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Order Ortervirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
In the 1990s, numerous studies were undertaken on the construction and expression in mammalian cells of the artificial recombinants of the Gag proteins of such prototype oncogenic retroviruses as Rous sarcoma virus (RSV) of the genus Alpharetrovirus and murine leukemia virus (MLV) of the genus Gammaretrovirus with other oncoretroviruses and lentiviruses; for example, there are pioneering studies of Deminie and Emerman (1993), Berkowitz et al. (1995), Campbell and Vogt (1995), Zhang Y and Barklis (1995), Bowzard et al. (1998), Bennett and Wills (1999).
The science of biotechnology
Published in Ronald P. Evens, Biotechnology, 2020
Additionally, clinical use of a gene/vector product needs ease of administration with practical cell/genetic manipulation and safety in patients. Manufacturing needs for a vector/gene package include ease of fabrication, inexpensive synthesis, and facile purification. These manifold challenges have been overcome successfully with the regulatory approval worldwide in 2016–2019 of four gene therapies: alipogene tiparvovec (Glybera®) for lipoprotein deficiency (adeno-associated virus serotype 1 vector), autologous gammaretroviral gene therapy (Strimvelis®) for SCID (CD34+ cells with gamma-retro virus vector), both in Europe, plus voretigene neparvovec (Luxtruna®) for retinal atrophy (adeno-associated virus type 2 vector) and onasemnogene abeparvovec (Zolgensma®) for spinal muscular atrophy (vector – recombinant adeno-associated virus 9).
Cancer-Causing Viruses
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Satya P. Gupta, Vertika Gautam
XMRV is a murine leukemia virus (MLV) that formed through the recombination of the genomes of two parent MLVs known as preXMRV-1 and preXMRV-2 (Cingöz et al. 2012). MLV is a gammaretrovirus, a genus of the Retroviridae family, and has a single-stranded RNA genome that replicates through a DNA intermediate. The name XMRV was given because the discoverers of the virus initially thought that it was a novel potential human pathogen that was related to but distinct from MLVs. XMRV has now been established as a laboratory contaminant. This contamination hypothesis has been supported by several studies (Smith 2010).
Treatment of cerebral adrenoleukodystrophy: allogeneic transplantation and lentiviral gene therapy
Published in Expert Opinion on Biological Therapy, 2022
Ashish O Gupta, Gerald Raymond, Elizabeth I Pierpont, Stephan Kemp, R Scott McIvor, Arpana Rayannavar, Bradley Miller, Troy C Lund, Paul J Orchard
We are unaware of reports of MDS as a factor in other lentiviral-based trials other than those described above. In a recent review, Tucci et al. summarized the risk due to insertional mutagenesis across 55 studies including a total of 406 participants using lentiviral and gammaretroviral vectors [89]. This study reported an overall incidence rate of 21 genotoxic events/1504 person-years of observation (PYO), or an overall incidence of 0.078 events/100 PYO. A key difference between the SCD trials and the ALD trials is use of the MND promoter (as described above; Figure 3) to regulate expression of the ABCD1 gene product in the ALD trials, while Lentiglobin employs elements of the natural globin locus to regulate gene expression. Murine leukemia virus elements from which MND was derived are well known for strong enhancer activity that can upregulate expression of nearby genes, including proto-oncogenes and other growth regulatory genes. These are the same elements that contributed to the earliest cases of adverse leukemogenesis in the early trials of gene therapy for X-linked SCID [76]. All of this suggests that the Lenti-D vector construct may play a role in the emergence of MDS in the ALD clinical trial, but this has not been confirmed.
Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer
Published in Expert Opinion on Biological Therapy, 2021
Sara A. Collins, Ashish H. Shah, Derek Ostertag, Noriyuki Kasahara, Douglas J. Jolly
Design and construction of the RRV has been facilitated by the relatively small size of the genome, the availability of in-depth knowledge of mouse gammaretrovirus biology, and the relative ease with which high-titer vector preparations for both laboratory-based and clinical studies can be produced. For example, initial virus production can be achieved by transient transfection of 293T cells with a cloned full-length proviral vector genome encoded on a single plasmid. In addition, the technology of permanent producer cell lines [29] allows relatively simple scale-up and purification from preclinical to clinical and commercial scale, as the virus can be harvested from culture supernatant, analogous to methods of harvesting monoclonal antibodies. This in turn has allowed development of serum-free suspension cultures for vector production, with continuous perfusion technology rather than batch production, and with single-use production materials [30].
Immunotherapy with NK cells: recent developments in gene modification open up new avenues
Published in OncoImmunology, 2020
Lisa Marie Reindl, Nawid Albinger, Tobias Bexte, Stephan Müller, Jessica Hartmann, Evelyn Ullrich
Different systems, which can be classified as viral and nonviral technologies, can be used for the genetic modification of NK cells and NK cell lines. Many viral vector systems, including alpharetroviral (α-RV), gammaretroviral (γ-RV) and lentiviral (LV) systems have been developed, with retroviral vectors being the most commonly used (for review see Matosevic et al.).73 Transduction efficiencies differ between published studies and depend on the NK cell source, the viral vector system and the transduction enhancer used.73 For instance, γ-RV vector systems have achieved high transduction efficiencies in expanded PB- and UCB-derived NK cells.74–76 Interestingly, most protocols used gene-modified K562 feeder cells expressing membrane-bound cytokines (mbIL-21 or IL-15) and 4–1BB to enhance NK cell expansion and potentially improve the transduction efficiency. It is still unknown whether high transduction rates solely depend on the γ-RV vectors or whether other conditions play a significant role as well. Nevertheless, the use of γ-RV vectors is associated with the risk of insertional mutagenesis and oncogenesis. In a study of X-linked severe combined immunodeficiency (SCID), nine out of ten patients were cured using γ-RV-mediated gene therapy, but four of them developed T cell leukemia, indicating the need for viral vector systems with a safer integration pattern and a decreased risk of insertion mutation (i.e., LV and α-RV vectors or a nonviral approach).77,78