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)
Article
Immunology
Chenjuan Shi, Li Tian, Wenwen Zheng, Yelei Zhu, Peilu Sun, Lele Liu, Wenkai Liu, Yanyan Song, Xianzhu Xia, Xianghong Xue, Xuexing Zheng
Summary: The study found that AAV9-RABVG is a single-dose vaccine candidate that can induce robust, long-term humoral responses and Th1 and Th2 cell-mediated immune responses in mice and non-human primates.
EMERGING MICROBES & INFECTIONS
(2022)
Article
Biotechnology & Applied Microbiology
Sandeep R. P. Kumar, Dongsheng Duan, Roland W. W. Herzog
Summary: Muscle-directed gene therapy using AAV vectors is promising for treating neuromuscular disorders. However, there are concerns about immune responses against the vector or transgene products. This review discusses clinical observations and future prospects for addressing these issues through vector engineering and immune modulation.
HUMAN GENE THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Lisa Strasser, Stefano Boi, Felipe Guapo, Nicholas Donohue, Niall Barron, Alana Rainbow-Fletcher, Jonathan Bones
Summary: AAV vectors are crucial for gene therapy, but manufacturing remains a challenge. This study investigated the host cell proteome of AAV5-producing cells, uncovering differential expression of proteins related to cellular metabolism, proliferation, cell death, as well as endocytosis and lysosomal degradation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
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
Cell & Tissue Engineering
Joanna Szumska, Dirk Grimm
Summary: Adeno-associated virus (AAV) has become a versatile and exciting tool for gene therapy due to its naturally occurring capsid variants and amenability to molecular evolution. Recent advancements in technologies such as barcoding and high-throughput screening, transduction-competent AAV vector selection, expression-competent AAV variant enrichment, and high-resolution stratification of AAV capsid libraries hold exceptional potential for advancing directed AAV capsid evolution, ultimately accelerating the AAV vector revolution. These innovative techniques, along with other emerging strategies like rational design and machine learning, can greatly contribute to the advancement of AAV research and development.
Review
Biochemistry & Molecular Biology
Nancy L. Meyer, Michael S. Chapman
Summary: Adeno-associated virus (AAV) is a leading vector for gene therapy of inherited diseases. The interactions between virus and host cells are complex and serotype-specific. Cryogenic electron microscopy (cryo-EM) provides a way to understand the structural details of virus-host complexes and uncover the steps of viral entry. Comparisons with antibody complexes also provide insights for improving immune neutralization.
TRENDS IN MICROBIOLOGY
(2022)
Review
Immunology
Kleopatra Rapti, Dirk Grimm
Summary: Adeno-associated viruses (AAV) have become the leading vector in gene therapy due to their sustained and robust transgene expression, but recent safety concerns have raised caution. Issues such as pre-existing anti-AAV antibodies and cellular immune responses in the human population continue to be a challenge for AAV gene therapies.
FRONTIERS IN IMMUNOLOGY
(2021)
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
Biochemistry & Molecular Biology
Jalish M. Riyad, Thomas Weber
Summary: Recombinant adeno-associated virus has become the most popular gene therapy vector in the last two decades, with higher doses increasing the risk of adverse events. FDA has recently approved AAV gene therapy for two rare genetic disorders, highlighting the need for better vectors to achieve therapeutic levels with lower doses. The review discusses cellular roadblocks that AAV must overcome and recent advancements in AAV biology that can improve vector performance for safer gene therapy.
Review
Immunology
Hildegund C. J. Ertl
Summary: Adeno-associated virus (AAV)-mediated gene transfer has shown benefits in treating patients with inherited diseases like hemophilia B, but challenges remain due to potential rejection of AAV-transduced cells. Immunosuppression may prevent rejection in some patients. CD8(+) T cells induced by AAV infections may recognize AAV vector's capsids and eliminate cells expressing degraded capsid antigens, or AAV vectors themselves may induce de novo T cell responses, particularly at high doses. This chapter discusses strategies to prevent activation of CD8(+) T cell responses to AAV infections and gene transfer.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Oncology
Xin Xu, Wenli Chen, Wenjun Zhu, Jing Chen, Bin Ma, Jianxia Ding, Zaichuan Wang, Yifei Li, Yeming Wang, Xiaochun Zhang
Summary: Glioblastoma (GBM) is a common and malignant brain tumor with poor prognosis. Adeno-associated virus (AAV)-mediated gene therapy shows promise as a new treatment approach for GBM, with ongoing experimental trials and research on different injection methods.
CANCER CELL INTERNATIONAL
(2021)
Review
Medicine, Research & Experimental
Darnel Prakoso, Mitchel Tate, Miles J. De Blasio, Rebecca H. Ritchie
Summary: Diabetes increases the prevalence of heart failure by 6-8-fold, independent of other comorbidities, such as hypertension and coronary artery disease, leading to a condition known as diabetic cardiomyopathy. Current pharmacological treatments can delay disease progression, but gene therapy using adeno-associated viral vectors (AAV) is being explored as a potential lifelong cure for diabetic cardiomyopathy.
Article
Immunology
Corinne J. J. Smith, Nikki Ross, Ali Kamal, Kevin Y. Kim, Elizabeth Kropf, Pascal Deschatelets, Cedric Francois, William J. Quinn, Inderpal Singh, Anna Majowicz, Federico Mingozzi, Klaudia Kuranda
Summary: AAV gene transfer shows promise in treating genetic diseases, but the host immune response poses challenges. This study characterizes the innate immune response to AAV in human whole blood, finding that high levels of neutralizing antibodies can increase inflammation and vector uptake. Inhibiting the complement pathway may be a strategy for reducing immunogenicity in AAV-based therapies.
FRONTIERS IN IMMUNOLOGY
(2022)