Adenovirus Vector
Adenovirus vectors are genetically engineered viruses that are used as delivery vehicles for gene therapy and vaccine development. They are modified to be safe and non-replicating, allowing them to efficiently deliver genetic material into target cells. Adenovirus vectors have shown promise in various medical applications due to their ability to induce strong immune responses and deliver therapeutic genes.
4 Key excerpts on "Adenovirus Vector"
eBook - ePub- Phoebe Lostroh(Author)
- 2019(Publication Date)
- Garland Science(Publisher)
...(B) In first-generation adenovirus gene therapy vectors such as the one used in the Phase I trial that killed Jesse Gelsinger, the therapeutic transgene replaced the E1 region of the viral genome. Despite its early failures, research into gene therapy remains popular. The most common gene therapy vectors in development today are modified adenoviruses (dsDNA Class I; see Figure 16.25), parvoviruses (ssDNA Class II), or retroviruses (Class IV) (Figure 16.26). Although adenoviruses and parvoviruses can infect both dividing and nondividing cells, the most common retroviral vectors in use only infect dividing cells. The lentivirus group of retroviruses, to which HIV belongs, can infect nondividing cells, and lentiviral vectors are therefore increasingly popular. Although all three deliver packaged DNA into the nucleus during the final stages of uncoating, neither adenovirus nor parvovirus genomes recombine with host chromosomes, leading to loss of viral DNA when the cells proliferate. The integrated proviral DNA from a retrovirus is instead maintained for the lifetime of the host cell and so provides the longest lasting expression of the therapeutic gene. Insertion of proviral DNA can also cause cancer, however, and so carries risks (see Chapter 13). Figure 16.26 Genomes of a parvovirus and retrovirus. Adenoviruses (see Figure 16.25), parvoviruses, and retroviruses are the most common vectors in development as gene therapy agents. (A) Adeno-associated virus-2 is an example of a parvovirus. Its single-stranded genome is about 4.6 kbp long and encodes four nonstructural proteins and three capsomeres. (B) A lentivirus is an example of a retrovirus. Its RNA genome is converted into proviral DNA, which is about 9.2 kbp long. Gag and Env encode structural proteins such as the capsomeres and transmembrane spikes. Pol encodes enzymes such as the reverse transcriptase, protease, and integrase...
eBook - ePubTranslating Gene Therapy to the Clinic
Techniques and Approaches
- Jeffrey Laurence, Michael Franklin, 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- Rajesh V. Thakker, Michael P. Whyte, John Eisman, Takashi Igarashi, 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 - ePub- Dongyou Liu, Dongyou Liu(Authors)
- 2018(Publication Date)
- CRC Press(Publisher)
...The emergence of new HAdV types of species D during the AIDS epidemic suggests a role for persistence of viruses under impaired immunity. 4 Adenoviruses are nonenveloped double-stranded DNA viruses ranging in size from 70 to 90 nm in diameter. The virion is composed of a complex proteic capsid, formed by 252 capsomeres, and a nucleoprotein core that contains the viral genome. The capsid is icosahedral and consists of 240 trimeric hexons, and 12 pentameric pentons on the vertices (Figure 2.1). 6 From each vertex, a long fiber extends, whose length varies among the different serotypes. 7 The fiber has three distinct regions: tail, shaft, and knob. The tail domain is the binding site for the penton base; the shaft is essential for virus entry via the CAR-integrin pathway; and the knob domain binds the virus to the primary host cell receptor. 8, 9 HAdV-40 and HAdV-41 have unique structural features compared to other human adenoviruses, since the virions contain two different fibers (long and short) that are encoded by separate genes. 10, 11 Hexons are the main building block of the AdV capsid and have a role in tropism determination, receptor binding, and entry. 12 The size of the hexon molecule can vary among different serotypes; the largest described is from HAdV2 and comprises of 967 aa. 13 Up to nine hypervariable regions are present in each hexon molecule...
