Review
Virology
Edward E. Large, Mark A. Silveria, Grant M. Zane, Onellah Weerakoon, Michael S. Chapman
Summary: Human gene therapy has advanced significantly from the concept in the 20th century to a reality in the 21st century, with recombinant Adeno-Associated Virus (rAAV) being a major gene therapy vector. Research is continuously working on improving the safety and efficacy of rAAV through various AAV capsid modification strategies, focusing on factors such as neutralizing antibodies and receptor binding to enhance transduction efficiency. Advances in understanding molecular interactions during rAAV cell entry, in combination with improved capsid modulation strategies, will lead to the design of safer and more efficient rAAV gene therapy vectors.
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
Biotechnology & Applied Microbiology
Min Lu, Zion Lee, Yu-Chieh Lin, Ibrahim Irfanullah, Wen Cai, Wei-Shou Hu
Summary: A synthetic biology approach was used to establish stable cell lines for recombinant adeno-associated virus (rAAV) production. Productivity of the cell lines was improved by reducing gene of interest expression, optimizing induction profiles, and alleviating capsid protein degradation, bringing it close to traditional multiple plasmid transfection.
BIOTECHNOLOGY AND BIOENGINEERING
(2023)
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
Biotechnology & Applied Microbiology
Ngoc Tam Tran, Emilie Lecomte, Sylvie Saleun, Suk Namkung, Cecile Robin, Kristina Weber, Eric Devine, Veronique Blouin, Oumeya Adjali, Eduard Ayuso, Guangping Gao, Magalie Penaud-Budloo, Phillip W. L. Tai
Summary: Over the past two decades, significant progress has been made in the manufacturing of adeno-associated virus (AAV) vectors to meet the production demands for preclinical and clinical trials. However, the presence of empty AAV capsids and particles containing inaccurate vector genomes remains a concern. Different methods have been utilized to separate empty capsids from full particles, but no single technique can completely eliminate empty or partial capsids. This study reveals that vectors produced by different manufacturing systems exhibit varying degrees of truncated and unresolved species, and purified empty particles actually contain genomes composed of a single truncated and/or unresolved inverted terminal repeat (ITR). These findings provide valuable insights into the efficacy, safety, and quantification of clinical vectors.
HUMAN GENE THERAPY
(2022)
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)
Article
Engineering, Chemical
Abhiram Arunkumar, Nripen Singh
Summary: This study quantitatively investigated the ultrafiltration behavior of AAVs using different membrane molecular weight cut-off and operating conditions, showing that these factors can impact the flux and transmission of AAV. The study found that a 100 kDa ultrafiltration membrane can act as a completely retentive membrane or as significantly permeable to AAV serotypes depending on the operating conditions.
JOURNAL OF MEMBRANE SCIENCE
(2021)
Article
Clinical Neurology
Amanda L. Gross, Heather L. Gray-Edwards, Cassie N. Bebout, Nathan L. Ta, Kayly Nielsen, Brandon L. Brunson, Kalajan R. Lopez Mercado, Devin E. Osterhoudt, Ana Rita Batista, Stacy Maitland, Thomas N. Seyfried, Miguel Sena-Esteves, Douglas R. Martin
Summary: Researchers have found that intravenous administration of AAV9 vector can effectively treat GM1 gangliosidosis, increasing the lifespan of animals and improving their quality of life and neurological function. After treatment, neurological abnormalities were mild, CSF biomarkers were normalized, and urinary glycosaminoglycans decreased to normal levels.
Article
Cell Biology
Gijung Kwak, Olesia Gololobova, Neeraj Sharma, Colin Caine, Marina Mazur, Kathleen Mulka, Natalie E. West, George M. Solomon, Garry R. Cutting, Kenneth W. Witwer, Steven M. Rowe, Michael Paulaitis, George Aslanidi, Jung Soo Suk
Summary: Clinical implementation of inhaled gene therapy using adeno-associated virus (AAV) vector has been challenging due to difficulty in transducing lung airway cells. However, by combining AAV serotype 6 (AAV6) with extracellular vesicles (EVs), researchers have discovered a method that greatly enhances gene expression in respiratory cells, offering a safe and effective treatment strategy.
JOURNAL OF EXTRACELLULAR VESICLES
(2023)
Article
Virology
L. Patrick Havlik, Anshuman Das, Mario Mietzsch, Daniel K. Oh, Jonathan Ark, Robert McKenna, Mavis Agbandje-McKenna, Aravind Asokan
Summary: New AAV variants with enhanced cellular binding, uptake, and transduction have been evolved through infectious cycling, with one able to recognize sulfated glycosaminoglycans and another switching receptors from AAVR to integrin beta 1. The visualization of the AAVhum.8 capsid revealed a newly acquired integrin recognition motif, providing insights into designing viruses with improved attributes for gene therapy applications.
JOURNAL OF VIROLOGY
(2021)
Article
Virology
Sean M. Crosson, Antonette Bennett, Diego Fajardo, James J. Peterson, Hangning Zhang, Wei Li, Matthew T. Leahy, Colin K. Jennings, Ryan F. Boyd, Sanford L. Boye, Mavis Agbandje-McKenna, Shannon E. Boye
Summary: Rationally designed AAV2-based capsid variants with specific hydrophilic and hydrophobic amino acid mutations can significantly enhance retinal transduction, especially when considering the impact of these mutations on HSPG binding and vector tropism in a clinically relevant animal model.
JOURNAL OF VIROLOGY
(2021)
Article
Virology
Anshuman Das, Madhuvanthi Vijayan, Eric M. Walton, V. Grace Stafford, David N. Fiflis, Aravind Asokan
Summary: This study provides evidence that the double-stranded DNA binding protein NP220, in association with the human silencing hub (HUSH) complex, mediates transcriptional silencing of single-stranded as well as self-comple- mentary rAAV genomes. The AAV capsid appears to play an important role in NP220-mediated silencing of packaged genomes. Modulation of epigenetic pathways could potentially improve rAAV expression.
JOURNAL OF VIROLOGY
(2022)
Article
Pharmacology & Pharmacy
Yuechuan Xu, Bowen Jiang, Poulami Samai, Sven-Moller Tank, Mohammed Shameem, Dingjiang Liu
Summary: This study characterized the impact of freeze-thaw cycles on AAV8 and found that it resulted in an increase in free single-stranded DNA (ssDNA) leaked from AAV8. Next Generation Sequencing revealed that the leaked ssDNA primarily consisted of genome DNA. Similar behavior was observed in different serotypes of AAV. Furthermore, formulation screening showed that the addition of 10% sucrose and 0.1% poloxamer 188 could reduce ssDNA leakage in AAV samples after freeze-thaw cycles.
INTERNATIONAL JOURNAL OF PHARMACEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Faik N. Musayev, Francisco Zarate-Perez, Martino Bardelli, Clayton Bishop, Emil F. Saniev, R. Michael Linden, Els Henckaerts, Carlos R. Escalante
Article
Virology
Karl Petri, Richard Gabriel, Leticia Agundez, Raffaele Fronza, Saira Afzal, Christine Kaeppel, R. Michael Linden, Els Henckaerts, Manfred Schmidt
JOURNAL OF VIROLOGY
(2015)
Meeting Abstract
Oncology
K. Zaki, L. Agundez, B. Sanchez, M. Linden, E. Henckaerts, Y. Takeuchi, M. Collins
ANNALS OF ONCOLOGY
(2016)
Article
Virology
Martino Bardelli, Francisco Zarate-Perez, Leticia Agundez, R. Michael Linden, Carlos R. Escalante, Els Henckaerts
JOURNAL OF VIROLOGY
(2016)
Article
Clinical Neurology
Julie Tordo, Claire O'Leary, Andre S. L. M. Antunes, Nuria Palomar, Patrick Aldrin-Kirk, Mark Basche, Antonette Bennett, Zelpha D'Souza, Helene Gleitz, Annie Godwin, Rebecca J. Holley, Helen Parker, Ai Yin Liao, Paul Rouse, Amir Saam Youshani, Larbi Dridi, Carla Martins, Thierry Levade, Kevin B. Stacey, Daniel M. Davis, Adam Dyer, Nathalie Clement, Tomas Bjoerklund, Robin R. Ali, Mavis Agbandje-McKenna, Ahad A. Rahim, Alexey Pshezhetsky, Simon N. Waddington, R. Michael Linden, Brian W. Bigger, Els Henckaerts
Article
Biochemistry & Molecular Biology
Michael P. Hughes, Dave A. Smith, Lauren Morris, Claire Fletcher, Alexandria Colaco, Mylene Huebecker, Julie Tordo, Nuria Palomar, Giulia Massaro, Els Henckaerts, Simon N. Waddington, Frances M. Platt, Ahad A. Rahim
HUMAN MOLECULAR GENETICS
(2018)
Article
Multidisciplinary Sciences
Sarah Smith-Moore, Stuart J. D. Neil, Cornel Fraefel, R. Michael Linden, Mathieu Bollen, Helen M. Rowe, Els Henckaerts
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2018)
Article
Biochemistry & Molecular Biology
Ramin Raouf, Stephane Lolignier, Jane E. Sexton, Queensta Millet, Sonia Santana-Varela, Anna Biller, Alice M. Fuller, Vanessa Pereira, Jyoti S. Choudhary, Mark O. Collins, Stephen E. Moss, Richard Lewis, Julie Tordo, Els Henckaerts, Michael Linden, John N. Wood
Article
Biochemistry & Molecular Biology
Ramin Raouf, Stephane Lolignier, Jane E. Sexton, Queensta Millet, Sonia Santana-Varela, Anna Biller, Alice M. Fuller, Vanessa Pereira, Jyoti S. Choudhary, Mark O. Collins, Stephen E. Moss, Richard Lewis, Julie Tordo, Els Henckaerts, Michael Linden, John N. Wood
Article
Multidisciplinary Sciences
Leticia Agundez, Francisco Zarate-Perez, Anita F. Meier, Martino Bardelli, Matxalen Llosa, Carlos R. Escalante, R. Michael Linden, Els Henckaerts
Article
Biotechnology & Applied Microbiology
Anna L. Gray, Claire O'Leary, Aiyin Liao, Leticia Agundez, Amir S. Youshani, Helene F. Gleitz, Helen Parker, Jessica T. Taylor, Olivier Danos, Michael Hocquemiller, Nuria Palomar, R. Michael Linden, Els Henckaerts, Rebecca J. Holley, Brian W. Bigger
HUMAN GENE THERAPY
(2019)
Article
Clinical Neurology
Carl Rosenblad, Qin Li, Elsa Y. Pioli, Sandra Dovero, AndrE S. L. M. Antunes, Leticia AgUndez, Martino Bardelli, R. Michael Linden, Els Henckaerts, Anders BjOrklund, Erwan Bezard, Tomas BjOrklund
Article
Multidisciplinary Sciences
Rajvinder Karda, Ahad A. Rahim, Andrew M. S. Wong, Natalie Suff, Juan Antinao Diaz, Dany P. Perocheau, Maha Tijani, Joanne Ng, Julien Baruteau, Nuria Palomar Martin, Michael Hughes, Juliette M. K. M. Delhove, John R. Counsell, Jonathan D. Cooper, Els Henckaerts, Tristan R. Mckay, Suzanne M. K. Buckley, Simon N. Waddington
SCIENTIFIC REPORTS
(2020)
Article
Virology
Anita Felicitas Meier, Kurt Tobler, Kevin Michaelsen, Bernd Vogt, Els Henckaerts, Cornel Fraefel
Summary: The study shows that HSV-1 modulates AAV genome end recombination, potentially through mechanisms involving the ICP8 protein. Despite changes in the type of end recombination, no significant alteration in circular AAV genome abundance was observed.
JOURNAL OF VIROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Antonette Bennett, Joshua Hull, Nelly Jolinon, Julie Tordo, Katie Moss, Enswert Binns, Mario Mietzsch, Cathleen Hagemann, R. Michael Linden, Andrea Serio, Paul Chipman, Duncan Sousa, Felix Broecker, Peter Seeberger, Els Henckaerts, Robert McKenna, Mavis Agbandje-McKenna
Summary: AAV-TT, a variant of AAV2, shows higher neurotropism compared to wild type AAV2 and is currently being evaluated for central nervous system applications. It differs from AAV2 by 14 amino acids, including R585S and R588T, which have been shown to be essential for heparan sulfate binding of AAV2.
JOURNAL OF STRUCTURAL BIOLOGY
(2021)