Chapter 16 : Gene Therapy and Viruses

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Gene therapy is an emerging medical approach which seeks to apply molecular techniques to attack diseases at the fundamental level of the genes. The first techniques which were developed for genetic manipulation of mammalian cells involved direct introduction of genes in the forms of expression plasmids by physical methods. However, other gene therapy applications require stable persistence of the transferred gene in the target cells, so that the gene will be retained with each cell division and inherited by all progeny cells. The viruses which have been adapted and most widely studied for gene transfer include retroviruses, adenovirus (Ad), adeno-associated virus (AAV), herpesviruses, and, most recently, lentiviruses. Importantly, lentiviral vectors tolerate complex genetic elements better than retroviral vectors, possibly aided by the Rev/Rev response element-mediated mechanism for nuclear-to-cytoplasmic export of HIV-1 transcripts. Complement fixation (CF) appeared to be an attractive target for gene therapy, and extensive preclinical studies of the safety and toxicity of an AAV-CF transmembrane regulator (CFTR) vector were performed by delivery of vector particles directly to the lungs in rabbits and nonhuman primates. Importantly, sperm is generally negative for vector sequences, which diminishes the likelihood of modifying germ line cells. The use of viruses with improved initial intratumoral distribution and carrying genes that both overcome innate immune responses and promote an intra-cellular proapoptotic state should improve the potency of herpes simplex virus (HSV) cancer gene therapy vectors without compromising safety.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16

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Equine infectious anemia virus
Human immunodeficiency virus 1
Acute Respiratory Distress Syndrome
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Image of FIGURE 1

Diagrams of typical simple retrovirus and retroviral vector. (Top) Retroviruses have LTR at each end, the psi encapsidation sequences (ψ), and regions encoding the Gag, Pol, and Env polyproteins. Splice donor (D) and acceptor (A) sites allow some of the vector transcripts to be spliced to generate subgenomic RNA for translation of the gene. (Bottom) Retrovirus vectors contain the LTR and ψ regions of the retrovirus with the exogenous gene(s) sequences cloned between.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 2

Retroviral vector packaging constructs. First-generation packaging constructs had the packaging region deleted to prevent packaging of the transcripts encoding the viral proteins. Second-generation packaging constructs were further altered to minimize the potential for generation of RCR through recombination with sequences in the vector. The 5′ end of the 5′ LTR was deleted and the entire 3′ LTR was replaced with an exogenous polyadenylation signal. Third-generation packaging systems had the open reading frames for Gag-Pol and Env placed on separate plasmids to further minimize the potential for recombination to generate RCR. SV40, simian virus 40.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 3

Production of lentiviral vectors from stable packaging cell lines and by transient transfection. (A) Stable packaging cell lines can be developed by stable transfection of a cell line to express the Gag, Pol, and Env proteins. Subsequent transfection of the plasmid encoding a retrovirus vector allows the vector genomic RNA to be packaged by the retroviral proteins. (B) Retroviral vectors can be produced by transient transfection of a susceptible cell line, such as 293T, with all of the plasmids encoding the vector, the virion proteins, and an envelope protein.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 4

Life cycle of a retroviral vector. Retroviral vectors are constructed as plasmids to contain the essential retroviral elements (LTR and psi region) and the transgene and other expression regulatory elements. The plasmid is transfected into a cell for packaging, with either stable or transient coexpression of the necessary retroviral proteins in The vector transcripts serve as the virion genome and are packaged into virions and released from the cell. The vector virions can then be used to transduce a target cell, where the vector RNA genome is reverse transcribed into double-stranded (ds) DNA and integrated into the target cell chromosomes as a provirus. The proviral sequences can be transcribed into mRNA that is translated to make the transgene product. ss, single stranded.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 5

Potential mechanisms of insertional oncogenesis by retroviral vectors. Retroviral vectors integrate into the target cell chromosomes and may affect the expression of nearby cellular genes. Gene disruption may occur if the retroviral vector integrates within the cellular gene; tumor suppressor genes may be inactivated by this process. Transcriptional read-through may occur from integrated vector proviruses into downstream cellular genes in the same orientation; inappropriate expression of cellular oncogenes may occur by this process. Enhancement of expression of cellular genes may occur if strong enhancer elements of the vectors activate expression from the promoters of nearby cellular genes, independently of the relative orientation of the vector (depicted as an upside-down vector in reverse transcriptional orientation relative to the cellular gene). (Figure kindly provided by Erin Weber, U.S.C. Keck School of Medicine.)

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 6

SIN lentiviral vectors. The SIN vector plasmid contains deletion of the enhancer and promoter of the 3′ LTR, which are not needed for expression from the plasmid in a packaging cell line. Following packaging of the vector and reverse transcription of the vector genome in a target cell, the 3′ LTR with the deletions of the enhancer and promoter is used as the template for the analogous region of the 5′ LTR, leading to a provirus with both LTR being transcriptionally inactive. Expression of the exogenous gene will then be driven from the internal promoter (Int Prom), which may be lineage specific or have other useful expression patterns. CMV, cytomegalovirus.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 7

Maps of the genomes of wild-type AAV serotype 2 and AAV vector. (A) The AAV serotype 2 genome is 4,681 nucleotides long and is shown on a linear scale of 100 map units. The open boxes show the ITR. The closed circles show the transcription promoters at 5, 19, and 40 map units. The gene is transcribed from both the p5 and p19 promoters. The gene is transcribed from the p40 promoter. (B) Schematic diagram of an AAV vector. The entire AAV coding sequence, including the and genes, is removed, leaving only the ITR that are required for the origin of replication and for encapsidation. The gene of interest, with appropriate regulatory sequences such as transcription promoter (p) and polyadenylation site (A), is inserted between the ITR.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 8

AAV life cycle. In the absence of helper virus, AAV enters a latent phase. In cultured cells in vitro, this latent phase leads to chromosomal integration of the AAV genome (see text). In vivo, such as in humans, latency may involve persistence of the AAV genome as an episome. The productive phase occurs if helper virus is present and coinfects the host cells. If latently infected cells in vitro are later infected with helper virus, the AAV DNA can be rescued from the host cell genome by replication. This rescue and amplification of AAV from latently infected cells in vitro together form the basis for production of AAV vectors as discussed in the text.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Image of FIGURE 9

Generation of three major types of HSV vectors on the basis of the genes targeted for deletion. (A) Replication-competent vectors are generated by deletion of accessory genes to replicate in tumor cells preferentially over normal cells; (B) replication-defective vectors are generated by deletion of an essential gene(s) to block virus growth; (C) amplicon vectors are generated using plasmids bearing the HSV origin of DNA replication.

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Clinical applications of gene therapy

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16
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Comparison of genetic vectors

Citation: Kohn D, Carter B, Grandi P, Glorioso J. 2009. Gene Therapy and Viruses, p 351-370. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch16

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