemophilia A is a rare disorder where autoantibodies to coagulation factor VIII lead to bleeding tendencies. Diagnosis should be suspected in patients with new-onset bleeding without a history of bleeding, and confirmed through specific assays. Treatment involves hemostatic therapies and immune modulation strategies.
JOURNAL OF BLOOD MEDICINE
(2022)
Meeting Abstract
Hematology
Lucas Van Gorder, Bhavya S. Doshi, Elinor Willis, Matthew Lanza, Valder R. Arruda, Mary Beth Callan, Ben J. Samelson-Jones
Meeting Abstract
Hematology
Bhavya S. Doshi, Ben J. Samelson-Jones, Timothy C. Nichols, Elizabeth P. Merricks, Valder R. Arruda, Mary Beth Callan
Editorial Material
Hematology
Kandace Gollomp, David T. Teachey
Summary: In this issue of Blood, Kumar et al investigate the impact of sirolimus on immune health in children with multilineage immune cytopenias (m-ICs). Sirolimus, also known as rapamycin, is an antifungal compound first discovered in a soil sample from Easter Island (Rapa Nui) in the 1960s. It has been found to be a potent immunosuppressive agent that inhibits the activation of the protein kinase mTOR, leading to cell cycle arrest and autophagy. Sirolimus has been approved for use in preventing solid organ transplant rejection and has demonstrated a good safety profile over the past two decades.
Review
Hematology
Anh T. P. Ngo, Veronica Bochenek, Kandace Gollomp
Summary: This review discusses the complex interplay of PF4 and polyanions, providing important insights into the treatment of infectious diseases and the pathogenesis of thrombotic disorders driven by anti-PF4/polyanion and anti-PF4 antibodies.
CURRENT OPINION IN HEMATOLOGY
(2023)
Article
Hematology
Wenjing Cao, Aria R. Trask, Antonia I. Bignotti, Lindsey A. George, Bhavya S. Doshi, Denise E. Sabatino, Noritaka Yada, Liang Zheng, Rodney M. Camire, X. Long Zheng
Summary: This study aims to determine the effect of FVIII on VWF proteolysis and homeostasis. Through mouse models, recombinant FVIII infusion, and patients with hemophilia A, the study concludes that FVIII plays a pivotal role in regulating VWF proteolysis and homeostasis under various conditions.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Review
Hematology
Anh T. P. Ngo, Kandace Gollomp
Summary: Infectious and inflammatory stimuli induce the release of cell-free DNA complexed with histones and antimicrobial proteins, which form webs called neutrophil extracellular traps (NETs) that capture and kill pathogens. Excessive NET release can lead to the release of harmful substances that damage microvasculature. Clearing or neutralizing these substances improves disease outcomes, demonstrating the causal link between NETs and disease.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2022)