Hybrid vector designs to control the delivery, fate and expression of transgenes

Lam, Paula Yeng Po; Breakefield, Xandra O.

doi:10.1002/1521-2254(200011/12)2:6<395::aid-jgm146>3.0.co;2-k

Cited by 23 publications

(6 citation statements)

References 150 publications

(115 reference statements)

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“…Based on the local, non‐metastatic growth pattern of gliomas, gene therapy has been considered as a possible new approach for the treatment of these tumors. Vector systems used in gene therapy for gliomas include replication‐defective retroviruses, adenoviruses (Ad), herpes simplex viruses (HSV) and hybrid vectors derived from them 3, 4, 5, 6, 7, 8, 9, 10. These vectors have been used to deliver a therapeutic (suicide) gene expressing e.g.…”

mentioning

confidence: 99%

Expression of the coxsackie and adenovirus receptor in human astrocytic tumors and xenografts

Fuxe

Liu

Malin³

et al. 2002

Intl Journal of Cancer

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The sensitivity of human tissues and tumors to infection with type C adenoviruses correlates with the expression of the human coxsackie B-and adenovirus receptor, hCAR. HCAR is heterogeneously expressed in various tissues and types of human cancer cells, which has implications for the use of adenoviruses as vectors in cancer gene therapy. Using immunoblotting, real-time PCR, FACS-analysis and sensitivity to infection with adenovirus-lacZ, we analyzed the expression level of hCAR in glioma Grade IV cell lines. With realtime PCR, we also analyzed hCAR expression in primary human astrocytomas of different malignancy grades, as well as in their xenograft derivatives. Analysis of a set of 10 cell lines showed great variation in hCAR expression. Susceptibility to Ad5lacZ correlated well with hCAR expression, whereas no correlation was observed with the expression of ␣v␤3/␣v␤5 integrins, proposed to function as co-receptors for adenoviruses. A great variation of CAR expression was also observed in primary astrocytomas of different malignancy grades. The mean value of CAR expression was significantly lower in 22 Grade IV tumors as compared to the values for 6 Grade II (p ‫؍‬ 0.01) and 6 Grade III (p ‫؍‬ 0.01) tumors. When the hCAR expression in 11 xenografts derived from Grade IV gliomas were compared to the levels detected in the original parental tumors, a mean 12-fold higher expression was seen in the xenografts (P ‫؍‬ 0.01). Two xenografts with low hCAR expression grew considerably faster than the hCAR-expressing cells. Our results have relevance for the use of adenoviruses in gene therapy against astrocytomas.

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confidence: 99%

Expression of the coxsackie and adenovirus receptor in human astrocytic tumors and xenografts

Fuxe

Liu

Malin³

et al. 2002

Intl Journal of Cancer

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“…Development of viral vectors allowing for a long-term expression 25,26 combined with a targeted delivery and/or cell-specific expression of therapeutic proteins 27,28 will allow to increase the level of antibody production while reducing the vector and transgene-associated toxicity. In addition, the combination of antiangiogenic therapy using recombinant adenoviruses encoding scFv V65 and its derivatives and radio-or low-dose chemotherapy, which proved to be beneficial for other antiangiogenic drugs, [29][30][31] can be a useful strategy to improve the performance of the anti-VEGF scFv.…”

Section: Discussionmentioning

confidence: 99%

Single-chain antibody and its derivatives directed against vascular endothelial growth factor: application for antiangiogenic gene therapy

et al. 2003

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Single-chain antibodies (scFv) have an enormous potential for clinical application. However, rapid blood clearance and difficulties in large-scale production of active scFvs have limited the practical use of these antibody fragments. Recently, an anti-vascular endothelial growth factor (VEGF) scFv (scFv V65) was selected in our laboratory from a human antibody phage-display library. This antibody was able to reduce tumor growth in mice by approximately 50%. Here, we employ a gene therapy strategy for sustained in vivo expression of scFv V65 and its derivatives. scFv fusion proteins containing parts of the constant IgG1 region were generated (minibody and scFv V65-Fc) to increase the serum half-life of the scFv V65. Systemic administration of recombinant adenovirus encoding scFv V65 resulted in substantial tumor inhibition. This effect could be improved by multiple virus injections. We found that the efficacy of different scFv V65 formats was dependent on the mode of administration: whereas scFv V65-Fc was the most efficient when expressed locally, scFv V65 was superior when delivered systemically. Our results show that therapeutic levels of scFv V65 can be obtained by systemic injection of recombinant adenoviruses. Therefore, therapeutic gene delivery of scFv is a feasible strategy that overcomes several limitations of conventional antibody therapy.

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“…However, clinical trials showed that these vectors have some inherent limitations for therapy, namely, immunogenicity, toxicity, limited loading capacity, and failure of long-term adequate transgene expression. To overcome these drawbacks, attempts have been made, in order to combine the best characteristics of different viruses, by means of hybrid vectors [69].…”

Section: Hybrid or Chimeric Vectorsmentioning

confidence: 99%

Treatment Possibilities for Acquired and Hereditary Diseases by Gene Therapy: A Review

KUMARI¹,

EKSHITHA²

2021

Int J App Pharm

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Therapeutic nucleic acids demand specificity and accuracy in design as well as delivery strategies used in replacement or silencing of the target gene. Gene therapy is believed to be the therapy in which the root cause of the diseases can be treated at the molecular level. Generally gene therapy helps in the identification of the origin of the disorder instead of using drugs to diminish or control the symptoms. The application of nucleic acids to treat and control diseases is known as “gene therapy.” Gene therapy consists on the substitution or addition of a functional gene into the nucleus of a living cell, in order to treat a disease or repair a dysfunction, caused by this gene failure. This therapy is used to correct defective genes, which are responsible for genetic diseases. Thus, gene therapy can be used to prevent, treat or regulate hereditary or acquired disorders, by the production of therapeutic proteins. The gene therapy is mediated by the use of viral and non-viral vectors to transport foreign genes into somatic cells to restorative defective genes. This review focuses on viral vectors in detail.

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Hybrid vector designs to control the delivery, fate and expression of transgenes

Cited by 23 publications

References 150 publications

Expression of the coxsackie and adenovirus receptor in human astrocytic tumors and xenografts

Expression of the coxsackie and adenovirus receptor in human astrocytic tumors and xenografts

Single-chain antibody and its derivatives directed against vascular endothelial growth factor: application for antiangiogenic gene therapy

Treatment Possibilities for Acquired and Hereditary Diseases by Gene Therapy: A Review

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