Cell entry targeting restricts biodistribution of replication-competent retroviruses to tumour tissue

Duerner, Lydia; Schwantes, Astrid; Schneider, Irene C.; Cichutek, Klaus; Buchholz, Christian J.

doi:10.1038/gt.2008.92

Cited by 26 publications

(26 citation statements)

References 29 publications

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“…Anticancer efficacy has been demonstrated in a number of rodent models (Tai et al, 2005;Wang et al, 2006;Ostertag et al, 2012;Yin et al, 2013). Initial investigation of the spread of related RRVs has shown significant infection in lymphoid tissues in nude mice (Duerner et al, 2008), but restricted spread in immune-competent mice, rats (Wang et al, 2006;Hiraoka et al, 2007;Ostertag et al, 2012), and dogs (our unpublished data). Although amphotropic MLV can enter human lymphocytes and integrate into the host genome, it does not spread efficiently in primary lymphocytes in culture (Cornetta et al, 1993;Ebeling et al, 2003), likely in part because of the relatively high levels of the antiretroviral protein APOBEC3G (apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G) ( Jin et al, 2005;Mous et al, 2011), the expression of which can be modulated by the interferon signaling pathway (Chen et al, 2006;Mous et al, 2011).…”

Section: Introductionmentioning

confidence: 79%

MicroRNA 142-3p Attenuates Spread of Replicating Retroviral Vector in Hematopoietic Lineage-Derived Cells While Maintaining an Antiviral Immune Response

et al. 2014

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We are developing a retroviral replicating vector (RRV) encoding cytosine deaminase as an anticancer agent for gliomas. Despite its demonstrated natural selectivity for tumors, and other safety features, such a virus could potentially cause off-target effects by productively infecting healthy tissues. Here, we investigated whether incorporation of a hematopoietic lineage-specific microRNA target sequence in RRV further restricts replication in hematopoietic lineage-derived human cells in vitro and in murine lymphoid tissues in vivo. One or four copies of a sequence perfectly complementary to the guide strand of microRNA 142-3p were inserted into the 3' untranslated region of the RRV genome expressing the transgene encoding green fluorescent protein (GFP). Viral spread and GFP expression of these vectors in hematopoietic lineage cells in vitro and in vivo were measured by qPCR, qRT-PCR, and flow cytometry. In hematopoietic lineage-derived human cell lines and primary human stimulated peripheral blood mononuclear cells, vectors carrying the 142-3pT sequence showed a remarkable decrease in GFP expression relative to the parental vector, and viral spread was not observed over time. In a syngeneic subcutaneous mouse tumor model, RRVs with and without the 142-3pT sequences spread equally well in tumor cells; were strongly repressed in blood, bone marrow, and spleen; and generated antiviral immune responses. In an immune-deficient mouse model, RRVs with 142-3pT sequences were strongly repressed in blood, bone marrow, and spleen compared with unmodified RRV. Tissue-specific microRNA-based selective attenuation of RRV replication can maintain antiviral immunity, and if needed, provide an additional safeguard to this delivery platform for gene therapy applications.

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Section: Introductionmentioning

confidence: 79%

MicroRNA 142-3p Attenuates Spread of Replicating Retroviral Vector in Hematopoietic Lineage-Derived Cells While Maintaining an Antiviral Immune Response

et al. 2014

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“…The vast amount of A␤ retroparticles will most likely accumulate in spleen and liver after i.v. injection as observed for retroviruses (33,34). However, a small amount of particles may also be transported to lymph nodes via dendritic cells within minutes after injection (35), which may well contribute to their strong immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

Bach

Tschäpe

Kopietz

et al. 2009

The Journal of Immunology

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In transgenic animal models, humoral immunity directed against the β-amyloid peptide (Aβ), which is deposited in the brains of AD patients, can reduce Aβ plaques and restore memory. However, initial clinical trials using active immunization with Aβ1–42 (plus adjuvant) had to be stopped as a subset of patients developed meningoencephalitis, likely due to cytotoxic T cell reactions against Aβ. Previously, we demonstrated that retrovirus-like particles displaying on their surface repetitive arrays of self and foreign Ags can serve as potent immunogens. In this study, we generated retrovirus-like particles that display the 15 N-terminal residues of human Aβ (lacking known T cell epitopes) fused to the transmembrane domain of platelet-derived growth factor receptor (Aβ retroparticles). Western blot analysis, ELISA, and immunogold electron microscopy revealed efficient incorporation of the fusion proteins into the particle membrane. Without the use of adjuvants, single immunization of WT mice with Aβ retroparticles evoked high and long-lived Aβ-specific IgG titers of noninflammatory Th2 isotypes (IgG1 and IgG2b) and led to restimulatable B cell memory. Likewise, immunization of transgenic APP23 model mice induced comparable Ab levels. The CNS of immunized wild-type mice revealed neither infiltrating lymphocytes nor activated microglia, and no peripheral autoreactive T cells were detectable. Importantly, vaccination not only reduced Aβ plaque load to ∼60% of controls and lowered both insoluble Aβ40 as well as Aβ42 in APP23 brain, but also significantly reduced cerebral soluble Aβ species. In summary, Aβ retroparticle vaccination may thus hold promise as a novel efficient future candidate vaccine for active immunotherapy of Alzheimer’s disease.

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“…In addition, several layers of selective viral entry to tumour tissue have been developed by our group and others and may be added to enhance restricted shRNA delivery. 10,43 Thus, the system presented in this study extends the repertoire of RNAi delivery vehicles, offering unique advantages for gene function studies and novel therapeutic strategies.…”

Section: Rcr-mediated Gene Silencing T Schaser Et Almentioning

confidence: 99%

“…Twenty-four days after virus application, mice were sacrificed and tumour tissue was isolated. Homogenised tissue was used for recultivation of tumour cells to determine the percentage of infected cells by immunocytochemistry as described previously 10 and for isolation of genomic DNA. For analysis of luc expression, tissue homogenate was lysed in 500 ml ice-cold Passive Lysis Buffer (Promega) in Lysing Matrix D tubes with a Fastprep homogenizer (MP Biomedicals, Illkirch, France).…”

Section: Animal Proceduresmentioning

confidence: 99%

“…9 This way, genes of interest can be delivered to 95% of tumour cells in a solid subcutaneous tumour upon tail-vein injection of replicationcompetent MLV vectors. 10 Preclinical data on tumour mouse models demonstrated proof of principle for effective treatment of gliomas and colorectal cancer using MLV equipped with suicide genes after prodrug administration. [11][12][13] MLV accepts shRNA expression cassettes integrated in the 3¢-UTR of the env gene for several infection cycles without impaired replication kinetics.…”

Section: Introductionmentioning

confidence: 99%

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RNAi-mediated gene silencing in tumour tissue using replication-competent retroviral vectors

et al. 2011

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RNAi represents a powerful technology to specifically downregulate the expression of target genes. For cancer research and therapy, an efficient in vivo delivery system is supposed to distribute RNAi to all tumour cells upon systemic administration. We present replication-competent murine leukaemia virus (MLV) vectors, which deliver RNAi to tumour tissue upon tail vein injection. In HT1080 cells stably expressing GFP or luciferase, GFP expression was suppressed by more than 80% and luciferase (luc) activity by more than 90%, even when only 0.1% of the cells were initially infected with reporter gene specific vectors. To demonstrate its potential, PLK1-and MMP14-specific small hairpin RNA expression cassettes were applied in the system. Upon infection, PLK1 and MMP14 levels were reduced on mRNA and protein level. MLV-shPLK1-infected cells were arrested in the G2-phase and underwent apoptosis. MLV-shMMP14-infected cells showed reduced MMP2 activity, as well as substantially reduced invasion and tumour growth. In vivo, MLV-shLuc silenced luc expression in HT1080-luc tumour tissue by more than 80% and MLV-shPLK1 reduced tumour growth substantially, demonstrating the therapeutic relevance of this system. This RNAi vector system allows long-term downregulation of target gene expression as well as efficient delivery to and distribution throughout tumour tissue in vivo.

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Cell entry targeting restricts biodistribution of replication-competent retroviruses to tumour tissue

Cited by 26 publications

References 29 publications

MicroRNA 142-3p Attenuates Spread of Replicating Retroviral Vector in Hematopoietic Lineage-Derived Cells While Maintaining an Antiviral Immune Response

MicroRNA 142-3p Attenuates Spread of Replicating Retroviral Vector in Hematopoietic Lineage-Derived Cells While Maintaining an Antiviral Immune Response

Vaccination with Aβ-Displaying Virus-Like Particles Reduces Soluble and Insoluble Cerebral Aβ and Lowers Plaque Burden in APP Transgenic Mice

RNAi-mediated gene silencing in tumour tissue using replication-competent retroviral vectors

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