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Nature Reviews. Genetics Apr 2020Adeno-associated virus (AAV) vector-mediated gene delivery was recently approved for the treatment of inherited blindness and spinal muscular atrophy, and long-term... (Review)
Review
Adeno-associated virus (AAV) vector-mediated gene delivery was recently approved for the treatment of inherited blindness and spinal muscular atrophy, and long-term therapeutic effects have been achieved for other rare diseases, including haemophilia and Duchenne muscular dystrophy. However, current research indicates that the genetic modification of AAV vectors may further facilitate the success of AAV gene therapy. Vector engineering can increase AAV transduction efficiency (by optimizing the transgene cassette), vector tropism (using capsid engineering) and the ability of the capsid and transgene to avoid the host immune response (by genetically modifying these components), as well as optimize the large-scale production of AAV.
Topics: Adaptive Immunity; Dependovirus; Genetic Engineering; Genetic Therapy; Genetic Vectors; Immunity, Innate
PubMed: 32042148
DOI: 10.1038/s41576-019-0205-4 -
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 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 -
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 -
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 -
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 -
European Journal of Pharmaceutics and... Sep 2023Gene therapies offer promising therapeutic alternatives for many disorders that currently lack efficient treatment options. Due to their chemical nature and... (Review)
Review
Gene therapies offer promising therapeutic alternatives for many disorders that currently lack efficient treatment options. Due to their chemical nature and physico-chemical properties, delivery of polynucleic acids into target cells and subcellular compartments remains a significant challenge. Adeno-associated viruses (AAV) have gained a lot of interest for the efficient delivery of therapeutic single-stranded DNA (ssDNA) genomes over the past decades. More than a hundred products have been tested in clinical settings and three products have received market authorization by the US FDA in recent years. A lot of effort is being made to generate potent recombinant AAV (rAAV) vectors that show favorable safety and immunogenicity profiles for either local or systemic administration. Manufacturing processes are gradually being optimized to deliver a consistently high product quality and to serve potential market needs beyond rare indications. In contrast to protein therapeutics, most rAAV products are still supplied as frozen liquids within rather simple formulation buffers to enable sufficient product shelf life, significantly hampering global distribution and access. In this review, we aim to outline the hurdles of rAAV drug product development and discuss critical formulation and composition aspects of rAAV products under clinical evaluation. Further, we highlight recent development efforts in order to achieve stable liquid or lyophilized products. This review therefore provides a comprehensive overview on current state-of-the-art rAAV formulations and can further serve as a map for rational formulation development activities in the future.
Topics: Dependovirus; Genetic Vectors; Genetic Therapy
PubMed: 37423416
DOI: 10.1016/j.ejpb.2023.07.002 -
Biotechnology Journal Jan 2021For adeno-associated virus (AAV)-based human gene therapy, challenges for the translation of promising research results to successful clinical development include... (Review)
Review
For adeno-associated virus (AAV)-based human gene therapy, challenges for the translation of promising research results to successful clinical development include optimization of vector design and manufacturing processes to ensure that vectors prepared for administration to human subjects have attributes consistent with safe and durable expression. This article briefly reviews quality control methods for routine testing and supplemental characterization of AAV vectors for investigational product development. The relationship of vector and manufacturing process design with product critical quality attributes is discussed.
Topics: Dependovirus; Genetic Therapy; Genetic Vectors; Humans; Quality Control
PubMed: 33146911
DOI: 10.1002/biot.202000022