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Nature Reviews. Drug Discovery May 2019Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing... (Review)
Review
Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.
Topics: Animals; Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans
PubMed: 30710128
DOI: 10.1038/s41573-019-0012-9 -
Cells Mar 2023Despite scientific discoveries in the field of gene and cell therapy, some diseases still have no effective treatment. Advances in genetic engineering methods have... (Review)
Review
Despite scientific discoveries in the field of gene and cell therapy, some diseases still have no effective treatment. Advances in genetic engineering methods have enabled the development of effective gene therapy methods for various diseases based on adeno-associated viruses (AAVs). Today, many AAV-based gene therapy medications are being investigated in preclinical and clinical trials, and new ones are appearing on the market. In this article, we present a review of AAV discovery, properties, different serotypes, and tropism, and a following detailed explanation of their uses in gene therapy for disease of different organs and systems.
Topics: Serogroup; Genetic Vectors; Genetic Therapy; Genetic Engineering; Tropism; Dependovirus
PubMed: 36899921
DOI: 10.3390/cells12050785 -
BioDrugs : Clinical Immunotherapeutics,... Aug 2017There has been a resurgence in gene therapy efforts that is partly fueled by the identification and understanding of new gene delivery vectors. Adeno-associated virus... (Review)
Review
There has been a resurgence in gene therapy efforts that is partly fueled by the identification and understanding of new gene delivery vectors. Adeno-associated virus (AAV) is a non-enveloped virus that can be engineered to deliver DNA to target cells, and has attracted a significant amount of attention in the field, especially in clinical-stage experimental therapeutic strategies. The ability to generate recombinant AAV particles lacking any viral genes and containing DNA sequences of interest for various therapeutic applications has thus far proven to be one of the safest strategies for gene therapies. This review will provide an overview of some important factors to consider in the use of AAV as a vector for gene therapy.
Topics: Animals; Capsid; Cell Line; Dependovirus; Drug Delivery Systems; Genetic Therapy; Genetic Vectors; Humans; Insecta; Transfection
PubMed: 28669112
DOI: 10.1007/s40259-017-0234-5 -
Annual Review of Neuroscience Jul 2022Recombinant adeno-associated viruses (AAVs) are commonly used gene delivery vehicles for neuroscience research. They have two engineerable features: the capsid (outer... (Review)
Review
Recombinant adeno-associated viruses (AAVs) are commonly used gene delivery vehicles for neuroscience research. They have two engineerable features: the capsid (outer protein shell) and cargo (encapsulated genome). These features can be modified to enhance cell type or tissue tropism and control transgene expression, respectively. Several engineered AAV capsids with unique tropisms have been identified, including variants with enhanced central nervous system transduction, cell type specificity, and retrograde transport in neurons. Pairing these AAVs with modern gene regulatory elements and state-of-the-art reporter, sensor, and effector cargo enables highly specific transgene expression for anatomical and functional analyses of brain cells and circuits. Here, we discuss recent advances that provide a comprehensive (capsid and cargo) AAV toolkit for genetic access to molecularly defined brain cell types.
Topics: Brain; Capsid; Dependovirus; Gene Transfer Techniques; Genetic Vectors
PubMed: 35440143
DOI: 10.1146/annurev-neuro-111020-100834 -
Trends in Microbiology May 2022Adeno-associated virus (AAV) is the leading vector in emerging treatments of inherited diseases. Higher transduction efficiencies and cellular specificity are required... (Review)
Review
Adeno-associated virus (AAV) is the leading vector in emerging treatments of inherited diseases. Higher transduction efficiencies and cellular specificity are required for broader clinical application, motivating investigations of virus-host molecular interactions during cell entry. High-throughput methods are identifying host proteins more comprehensively, with subsequent molecular studies revealing unanticipated complexity and serotype specificity. Cryogenic electron microscopy (cryo-EM) provides a path towards structural details of these sometimes heterogeneous virus-host complexes, and is poised to illuminate more fully the steps in entry. Here presented, is progress in understanding the distinct steps of glycan attachment, and receptor-mediated entry/trafficking. Comparison with structures of antibody complexes provides new insights on immune neutralization with implications for the design of improved gene therapy vectors.
Topics: Dependovirus; Genetic Vectors; Polysaccharides; Receptors, Cell Surface; Serogroup; Virus Internalization
PubMed: 34711462
DOI: 10.1016/j.tim.2021.09.005 -
Viruses Jun 2020The adeno-associated virus (AAV) is a small, nonpathogenic parvovirus, which depends on helper factors to replicate. Those helper factors can be provided by coinfecting... (Review)
Review
The adeno-associated virus (AAV) is a small, nonpathogenic parvovirus, which depends on helper factors to replicate. Those helper factors can be provided by coinfecting helper viruses such as adenoviruses, herpesviruses, or papillomaviruses. We review the basic biology of AAV and its most-studied helper viruses, adenovirus type 5 (AdV5) and herpes simplex virus type 1 (HSV-1). We further outline the direct and indirect interactions of AAV with those and additional helper viruses.
Topics: Adenoviridae; Coinfection; Dependovirus; Helper Viruses; Herpesvirus 1, Human; Humans; Parvoviridae Infections; Viral Proteins; Virus Replication
PubMed: 32575422
DOI: 10.3390/v12060662 -
Journal of Pharmaceutical Sciences Jul 2021Adeno-associated virus (AAV) has emerged as a leading platform for gene delivery for treating various diseases due to its excellent safety profile and efficient... (Review)
Review
Adeno-associated virus (AAV) has emerged as a leading platform for gene delivery for treating various diseases due to its excellent safety profile and efficient transduction to various target tissues. However, the large-scale production and long-term storage of viral vectors is not efficient resulting in lower yields, moderate purity, and shorter shelf-life compared to recombinant protein therapeutics. This review provides a comprehensive analysis of upstream, downstream and formulation unit operation challenges encountered during AAV vector manufacturing, and discusses how desired product quality attributes can be maintained throughout product shelf-life by understanding the degradation mechanisms and formulation strategies. The mechanisms of various physical and chemical instabilities that the viral vector may encounter during its production and shelf-life because of various stressed conditions such as thermal, shear, freeze-thaw, and light exposure are highlighted. The role of buffer, pH, excipients, and impurities on the stability of viral vectors is also discussed. As such, the aim of this review is to outline the tools and a potential roadmap for improving the quality of AAV-based drug products by stressing the need for a mechanistic understanding of the involved processes.
Topics: Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors
PubMed: 33812887
DOI: 10.1016/j.xphs.2021.03.024 -
BioDrugs : Clinical Immunotherapeutics,... May 2023Recombinant adeno-associated viruses (AAVs) have emerged as promising gene delivery vehicles resulting in three US Food and Drug Administration (FDA) and one European... (Review)
Review
Recombinant adeno-associated viruses (AAVs) have emerged as promising gene delivery vehicles resulting in three US Food and Drug Administration (FDA) and one European Medicines Agency (EMA)-approved AAV-based gene therapies. Despite being a leading platform for therapeutic gene transfer in several clinical trials, host immune responses against the AAV vector and transgene have hampered their widespread application. Multiple factors, including vector design, dose, and route of administration, contribute to the overall immunogenicity of AAVs. The immune responses against the AAV capsid and transgene involve an initial innate sensing. The innate immune response subsequently triggers an adaptive immune response to elicit a robust and specific response against the AAV vector. AAV gene therapy clinical trials and preclinical studies provide important information about the immune-mediated toxicities associated with AAV, yet studies suggest preclinical models fail to precisely predict the outcome of gene delivery in humans. This review discusses the contribution of the innate and adaptive immune response against AAVs, highlighting the challenges and potential strategies to mitigate these responses, thereby enhancing the therapeutic potential of AAV gene therapy.
Topics: Humans; Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Immunity, Innate
PubMed: 36862289
DOI: 10.1007/s40259-023-00585-7 -
Trends in Biotechnology Oct 2023Accelerating the scale up of adeno-associated virus (AAV) manufacture is highly desirable to meet the increased demand for gene therapies. However, the development of... (Review)
Review
Accelerating the scale up of adeno-associated virus (AAV) manufacture is highly desirable to meet the increased demand for gene therapies. However, the development of bioprocesses for AAV gene therapies remains time-consuming and challenging. The quality by design (QbD) approach ensures bioprocess designs that meet the desired product quality and safety profile. Rapid stress tests, developability screens, and scale-down technologies have the potential to streamline AAV product and manufacturing bioprocess development within the QbD framework. Here we review how their successful use for antibody manufacture development is translating to AAV, but also how this will depend critically on improved analytical methods and adaptation of the tools as more understanding is gained on the critical attributes of AAV required for successful therapy.
Topics: Dependovirus; Genetic Therapy; Commerce; Quality Control; Genetic Vectors
PubMed: 37127491
DOI: 10.1016/j.tibtech.2023.04.002 -
Cell Apr 2020The development of clustered regularly interspaced short-palindromic repeat (CRISPR)-based biotechnologies has revolutionized the life sciences and introduced new... (Review)
Review
The development of clustered regularly interspaced short-palindromic repeat (CRISPR)-based biotechnologies has revolutionized the life sciences and introduced new therapeutic modalities with the potential to treat a wide range of diseases. Here, we describe CRISPR-based strategies to improve human health, with an emphasis on the delivery of CRISPR therapeutics directly into the human body using adeno-associated virus (AAV) vectors. We also discuss challenges facing broad deployment of CRISPR-based therapeutics and highlight areas where continued discovery and technological development can further advance these revolutionary new treatments.
Topics: Animals; CRISPR-Cas Systems; Dependovirus; Gene Editing; Genetic Therapy; Genetic Vectors; Humans
PubMed: 32243786
DOI: 10.1016/j.cell.2020.03.023