Review
Medicine, Research & Experimental
Benjamin J. Samelson-Jones, Lindsey A. George
Summary: In vivo gene therapy is rapidly developing as a new treatment approach for monogenic disorders. Hemophilia A and Hemophilia B have been key diseases in the development of gene therapy. Recent adenoassociated viral vector gene addition trials for Hemophilia A and Hemophilia B have shown promising results, with regulatory approval expected in the near future. This review discusses the progress in AAV gene therapy for these diseases and explores the challenges encountered in clinical trials for hemophilia and other monogenic disorders.
ANNUAL REVIEW OF MEDICINE
(2023)
Article
Biotechnology & Applied Microbiology
Jenny A. Greig, Melanie K. Smith, Jayme M. L. Nordin, Tamara Goode, Edward A. Chroscinski, Elizabeth L. Buza, Nicole Schmidt, Lisa M. Kattenhorn, Samuel Wadsworth, James M. Wilson
Summary: In a study on hemophilia A mouse model, the minimally effective dose (MED) of gene therapy vector was determined to be 3 x 10(11) GC/kg. Total bilirubin levels increased with higher vector doses, while no significant differences were observed in liver transaminase levels. There were no vector-related gross or histological findings detected.
HUMAN GENE THERAPY
(2022)
Article
Medicine, General & Internal
Junjiang Sun, Xiaojing Chen, Zheng Chai, Hongqian Niu, Amanda L. L. Dobbins, Timothy C. C. Nichols, Chengwen Li
Summary: Research has found that AAV gene therapy can improve clotting function in hemophilia patients, regardless of the presence of inhibitors. This treatment method has shown promising results in mouse models of hemophilia A and B, achieving effective hemostasis without the risk of thrombosis.
FRONTIERS IN MEDICINE
(2022)
Article
Cell Biology
Ying Kai Chan, Sean K. Wang, Colin J. Chu, David A. Copland, Alexander J. Letizia, Helena Costa Verdera, Jessica J. Chiang, Meher Sethi, May K. Wang, William J. Neidermyer, Yingleong Chan, Elaine T. Lim, Amanda R. Graveline, Melinda Sanchez, Ryan F. Boyd, Thomas S. Vihtelic, Rolando Gian Carlo O. Inciong, Jared M. Slain, Priscilla J. Alphonse, Yunlu Xue, Lindsey R. Robinson-McCarthy, Jenny M. Tam, Maha H. Jabbar, Bhubanananda Sahu, Janelle F. Adeniran, Manish Muhuri, Phillip W. L. Tai, Jun Xie, Tyler B. Krause, Andyna Vernet, Matthew Pezone, Ru Xiao, Tina Liu, Wei Wang, Henry J. Kaplan, Guangping Gao, Andrew D. Dick, Federico Mingozzi, Maureen A. McCall, Constance L. Cepko, George M. Church
Summary: The study engineered AAV vectors by incorporating short DNA oligonucleotides to antagonize TLR9 activation, reducing innate immune responses and enhancing gene expression in clinically relevant animal models. The engineered vectors can avoid adverse reactions in some models, demonstrating a potential wider therapeutic window for AAV therapies.
SCIENCE TRANSLATIONAL MEDICINE
(2021)
Article
Medicine, General & Internal
John Puetz
Summary: After years of research, gene therapy has been approved to treat hemophilia. However, advancements in other treatment methods have changed the landscape of hemophilia care. New data suggests that gene therapy may not be as beneficial as originally thought and could have more toxic effects. A reassessment of the risk/benefit estimation of gene therapy for hemophilia is needed.
FRONTIERS IN MEDICINE
(2023)
Article
Microbiology
Edward E. Large, Michael S. Chapman
Summary: Adeno-associated viruses (AAV) are widely used for gene therapy, and monoclonal antibodies against various AAV serotypes have been developed. Previous studies suggested that neutralizing antibodies inhibit binding to glycan receptors or interfere with post-entry steps. However, recent research has identified a protein receptor and revealed that antibody interference with protein receptor binding may be the predominant mechanism of neutralization.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Hematology
Sara Boyce, Izabela James, Savita Rangarajan, Nicola Curry, Catherine Bagot, Steven Austin, Mike Laffan, Sarah Mangles, Kandiah Chandrakumaran, Carina Mundy
Summary: This study investigated the prevalence of AAV6 neutralizing factors in UK people with hemophilia B and found no correlation with treatment with plasma-derived FIX products or hepatitis C exposure. The frequency of AAV6 neutralizing factors in our hemophilia B cohort is similar to UK people with hemophilia A and non-hemophilia populations.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Virology
Shonisani Wendy Limani, Njabulo Mnyandu, Abdullah Ely, Reubina Wadee, Anna Kramvis, Patrick Arbuthnot, Mohube Betty Maepa
Summary: The study demonstrated the use of recombinant adeno-associated viruses (AAVs) to model the replication of different hepatitis B virus (HBV) subgenotypes, showcasing the efficacy of the AAV8-A1 murine model for anti-HBV drug development.
Article
Pharmacology & Pharmacy
Yu (Zoe) Zhang, Roberto A. DePaz, Jared S. Bee, Tristan Marshall
Summary: The study developed a lyophilized AAV formulation that maintained stability for 24 months, showcasing the feasibility of a dried formulation for AAV gene therapy. By optimizing the composition and residual moisture range, as well as utilizing sucrose, citrate, and glycerol, AAV8 was protected from degradation and potency loss.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2021)
Review
Biochemistry & Molecular Biology
Leyao Li, Lakshmy Vasan, Bryan Kartono, Kevan Clifford, Ahmadreza Attarpour, Raghav Sharma, Matthew Mandrozos, Ain Kim, Wenda Zhao, Ari Belotserkovsky, Claire Verkuyl, Gerold Schmitt-Ulms
Summary: This review introduces the use of recombinant adeno-associated virus (rAAV) vectors in the treatment of neurodegenerative diseases, highlighting recent research advancements and challenges. It provides a reference for newcomers to the field and directs researchers struggling to keep up with the literature towards important studies. The review covers early milestones, current clinical trials, gene editing applications, and payload elements of rAAV vectors, as well as discusses the risks and mitigation strategies associated with off-target effects and immunogenicity.
Review
Neurosciences
Jing Wang, Mengna Zhu, Jingyi Sun, Lina Feng, Mingfeng Yang, Baoliang Sun, Leilei Mao
Summary: Stroke is associated with devastating clinical outcomes, and current treatment strategies are largely ineffective. Gene therapy using adeno-associated viruses (AAVs) as gene vectors has emerged as a promising approach for treating central nervous system diseases. This review provides an overview of the biological characteristics of AAV vectors and therapeutic advancements in preclinical models of ischemic stroke. It further investigates the potential of manipulating AAV vectors in preclinical applications, emphasizing the challenges and prospects in viral vector selection, drug delivery strategies, immune reactions, and clinical translation.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Review
Biotechnology & Applied Microbiology
Sha Sha, Andrew J. Maloney, Georgios Katsikis, Tam N. T. Nguyen, Caleb Neufeld, Jacqueline Wolfrum, Paul W. Barone, Stacy L. Springs, Scott R. Manalis, Anthony J. Sinskey, Richard D. Braatz
Summary: The article focuses on analyzing the bottlenecks in rAAV production during cell culture, comparing differences between wild-type and recombinant systems, and proposing future directions for improvement.
BIOTECHNOLOGY ADVANCES
(2021)
Article
Biochemical Research Methods
Logan Thrasher Collins, Selvarangan Ponnazhagan, David T. Curiel
Summary: Gene therapy has the potential to revolutionize disease treatment through direct genetic manipulation of cells. However, the high cost of Adeno-associated virus (AAV) gene therapy limits its accessibility, making it unaffordable for most patients. Therefore, efforts to decrease the production cost of AAVs using synthetic biology design have been proposed to make gene therapy more widely available.
ACS SYNTHETIC BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Mika Ito, Naomi Takino, Takamasa Nomura, Akihiko Kan, Shin-ichi Muramatsu
Summary: Modifying the AAV3 viral capsid by introducing three substitutions on the surface loop reduced its reactivity with pre-existing antibodies, leading to enhanced transduction efficiency in human hepatocytes. This engineered AAV3 variant, AAV.GT5, showed significantly higher transduction efficiency in hepatocytes compared to AAV8 vectors, making it a promising candidate for future liver-targeted gene therapy clinical trials.
SCIENTIFIC REPORTS
(2021)
Article
Multidisciplinary Sciences
Antonia Ho, Richard Orton, Rachel Tayler, Patawee Asamaphan, Vanessa Herder, Chris Davis, Lily Tong, Katherine Smollett, Maria Manali, Jay Allan, Konrad Rawlik, Sarah E. McDonald, Elen Vink, Louisa Pollock, Louise Gannon, Clair Evans, Jim McMenamin, Kirsty Roy, Kimberly Marsh, Titus Divala, Matthew T. G. Holden, Michael Lockhart, David Yirrell, Sandra Currie, Maureen O'Leary, David Henderson, Samantha J. Shepherd, Celia Jackson, Rory Gunson, Alasdair MacLean, Neil McInnes, Amanda Bradley-Stewart, Richard Battle, Jill A. Hollenbach, Paul Henderson, Miranda Odam, Primrose Chikowore, Wilna Oosthuyzen, Meera Chand, Melissa Shea Hamilton, Diego Estrada-Rivadeneyra, Michael Levin, Nikos Avramidis, Erola Pairo-Castineira, Veronique Vitart, Craig Wilkie, Massimo Palmarini, Surajit Ray, David L. Robertson, Ana da Silva Filipe, Brian J. Willett, Judith Breuer, Malcolm G. Semple, David Turner, J. Kenneth Baillie, Emma C. Thomson
Summary: An investigation found a possible association between AAV2 infection and host genetics in a recent outbreak of acute hepatitis in children in Scotland. The study used various methods to detect AAV2 infection in plasma and liver samples, and identified pathological features related to the virus in liver biopsy samples.
Review
Hematology
Glenn F. Pierce, Donna Coffin, David Lillicrap, Margareth Ozelo, John Pasi, Dawn Rotellini, Carlos Safadi Marquez, Thomas Sannie, Alok Srivastava, Marijke van den Berg, Alain Weill, Antonio Almeida, Alain Baumann, Mark Brooker, Luisa Durante, Mayss Naccache, Fiona Robinson
Article
Hematology
Bhavya S. Doshi, Leslie J. Raffini, Lindsey A. George
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2020)
Editorial Material
Hematology
Barbara A. Konkle, Donna Coffin, Glenn F. Pierce, Cary Clark, Lindsey George, Alfonso Iorio, Johnny Mahlangu, Mayss Naccache, Brian O'Mahony, Flora Peyvandi, Steve Pipe, Adrian Quartel, Eileen K. Sawyer, Mark W. Skinner, Bartholomew Tortella, Crystal Watson, Ian Winburn
Article
Biotechnology & Applied Microbiology
Lindsey A. George, Margaret Ragni, John E. J. Rasko, Leslie J. Raffini, Benjamin J. Samelson-Jones, Margareth Ozelo, Maria Hazbon, Alexa R. Runowski, Jennifer A. Wellman, Katie Wachtel, Yifeng Chen, Xavier M. Anguela, Klaudia Kuranda, Federico Mingozzi, Katherine A. High
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.
Review
Biotechnology & Applied Microbiology
Jerry R. Mendell, Samiah A. Al-Zaidy, Louise R. Rodino-Klapac, Kimberly Goodspeed, Steven J. Gray, Christine N. Kay, Sanford L. Boye, Shannon E. Boye, Lindsey A. George, Stephanie Salabarria, Manuela Corti, Barry J. Byrne, Jacques P. Tremblay
Summary: Hereditary diseases are caused by gene mutations, affecting millions of Americans, and gene therapy using adeno-associated virus (AAV) has shown promise in treating these diseases. Five treatments have been approved for commercialization, with many more in clinical trials, showcasing the potential of gene therapy in treating a wide range of genetic disorders.
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.
Article
Hematology
Mary M. Robinson, Lindsey A. George, Marcus E. Carr, Benjamin J. Samelson-Jones, Valder R. Arruda, John E. Murphy, Denis Rybin, Jeremy Rupon, Katherine A. High, Stefan Tiefenbacher
Summary: Differences in FIX:C levels were observed with different assay methods in hemophilia B patients receiving FIX-Padua gene therapy, with local laboratory results strongly correlating with central laboratory results and consistently lower absolute values at the central lab. Fixation of FIX:C values was seen across different assays, with Actin FSL APTT reagent resulting in lower values at the central lab, and the chromogenic assay showing the lowest FIX:C values. Compared with expected values, rHFIX-Padua protein-spiked samples showed similar results while rHFIX-nonacog alfa results fell below 25% in the chromogenic assay.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Editorial Material
Hematology
Benjamin J. Samelson-Jones, Lindsey A. George
BRITISH JOURNAL OF HAEMATOLOGY
(2021)
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
Education, Scientific Disciplines
Lindsey A. George
Summary: After 30 years of clinical trials, success in gene therapy for hemophilia A and B has been demonstrated. Current efforts are focused on using rAAV vectors for F8 or F9 gene addition, with optimism that regulatory approval for the first AAV vectors may be achieved within approximately 1 year.
HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM
(2021)
Review
Medicine, Research & Experimental
Benjamin J. Samelson-Jones, Lindsey A. George
Summary: In vivo gene therapy is rapidly developing as a new treatment approach for monogenic disorders. Hemophilia A and Hemophilia B have been key diseases in the development of gene therapy. Recent adenoassociated viral vector gene addition trials for Hemophilia A and Hemophilia B have shown promising results, with regulatory approval expected in the near future. This review discusses the progress in AAV gene therapy for these diseases and explores the challenges encountered in clinical trials for hemophilia and other monogenic disorders.
ANNUAL REVIEW OF MEDICINE
(2023)
Letter
Medicine, General & Internal
Feng Xue, PanJing Wang, Zhen Yuan, Chao Shi, Yunhai Fang, Wei Liu, Yuhua Wang, Xiao Xiao, Renchi Yang, Lindsey A. George, Lei Zhang
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Hematology
Barbara Konkle, Glen Pierce, Donna Coffin, Mayss Naccache, R. Cary Clark, Lindsey George, Alfonso Iorio, Brian O'Mahony, Steven Pipe, Mark Skinner, Crystal Watson, Flora Peyvandi, Johnny Mahlangu
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2020)
Article
Medicine, Research & Experimental
Benjamin J. Samelson-Jones, Jonathan D. Finn, Lindsey A. George, Rodney M. Camire, Valder R. Arruda