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Volume 2 - 1998

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Gene therapy for the mucopolysaccharidoses

Author(s): Dr. , Donald S. Anson,

Abstract: The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders in which the storage material is glycosaminoglycan. Each MPS is caused by the genetic deficiency of a single lysosomal enzyme. Due to the nature of these diseases and the characteristics of the enzymes that are deficient most of the MPS are good candidates for gene therapy. Studies in animal models have supported this contention and have shown that several different approaches to gene therapy for the MPS are possible. However, it is also clear that each of these approaches is limited by the currently available technology and that the development of new gene delivery technology is a priority.



Gene therapy strategies utilizing carcinoembryonic antigen as a tumor associated antigen for vaccination against solid malignancies

Author(s): Dr. , David J. Cole,

Abstract: Advanced solid malignancies represent a significant clinical problem with few effective treatment options. Carcinoembryonic antigen (CEA) is a well defined tumor-associated antigen on the surface of many solid malignancies that is currently used as a diagnostic and prognostic marker. Recent advances in tumor immunology, the understanding of antigen presentation, and gene transfer vector systems now provide gene therapy strategies in the form of a cancer vaccine which target CEA in an effort to induce a therapeutic immune response. This chapter provides a brief history of cancer vaccine development, discusses current strategies for generating or augmenting CEA-specific immunity, and focuses on ongoing CEA-based gene therapy approaches for the treatment of solid malignancies

Keywords: gene therapy, T-lymphocytes, tumor immunity, vaccination, CEA


Vaccine therapy for ovarian cancer using Herpes Simplex virus thymidine kinase (HSV- TK) suicide gene transfer technique: a phase I trial

Author(s): Dr. , William R. Robinson,

Abstract: Genetically altered tumor cells expressing the HSV-TK gene have been used as vaccine therapy for multiple cancers, based on their ability to kill adjacent native cancer cells and activate an antitumor immune response. Our in vitro studies demonstrate that transduction with the HSV-TK system confers ganciclovir (GCV) susceptibility to cultured ovarian cancer cells. A murine tumor model was developed using HSV-TK modified ovarian cancer cells to test efficacy in a preclinical setting. Mice bearing intraperitoneal tumors were injected with gene modified cells and ganciclovir (GCV). The mice were evaluated for survival and immune response by analysis of tumor samples collected post treatment. Murine HSV-TK tumors undergo hemorrhagic tumor necrosis and express a cytokine cascade including TNF-, IL-1, IL-6, IL-2, IFN- and GM-CSF following GCV treatment. Tumor regression occurs much less frequently in immune deficient mice than immune competent mice. These studies led to a Phase I trial of intraperitoneal administration of the vaccine in which 18 patients with recurrent chemotherapy resistant ovarian cancer were enrolled. The mean survival of patients in the Phase I trial was 11.9 months. 4/18 patients had responses based on physical findings or CA-125. One patient died of breast cancer with no evidence of ovarian cancer at 24 months. Toxicities include all patients developing grade I or II temperature elevations without other evidence of infection, seven patients who developed grade I abdominal discomfort or nausea, and one patient with a grade III elevation of kidney function tests. We conclude that the use of an HSV- TK modified vaccine is associated with tumor regression in mice, and results in the alteration of the tumor microenvironment, which becomes less immunosuppressive. The use of the vaccine in humans is technically feasible and associated with minimal toxicity. Survival in these heavily pretreated patients is similar to that seen using standard cytotoxic chemotherapy.



Exploiting stromal-epithelial interaction for model development and new strategies of gene therapy for prostate cancer and osteosarcoma metastases (review)

Author(s): Dr. , Leland W. K. Chung,

Abstract: Results of toxic gene therapy for the treatment of localized and disseminated prostate cancers showed that: (i) Ad-OC-TK expressed high levels of TK in both androgen-dependent and androgen-independent human prostate cancer cell lines; (ii) in parallel with the expression of Ad- OC-TK in tumor cell lines, the efficacy of Ad-OC-TK toxic gene therapy in target cells is directly correlated with the levels of TK expression in vitro; (iii) in two experimental models of human prostate cancer, C4-2 and PC-3, we demonstrated that Ad-OC-TK, when applied together with ACV, induced tumoricidal effects in vivo. Significant histomorphologic improvement of human prostate cancer growth in the bone was supported by bone scans in vivo. In the C4-2 model, we obtained evidence that Ad-OC-TK plus ACV diminished serum PSA, which is confirmed by the improvement of histomorphologic appearance of this tumor in the skeleton. Finally, we have focused our effort in the development of combined adenovirus and chemotherapy (i.e. chemogene therapy), the development of a concept of loco-regional delivery of therapeutic genes and drugs, and the exploration of using the homing mechanism to treat prostate cancer skeletal metastasis in vivo. Taking advantage of the reciprocal cellular interaction between prostate cancer and bone stroma, we have developed two novel gene therapy approaches to target prostate cancer growth in the bone. We have achieved for the first time the use of Ad-OC-TK/ACV as a novel therapeutic agent that can selectively target and induce the killing of both prostate and osteoblast lineage cells.



Cationic liposome-mediated transfection in vivo

Author(s): Dr. , Dexi Liu,

Abstract: Cationic liposomes have been widely used as a transfection reagent to introduce gene into cells. Although much has been learned about the factors affecting transfection efficiency of liposomes in vitro, understanding on how efficient these lipid carriers are in delivering gene into cells in vivo is still lacking. Recent studies using reporter genes show that significant level of gene expression can be obtained in different organs including the lung, heart, spleen, liver and kidneys following an intravenous administration of DNA/liposome complexes into mice. In these studies, the cationic lipid to DNA ratio, structure of cationic lipids, liposome composition, and particle size of lipid particles were found to be important in determining the transfection efficiency of cationic liposomes. It was also found that gene expression from a single administration is transient but can be maintained by repeated administration. In this paper, we review the data that characterize the in vivo transfection mediated by systemically administered cationic liposome.



The ability of tRNA-embedded ribozymes to prevent replication of HIV-1 in cell culture

Author(s): Dr. , Kazunari Taira,

Abstract: A trans-acting tRNA-embedded ribozyme targeted to HIV-1 RNA is flanked by cis-acting ribozymes at both its 5’ and its 3’ end so that, upon transcription, the trans-acting ribozyme is trimmed at both its 5’ and its 3’ end, with resultant liberation of a small tRNA-embedded ribozyme. The trans- acting ribozymes targeted to a different site in HIV-1 RNA were expressed under the control of the SR promoter and were examined in cell culture in a co-transfection transient assay with an HIV-1 infectious molecular clone, pNL4-3, for their ability to suppress HIV-1 replication. Although the extent of inhibition depended on the target site, all constructs caused significant inhibition of the HIV-1 p24 antigen production in culture supernatant. The ribozyme targeted to either 5’ SS (5’ major splicing site) or tat1 site within tat-coding region had the highest inhibitory effect (>80%) when the molar ratio of template DNA for the target HIV-1 RNA to that for the ribozyme was 1:8.

Keywords: AIDS, inhibition, enzyme, catalysis, transcription, cleavage


Ribozyme-catalyzed trimming reactions and the direct role of Mg2+ ions in the cleavage of RNA

Author(s): Dr. , Kazunari Taira,

Abstract: In the hypothetical RNA world divalent Mg2+ ions were exploited for cleavage (or ligation) of ribonucleic acids. Although some Mg2+ ions are involved in forming the tertiary structures of RNAs, the key Mg2+ ions are directly involved in catalysis not only in the case of hammerhead ribozymes but also in the case of Tetrahymena and, possibly, other types of ribozyme. RNA components bind the indispensable Mg2+ ions to the phosphodiester bonds that are being broken (or formed). Our analysis indicates that the chemical cleavage step of reactions catalyzed by the hammerhead ribozyme does not appear to have been perfected and, thus, it seems possible to create RNA-cleaving agents that are significantly more active than the standard hammerhead ribozyme. Moreover, RNA-cleaving mechanisms might converge as one unique and universal mechanism, exploited not only by various kinds of ribozyme but also by artificially created metal-ion-dependent DNAzymes and other RNA-cleaving agents that are yet to be identified.

Keywords: ribozyme, cleavage, trimming, RNA world, Mg2+ ion, metallo-enzyme


Regulation of neuronal differentiation and apoptosis by Brn-3 POU family transcription factors: - potential use in gene therapy

Author(s): Dr. , David S. Latchman,

Abstract: The Brn-3 sub group of POU family transcription factors has three members:- Brn-3a, Brn-3b and Brn-3c, all of which are expressed in distinct but overlapping groups of neuronal cells in the developing and adult nervous systems. Although these factors are closely related to one another, they have distinct functions. Thus, Brn-3a activates the expression of a number of different genes expressed in neuronal cells whereas Brn-3b represses their expression and inhibits activation by Brn-3a. These stimulatory effects of Brn-3a are paralleled by its ability to stimulate neurite outgrowth by neuronal cells and to protect them from apoptosis/programmed cell death. Thus Brn-3a may be of potential use in a gene therapy approach to human neurological diseases which involve either a failure of neurite outgrowth, such as spinal injury, or excessive neuronal cell death such as Alzheimer's or Parkinson's diseases.



EGR-1 prevents growth arrest by induction of c-myc

Author(s): Dr. , Vivek M. Rangnekar,

Abstract: The zinc-finger transcription factor EGR-1 provides protection from G1 phase growth arrest. We present here evidence that this protective effect of EGR-1 is linked to upregulation of c-myc RNA and protein by induction of the c-myc promoter. Growth arrest involves c-myc downregulation and hypophosphorylation of the retinoblastoma susceptibility protein RB, but upregulation of c-myc prevents hypophosphorylation of RB and provides protection from growth arrest. These findings suggest a downstream mechanism for EGR-1 function as an inhibitor of G1 phase growth arrest. Because Egr-1 and c-myc are involved in determining cell fate in response to diverse exogenous signals, the findings of the present study can be extended to model systems for proliferation, cellular differentiation, and programmed cell death.


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