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)
Review
Ophthalmology
Kirsten Bucher, Eduardo Rodriguez-Bocanegra, Daniyar Dauletbekov, M. Dominik Fischer
Summary: Recombinant adeno-associated virus (AAV) is a leading vector for gene therapy in the retina, efficiently transducing retinal cells but also causing intraocular inflammation and immune responses. The eye, being an immune-privileged site, may mitigate these responses, but further research is needed to understand influencing factors.
PROGRESS IN RETINAL AND EYE RESEARCH
(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.
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)
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)
Review
Pharmacology & Pharmacy
Boris Gorovits, Mitra Azadeh, George Buchlis, Michele Fiscella, Travis Harrison, Mike Havert, Sylvia Janetzki, Vibha Jawa, Brian Long, Yolanda D. Mahnke, Andrew McDermott, Mark Milton, Robert Nelson, Christian Vettermann, Bonnie Wu
Summary: The number of approved or investigational late phase viral vector gene therapies (GTx) is increasing rapidly, with adeno-associated virus vector (AAV) technology being the most commonly used platform. Pre-existing anti-AAV immunity has been established and is considered a potential barrier for successful AAV transduction, potentially impacting clinical efficacy and adverse events. This manuscript provides recommendations and guidance for the assessment of anti-AAV cellular immune response, including correlations with humoral responses, the value of cellular immunogenicity assessment, and critical parameters for monitoring assay performance.
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
Biotechnology & Applied Microbiology
Suyash Prasad, David P. Dimmock, Benjamin Greenberg, Jagdeep S. Walia, Chanchal Sadhu, Fatemeh Tavakkoli, Gerald S. Lipshutz
Summary: Adeno-associated viruses (AAVs) used in gene therapy can trigger immune responses that hinder the effectiveness of the therapy. Various immunomodulatory strategies have been used to minimize these responses and enhance the duration of gene therapy.
HUMAN GENE THERAPY
(2022)
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)
Review
Pharmacology & Pharmacy
Boris Gorovits, Mitra Azadeh, George Buchlis, Travis Harrison, Mike Havert, Vibha Jawa, Brian Long, Jim McNally, Mark Milton, Robert Nelson, Mark O'Dell, Karen Richards, Christian Vettermann, Bonnie Wu
Summary: This manuscript discusses the impact of anti-AAV antibodies in viral vector-based gene therapies and the methods for detecting these antibodies, providing recommendations and guidance for industry sponsors, academic laboratories, and regulatory agencies.
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)