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Current Opinion in Virology Dec 2016Viral replication by acquisition of the host cell biology represents a central part of a virus life cycle. Thereby, integration into the host genome constitutes a... (Review)
Review
Viral replication by acquisition of the host cell biology represents a central part of a virus life cycle. Thereby, integration into the host genome constitutes a successful strategy to ensure viral persistence and viruses have developed different mechanisms to integrate and benefit from cell's transcriptional and translational machinery. While lentiviral (e.g. HIV) integration is influenced by the chromatin landscape encountered upon nuclear entry, certain parvoviruses (e.g. AAV) integrate specifically within genomic regions bearing increasingly known sequence motifs. Gene therapy exploits these viral persistence strategies to achieve efficient and safe long-term transgene expression. Here we focus on two widely used vectors and their parental viruses, HIV and AAV, to discuss recent insights into lentiviral vector oncogenicity by alteration of endogenous transcripts as well as the unresolved AAV vectors genotoxic potential.
Topics: Animals; Carcinogenesis; DNA Damage; Dependovirus; Genetic Vectors; HIV; Host-Pathogen Interactions; Humans; Virus Integration
PubMed: 27474966
DOI: 10.1016/j.coviro.2016.07.004 -
Current Opinion in Virology Dec 2016In this review, a brief account of the historical perspective of the discovery of the first cellular receptor and co-receptor of the prototype adeno-associated virus... (Review)
Review
In this review, a brief account of the historical perspective of the discovery of the first cellular receptor and co-receptor of the prototype adeno-associated virus serotype 2 (AAV2) will be presented. The Subsequent discovery of a number of AAV serotypes, and attempts to identify the cellular receptors and co-receptors for these serotype vectors has had significant implications in their use in human gene therapy. As additional AAV serotypes are discovered and isolated, a detailed understanding of their tropism is certainly likely to play a key role in all future studies, both basic science as well as clinical.
Topics: Dependovirus; Genetic Vectors; Humans; Receptors, Virus; Viral Tropism; Virus Attachment; Virus Internalization
PubMed: 27596608
DOI: 10.1016/j.coviro.2016.08.003 -
Current Opinion in Virology Jun 2016Adeno-associated viruses (AAV) are currently at the forefront of human gene therapy clinical trials as recombinant vectors. Significant progress has been made in... (Review)
Review
Adeno-associated viruses (AAV) are currently at the forefront of human gene therapy clinical trials as recombinant vectors. Significant progress has been made in elucidating the structure, biology and tropisms of different naturally occurring AAV isolates in the past decade. In particular, a spectrum of AAV capsid interactions with host receptors have been identified and characterized. These studies have enabled a better understanding of key determinants of AAV cell recognition and entry in different hosts. This knowledge is now being applied toward engineering new, lab-derived AAV capsids with favorable transduction profiles. The current review conveys a structural perspective of capsid-glycan interactions and provides a roadmap for generating synthetic strains by engineering AAV receptor footprints.
Topics: Capsid; Capsid Proteins; Dependovirus; Genetic Engineering; Genetic Therapy; Genetic Vectors; Host-Pathogen Interactions; Humans; Polysaccharides; Receptors, Virus
PubMed: 27262111
DOI: 10.1016/j.coviro.2016.05.001 -
Biotechnology Journal Mar 2017Manufacturing practices for recombinant adeno-associated viruses (AAV) have improved in the last decade through the development of new platforms in conjunction with... (Review)
Review
Manufacturing practices for recombinant adeno-associated viruses (AAV) have improved in the last decade through the development of new platforms in conjunction with better production and purification methods. In this review, we discuss the advantages and limitations of the most popular systems and methods employed with mammalian cell platforms. Methods and systems such as transient transfection, packaging and producer cells and adenovirus and herpes simplex virus are described. In terms of best production yields, they are comparable with about 10 -10 vector genomes produced per cell but transient transfection of HEK293 cells is by far the most commonly used. For small-scale productions, AAV can be directly purified from the producing cell lysate by ultracentrifugation on a CsCl or iodixanol-step gradient whereas large-scale purification requires a combination of multiple steps. Micro/macrofiltration (i.e. including tangential flow filtration and/or dead-end filtration) and chromatography based-methods are used for large-scale purification. Purified AAV products must then be quantified and characterized to ensure quality. Recent purification methods and current analytical techniques are reviewed here. Finally, AAV technology is very promising, but manufacturing improvements are still required to meet the needs of affordable, safe and effective AAV vectors essential for licensing of gene therapy clinical protocols.
Topics: Dependovirus; Genetic Therapy; Genetic Vectors; HEK293 Cells; Humans; Transfection; Virus Cultivation
PubMed: 28177193
DOI: 10.1002/biot.201600193 -
Cell Sep 2021Directed evolution of AAV capsids has been a successful strategy for generating bespoke serotypes to target gene therapies more specifically to the intended tissue. This...
Directed evolution of AAV capsids has been a successful strategy for generating bespoke serotypes to target gene therapies more specifically to the intended tissue. This has now been achieved for the largest organ, skeletal muscle, by selecting for an RGD containing integrin binding heptamer in a hypervariable region of the capsid of AAV9.
Topics: Capsid; Capsid Proteins; Dependovirus; Genetic Vectors; Muscle, Skeletal
PubMed: 34534462
DOI: 10.1016/j.cell.2021.08.031 -
BioEssays : News and Reviews in... Sep 2022Cellular 3D structures, for example, organoids, are an excellent model for studying and developing treatments for various diseases, including hereditary ones. Therefore,... (Review)
Review
Cellular 3D structures, for example, organoids, are an excellent model for studying and developing treatments for various diseases, including hereditary ones. Therefore, they are increasingly being used in biomedical research. From the point of view of safety and efficacy, recombinant adeno-associated viral (rAAV) vectors are currently most in demand for the delivery of various transgenes for gene replacement therapy or other applications. The delivery of transgenes using rAAV vectors to various types of organoids is an urgent task, however, it is associated with a number of problems that are discussed in this review. Cellular heterogeneity and specifics of cultivation of 3D structures determine the complexity of rAAV delivery and are sometimes associated with low transduction efficiency. This review surveys the main ways to solve emerging problems and increase the efficiency of transgene delivery using rAAVs to organoids. A clear understanding of the stage of development of the organoid, its cellular composition and the presence of surface receptors will allow obtaining high levels of organoid transduction with existing rAAV vectors.
Topics: Dependovirus; Genetic Vectors; Organoids; Transduction, Genetic; Transgenes
PubMed: 35832008
DOI: 10.1002/bies.202200055 -
Microbiology Spectrum Aug 2015In the nearly five decades since its accidental discovery, adeno-associated virus (AAV) has emerged as a highly versatile vector system for both research and clinical... (Review)
Review
In the nearly five decades since its accidental discovery, adeno-associated virus (AAV) has emerged as a highly versatile vector system for both research and clinical applications. A broad range of natural serotypes, as well as an increasing number of capsid variants, has combined to produce a repertoire of vectors with different tissue tropisms, immunogenic profiles and transduction efficiencies. The story of AAV is one of continued progress and surprising discoveries in a viral system that, at first glance, is deceptively simple. This apparent simplicity has enabled the advancement of AAV into the clinic, where despite some challenges it has provided hope for patients and a promising new tool for physicians. Although a great deal of work remains to be done, both in studying the basic biology of AAV and in optimizing its clinical application, AAV vectors are currently the safest and most efficient platform for gene transfer in mammalian cells.
Topics: Animals; Dependovirus; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Mammals
PubMed: 26350320
DOI: 10.1128/microbiolspec.MDNA3-0052-2014 -
CPT: Pharmacometrics & Systems... Apr 2021As part of the US Food and Drug Administration (FDA)'s Prescription Drug User Fee Act (PDUFA) VI commitments, the Center for Biologics Evaluation and Research (CBER) and... (Review)
Review
As part of the US Food and Drug Administration (FDA)'s Prescription Drug User Fee Act (PDUFA) VI commitments, the Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) are conducting a model-informed drug development (MIDD) pilot program. Sponsor(s) who apply and are selected will be granted meetings that aim to facilitate the application of MIDD approaches throughout the product development lifecycle and the regulatory process. Due to their complex mechanisms of action and limited clinical experience, cell and gene therapies have the potential to benefit from the application of MIDD methods, which may facilitate their safety and efficacy evaluations. Leveraging data that are generated from all stages of drug development into appropriate modeling and simulation techniques that inform decisions remains challenging. Additional discussions regarding the application of quantitative modeling approaches to drug development decisions, such as through the MIDD pilot program, may be crucial for both the sponsor(s) and regulatory review teams. Here, we share some perspectives on the opportunities and challenges for utilizing MIDD approaches for product review, which we hope will encourage investigators to publish their experiences and application of MIDD in gene therapy product development.
Topics: Computer Simulation; Dependovirus; Drug Development; Genetic Therapy; Humans; Immunotherapy, Adoptive; Models, Biological; Oncolytic Virotherapy; Pharmacokinetics; Research Design; Safety; Technology Assessment, Biomedical; Treatment Outcome
PubMed: 33608998
DOI: 10.1002/psp4.12597 -
Gene Therapy Aug 2019Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the deterioration of alpha motor neurons in the brainstem and spinal... (Review)
Review
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is characterized by the deterioration of alpha motor neurons in the brainstem and spinal cord. Currently, there is no cure for SMA, which calls for an urgent need to explore affordable and effective therapies and to maximize patients' independence and quality of life. Adeno-associated virus (AAV) vector, one of the most promising and well-investigated vehicles for delivering transgenes, is a compelling candidate for gene therapy. Some of the hallmarks of AAVs are their nonpathogenicity, inability to incur an immune response, potential to achieve robust transgene expression, and varied tropism for several tissues of the body. Recently, these features were harnessed in a clinical trial conducted by AveXis in SMA patients, where AAV9 was employed as a vehicle for one-time administration of the SMN gene, the causative gene in SMA. The trial demonstrated remarkable improvements in motor milestones and rates of survival in the patients. This review focuses on the advent of SMA gene therapy and summarizes different preclinical studies that were conducted leading up to the AAV9-SMA trial in SMA patients.
Topics: Animals; Dependovirus; Genetic Therapy; Humans; Muscular Atrophy, Spinal; Survival of Motor Neuron 1 Protein
PubMed: 31243392
DOI: 10.1038/s41434-019-0085-4 -
Current Opinion in Virology Dec 2016Recombinant adeno-associated viral vectors (rAAV) are regarded as promising vehicles for therapeutic gene delivery. Continued development and new strategies are... (Review)
Review
Recombinant adeno-associated viral vectors (rAAV) are regarded as promising vehicles for therapeutic gene delivery. Continued development and new strategies are essential to improve the potency of AAV vectors and reduce the effective dose needed for clinical efficacy. In this regard, many studies have focused on understanding the cellular transduction mechanisms of rAAV, often with the goal of exploiting this knowledge to increase gene transfer efficiency. Here, we provide an overview of our evolving understanding of rAAV cellular trafficking pathways through the host cell, beginning with cellular entry and ending with transcription of the vector genome. Strategies to exploit this information for improving rAAV transduction are discussed.
Topics: Dependovirus; Drug Delivery Systems; Genetic Therapy; Genetic Vectors; Humans; Transduction, Genetic
PubMed: 27544821
DOI: 10.1016/j.coviro.2016.08.001