gammaretrovirus gene therapy

Avian reticuloendotheliosis virus infection results in a number of pathologic syndromes including: (1) neoplasia, principally B and T cell lymphomas, but also squamous cell carcinoma and adenocarcinoma; (2) immunosuppression; and (3) growth retardation or runting syndrome. Natural variations in this motif suppress the fusion activity of Env (Lavillette et al., 1998), whereas other changes in this motif can suppress the fusion defects resulting from mutation of the active histidine in the SPHQ motif (Zavorotinskaya and Albritton, 1999b).

[1], Many endogenous retroviruses, closely related to exogenous gammaretroviruses, are present in the DNA of mammals (including humans), birds, reptiles and amphibians. Some notable clinical trials using lentivirus as a vector in the eye have begun in recent years, focusing on a genetic form of blindness (Stargardt’s disease) as well as age-related macular degeneration [46].

The mechanisms of reticuloendotheliosis virus-induced immunosuppression and growth retardation are not well characterized. Mutation of the first cysteine residue of this motif inhibits infection and blocks isomerization, both of which were rescued by the reducing agent dithiothreitol (Li et al., 2008). This gene therapy has successfully enabled correction of the T cell defect. The virus is horizontally transmitted by direct contact or vertically from infected dams to their offspring.

An adequate human T cell repertoire from a single T cell progenitor: Lessons from an experiment of nature.

Epub 2020 Sep 22. The most recently integrated human-specific ERVs are derived from HML-2 family (human murine mammary tumor virus (MMTV)-like viruses) of HERV-K betaretrovirus. Taken together, these data reflect a mixed message: gammaretrovirus vectors in which the transgene is not a growth/survival-promoting factor may have a relatively low but still appreciable risk for inducing clonal dominance and eventual leukemia in patients treated with HSC-directed gene therapy.

Each LTR contains a U3 (unique 3’), R (repeated), and U5 (unique 5’) region. Further safety improvement may be achieved by deleting the enhancer and TATA elements within the 3′ LTR.

[3], The avian reticuloendotheliosis viruses are not strictly avian viruses—it appears that reticuloendotheliosis viruses are mammalian viruses that were accidentally introduced into birds in the 1930s during research on malaria.

[7][9], A specific gammaretrovirus called xenotropic murine leukemia virus-related virus (XMRV) has been found to infect prostate cancer tissue in laboratories. However, bats are the primary reservoir for many gammaretroviruses. In an extreme example, AKR mice usually become viremic at an early age and most of the animals eventually die of leukemia. It is an exogenous virus that causes T-cell lymphomas and immunodeficiencies, as well as severe aplastic anemia, in cats. Typically, HEK293 cells are co-transfected with plasmids containing the transgene cassette together with plasmids encoding pseudotyping (VSV-G), viral structural, regulatory (Rev), and enzymatic components. These viruses may be ecotropic (able to infect only mice), xenotropic (unable to infect mice but able to infect other animals, such as rats), or polytropic (able to infect both mice and other animals). FeLV remains a significant pathogen of the domestic cat although its prevalence has been reduced in some populations by removal of infected animals and the development of effective vaccines. FeLV oncogenesis involves insertional mutagenesis and recombination between FeLV and host proto-oncogenes leading to the formation of feline sarcoma viruses or lymphoma-inducing variants.
Successful Preclinical Development of Gene Therapy for Recombinase-Activating Gene-1-Deficient SCID. XMRV is a recombinant virus created in a laboratory accident in the mid-1990s. Animals that become persistently viremic with FeLV are at high risk of succumbing to immunosuppressive or neoplastic diseases, particularly of hematopoietic origin. Thornhill SI, Schambach A, Howe SJ, Ulaganathan M, Grassman E, Williams D, Schiedlmeier B, Sebire NJ, Gaspar HB, Kinnon C, Baum C, Thrasher AJ. Long-term persistence of a polyclonal T cell repertoire after gene therapy for X-linked severe combined immunodeficiency. Other methods of attenuating the effects of retroviral vectors on transcription have involved use of nonintegrating vectors [91] and, perhaps controversially, insulators that isolate the provirus from the neighboring cellular sequences [90,115,116]. The procedure typically entails initial transfection of packaging cells that produce murine ecotropic vectors and then infection of murine cells that produce amphotropic recombinant retroviruses. The double stranded DNA is highly stable and easily integrated into a host genome. This claim is supported by a sequencing transcriptome profiling technique, and a polymerase chain reaction. The resulting amphotropic vectors have a broad tissue and host range. doi: 10.1126/scitranslmed.3002715. Therefore, RV vectors have been used in the developing CNS to selectively label progenitor cells during different stages of development to follow their fate and to selectively deliver toxic genes to tumor cells. J.C. Neil, in Encyclopedia of Virology (Third Edition), 2008. Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Adams S, Howe SJ, Al Ghonaium A, Bayford J, Brown L, Davies EG, Kinnon C, Thrasher AJ. 22.1). It contains a nucleocapsid, reverse-transcriptase, integrase, capsid, protease, envelope and surface units.


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