Reproducible and efficient murine CNS gene delivery using a microprocessor-controlled injector

Brooks, Andrew I.; Halterman, Marc W.; Chadwick, Christopher A; Davidson, Beverly L.; Haak‐Frendscho, Mary; Radel, Clyde; Porter, Chris; Federoff, Howard J.

doi:10.1016/s0165-0270(97)00207-0

Cited by 37 publications

(15 citation statements)

References 22 publications

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“…The lack of therapeutic efficiency of this replication-deficient retrovirus vector system in clinical settings may be because of: (1) the inability to distribute vector-producer cells throughout the tumor; (2) vector-producer cell instability; (3) the low transduction efficiency of retrovirions; and (4) the heterogeneity of tumor tissue. To circumvent some of these problems and to serve improved distribution of vector particles within tumor tissue, replication-competent oncolytic viral vectors and certain vector infusion methods are being used, and they are being evaluated in combination with new or improved prodrug-suicide gene systems as part of a multimodal gene therapy approach (Brooks et al, 1998;Aghi et al, 1999;Wildner, 1999;Rogulski et al, 2000;Voges et al, 2002).…”

Section: Introduction T He Design Of Effective Gene Therapy Strategiementioning

confidence: 99%

Improved Herpes Simplex Virus Type 1 Amplicon Vectors for Proportional Coexpression of Positron Emission Tomography Marker and Therapeutic Genes

et al. 2003

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For the development of efficient and safe gene therapy protocols for clinical application it is desirable to determine the tissue dose of vector-mediated therapeutic gene expression noninvasively in vivo. The herpes simplex virus type 1 thymidine kinase gene (HSV-1-tk) has been shown to function as a marker gene for the direct noninvasive in vivo localization of thymidine kinase (TK) expression by positron emission tomography (PET). Using bicistronic or multicistronic gene-expressing cassettes with tk as the PET marker gene, the quantitative analysis of tk gene expression may indirectly indicate the distribution and the level of expression of linked and proportionally coexpressed genes. Here, we describe the construction and functional evaluation of HSV-1 amplicon vectors mediating proportional coexpression of HSV-1-tk as PET marker gene and the enhanced green fluorescent protein gene (gfp) as proof of principle and cell culture marker gene and the Escherichia coli cytosine deaminase (cd) as therapeutic gene. Several double-/triple-gene constructs expressing HSV-1-tk, gfp, and E. coli cd were engineered based on gene fusion or the use of an internal ribosome entry site (IRES). Functional analysis in cell culture (green fluorescent protein [GFP] fluorescence and sensitivity to the prodrugs ganciclovir [GCV] and 5-fluorocytosine [5-FC]) and Western blots were carried out after infection of proliferating rat 9L gliosarcoma and human Gli36 glioma cells with helper virus-free packaged HSV-1 amplicon vectors. To study the ability of PET to differentiate various levels of tk expression noninvasively in vivo, retrovirally transduced and selected populations of rat F98 and human Gli36dEGFR glioma cells with defined levels of proportionally coexpressed tk and gfp genes were grown as subcutaneous tumors in nude rats and nude mice, and tk imaging by PET was performed. To study HSV-1 amplicon vector-mediated gene coexpression in vivo, HSV-1 amplicon vectors bearing coexpression constructs were injected (4 x 10(7) to 1 x 10(8) transducing units) into subcutaneously growing Gli36dEGFR gliomas in nude animals, and tk imaging was performed 24 hr later. All vector constructs mediated GFP expression and sensitized 9L and Gli36 cells toward GCV- and 5-FC-mediated cell killing in a drug dose-dependent manner, respectively. The levels of gene expression varied depending on the location of the genes within the constructs indicating the influence of the IRES on the level of expression of the second gene. Moreover, functional proportional coexpression of the PET marker gene HSV-1-tk and the linked therapeutic E. coli cd gene was observed. In selected tumor cell populations, subtle IRES-dependent differences of tk gene expression could be noninvasively distinguished by PET with good correlation between quantitative assays for IRES-dependent attenuated GFP and TK expression in culture and in vivo. After infection of subcutaneously growing gliomas with HSV-1 amplicon vectors, various levels of TK expression were found ranging from 0.011-0.0...

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Section: Introduction T He Design Of Effective Gene Therapy Strategiementioning

confidence: 99%

Improved Herpes Simplex Virus Type 1 Amplicon Vectors for Proportional Coexpression of Positron Emission Tomography Marker and Therapeutic Genes

et al. 2003

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“…For liver targeting, we prepared liposomes containing ␤-sitosterol ␤-d-glucoside (Sit-G), which is the main component of SG (Sit-G-liposomes). To increase the positive charge in the liposomes, we selected Tfx-20 reagent (Tfx) and 3␤[N-(NЈ, NЈ-dimethylaminoethane)-carbamoyl] cholesterol (DC-Chol) as cationic lipids, because the former is composed of synthetic cationic lipid [N,N,NЈ,NЈ-tetramethyl-N,NЈ-bis(2-hydroxy ethyl)-2,3-di (oleoyloxy)-1,4-butanediammonium iodide] that leads to high transfection efficiency in cell lines 13 and the latter has already been used clinically for gene therapy. 14,15 To prepare small liposomes, we used the modified ethanol injection method.…”

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confidence: 99%

Liver-targeted gene transfer into a human hepatoblastoma cell line and in vivo by sterylglucoside-containing cationic liposomes

et al. 2001

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The major limitations of viral vectors, particularly those related to safety and immunogenicity, have prompted studies to improve methods of non-viral gene delivery. 1Among such non-viral vectors, cationic liposomes are one of the more promising non-viral systems for use in gene therapy.2 The efficient delivery of functional therapeutic genes into target cells is an important problem in gene therapy approaches for the treatment of cancer and metabolic diseases, as well as human immunodeficiency virus infection.A number of receptor-mediated gene delivery systems have been developed to introduce DNA into specific cell types in vivo. The liver is one of the important target organs for gene delivery, because this organ plays a central role in the metabolism and production of many kinds of enzymes. Asialoglycoprotein receptor ligands investigated for use especially for hepatocytes include galactose residues 3-5 and asialofetuin. 6-8 However, synthesis and purification of these ligands are expensive. We reported previously that liposomes containing soybean-derived sterylglucoside (SG) accumulate in the hepatocytes after intravenous injection at almost the same level as liposomes containing lactosylceramide, which is a galactose-

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“…114 Few studies have used naked DNA and cationic liposomes to transfer genes into cells of the rodent brain. 115,116 In the brain, as in peripheral tissues, nonviral vectors induce nearly no immune response or toxic effects. However, there is a low efficiency of expression of introduced genes compared with viral vectors.…”

Section: Lentivirus Vectorsmentioning

confidence: 99%

“…However, there is a low efficiency of expression of introduced genes compared with viral vectors. 116 Routes of delivery into brain Gene delivery to the brain presents several unique challenges: limited and risky access through the skull (thus limiting repeat injections); sensitivity to volumetric changes (thus minimizing the size of inoculums and presenting increased risk from inflammatory responses); critical functional nuclei controlling life functions (which must be protected); and a highly specialized blood-brain barrier (designed to prevent viruses from entering the brain). The heterogeneity of the CNS neurocircuitry provides the opportunity to target focal areas of disease pathogenesis, as seen, for example in Parkinson's disease, but further complicates delivery to more widespread CNS diseases, such as brain tumors and lysosomal storage diseases.…”

Section: Lentivirus Vectorsmentioning

confidence: 99%

Gene therapy in the CNS

et al. 2000

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Reproducible and efficient murine CNS gene delivery using a microprocessor-controlled injector

Cited by 37 publications

References 22 publications

Improved Herpes Simplex Virus Type 1 Amplicon Vectors for Proportional Coexpression of Positron Emission Tomography Marker and Therapeutic Genes

Improved Herpes Simplex Virus Type 1 Amplicon Vectors for Proportional Coexpression of Positron Emission Tomography Marker and Therapeutic Genes

Liver-targeted gene transfer into a human hepatoblastoma cell line and in vivo by sterylglucoside-containing cationic liposomes

Gene therapy in the CNS

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