Adeno Associated Virus Vector
Adeno-associated virus (AAV) vector is a small, non-pathogenic virus commonly used as a delivery system for gene therapy. It is capable of infecting both dividing and non-dividing cells, making it a valuable tool for introducing therapeutic genes into target cells. AAV vectors have shown promise in treating a wide range of genetic disorders and have become a popular choice for gene therapy applications.
4 Key excerpts on "Adeno Associated Virus Vector"
eBook - ePub- Rajesh V. Thakker, Michael P. Whyte, John Eisman, Takashi Igarashi(Authors)
- 2017(Publication Date)
- Academic Press(Publisher)
...particles. Science. 1965 ; 149 : 754 – 756. 20. Kotterman MA, Schaffer DV. Engineering adeno-associated viruses for clinical gene therapy. Nat Rev Genet. 2014 ; 15 : 445 – 451. 21. Büning H, Nicklin SA, Perabo L, Hallek M, Baker AH. AAV-based gene transfer. Curr Opin Mol Ther. 2003 ; 5 : 367 – 375. 22. Wu Z, Asokan A, Samulski RJ. Adeno-associated virus serotypes: vector toolkit for human gene. therapy. Mol Ther. 2006 ; 14 : 316 – 327. 23. Nakai H, Yant SR, Storm TA, Fuess S, Meuse L, Kay MA. Extrachromosomal recombinant adeno-associated virus vector genomes are primarily responsible for stable liver transduction in vivo. J Virol. 2001 ; 75 : 6969 – 6976. 24. Rosas LE, Grieves JL, Zaraspe K, La Perle KM, Fu H, McCarty DM. Patterns of scAAV vector insertion associated with oncogenic events in a mouse model for genotoxicity. Mol. Ther. 2012 ; 20 : 2098 – 2110. 25. Podsakoff G, Wong KK, Chatterjee S. Efficient gene transfer into nondividing cells by adeno-associated virus-based vectors. J Virol. 1994 ; 68 : 5656 – 5666. 26. Choi J-H, Yu N-K, Baek G-C, et al. Optimization of AAV expression cassettes to improve packaging capacity and transgene expression in neurons. Mol Brain. 2014 ; 7 : 17. 27. McCarty DM. Self-complementary AAV vectors; advances and applications. Mol. Ther. 2008 ; 16 : 1648 – 1656. 28. Escors D, Breckpot K. Lentiviral vectors in gene therapy: their current status and future potential. Arch Immunol Ther Exp (Warsz). 2010 ; 58 : 107 – 119. 29. Katz RA, Skalka AM. The retroviral enzymes. Annu Rev Biochem. 1994 ; 63 : 133 – 173. 30. Coil DA, Miller AD. Phosphatidylserine is not the cell surface receptor for vesicular stomatitis virus. J...
eBook - ePubTranslating Gene Therapy to the Clinic
Techniques and Approaches
- Jeffrey Laurence, Michael Franklin(Authors)
- 2014(Publication Date)
- Academic Press(Publisher)
...However, some of the limitations of the approach, not entirely identified in preclinical studies, became obvious in clinical studies. In particular, it is now clear that the host immune system represents one of the most important obstacles to be overcome in terms of both safety and efficacy of in vivo gene transfer with viral vectors, including AAV. This was well exemplified in a number of clinical studies, in which lack of efficacy, or short-lived transgene expression, were documented. 22 Over the past 10 years, gene therapists learned a lot about the complexity of immune responses triggered by in vivo gene transfer and, at least to some extent, how to modulate these responses. 6 Studies in humans have been the main source of this knowledge, mainly because experimental animal models failed to predict outcomes of AAV vector application in humans. 23 – 25 In this chapter, we will summarize the progress on the understanding of immune responses to the AAV vector capsid, with special attention to the clinical development of AAV-based therapeutics and possible strategies to overcome the limitations posed by the host immune system. 4.2. AAV Vectors Recombinant AAV vectors are engineered from a naturally occurring parvovirus, which was first isolated as a contaminant of an adenovirus preparation. 26 AAV are small (20–25 nm in diameter), non-enveloped viruses with a single-stranded DNA genome of ∼4.7 kilobases (Figure 4.1). They contain two sets of genes: the rep genes encoding a set of proteins required for replication, transcription control, and packaging; and the cap genes encoding the three capsid proteins (VP1, VP2, and VP3) and the assembly activating protein (AAP) (Figure 4.1)...
eBook - ePub- Phoebe Lostroh(Author)
- 2019(Publication Date)
- Garland Science(Publisher)
...The vector causes T cells to express a herpesvirus thymidine kinase gene (Figure 16.32). The gene is therapeutic because the herpesvirus thymidine kinase enzyme turns the pharmaceutical acyclovir into toxic metabolites that kill the cells expressing the herpesvirus thymidine kinase. If a patient transplanted with transformed cells and shows signs of GVHD, ganciclovir can be used to kill the problematic T cells. Figure 16.32 Cells transformed with the vector express herpesvirus thymidine kinase. Patients who receive bone marrow from a related but not identical donor can develop graft-versus-host disease (GVHD), caused by CD8 + T cells derived from the donated stem cells. To prevent GVHD, the donor cells are transformed ex vivo so that CD8 + T cells from the donor stem cells express herpesvirus thymidine kinase. After transplantation, the recipient is treated with acyclovir to kill CD8 + T cells from the donor, which would otherwise cause GVHD. An example of an approved gene therapy based on adeno-associated virus (AAV), a type of parvovirus, is alipogene tiparvovec. Adeno-associated viruses have ssDNA genomes and are called satellite viruses because they cannot replicate in the absence of co-infection with another virus such as adenovirus or herpesvirus (see Chapter 17). Instead, in the absence of co-infection, the host converts their small (< 5 kb) genomes into dsDNA that enters the nucleus and persists as an episome, where genes can be expressed but the genome cannot direct lytic reproduction without a helper virus. Gene therapy vectors derived from AAV are advantageous compared with retroviruses in that the DNA never inserts into a host chromosome, minimizing the risk of the therapy itself causing cancer. Alipogene tiparvovec treats familial lipoprotein lipase deficiency, a metabolic disorder that disrupts normal processing of fats and causes severe inflammation of the pancreas, leading to repeated hospitalizations and excruciating pain...
- Biaoru Li, Alan Larson, Shen Li(Authors)
- 2020(Publication Date)
- Bentham Science Publishers(Publisher)
...Because first clinical trials were initiated for children with severe combined immune deficiency (SCID) due to mutations in the adenosine deaminase (ADA) gene [ 8 ], the child has the concurrent treatment of ADA injections impairing the success of gene therapy, and thus, limit the technique development. After two decades' development, the “return of gene therapy” has considered a major scientific breakthrough since 2009 [ 9 ]. Typically, the concept of gene therapy includes ex vivo gene therapy, which is transferring the gene into cells that had been removed from the patient and in vivo gene therapy, which is directly infusing gene into the patient [ 10 ]. Clinically, ex vivo gene therapy with their techniques consist of viral vectors or non-viral process into hematopoietic stem cells (HSCs) and primary lymphocytes [ 11 ]. For transferring techniques of clinical application, viral delivery utilizes a viral vector such as AAVs, lentiviruses, and adenoviruses to encapsulate a gene, in RNA or DNA form, to facilitate efficient delivery [ 12 ]. Non-viral delivery includes physical methods (electroporation, micro-fluidic-based technologies), nanomaterial-based methods (cationic lipids, and cell-penetrating peptides), and self-assembled nanoparticle [ 13 ]. Although ex vivo transfection enables the use of physical methods that are not suitable very well for systemic application, viral vectors are commonly used to transfer genes into cells and tissue which have been achieved during the past decade. Now viral vector systems can provide useful tools to deliver genetic and genome-editing systems for both translational and clinical applications in vitro, ex vivo, and in vivo. Moreover, retroviral vectors, adenoviral vectors, and AAV vectors have been extensively studied in preclinical models, and thus, they have been tested in several clinical trials...
