Long–term hepatic adenovirus–mediated gene expression in mice following CTLA4Ig administration

Kay, Mark A.; Holterman, Ai Xuan; Meuse, Leonard; Gown, Allen M.; Ochs, Hans D.; Linsley, Peter S.; Wilson, Christopher

doi:10.1038/ng1095-191

Cited by 274 publications

(193 citation statements)

References 29 publications

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“…However, Tripathy et al 34 reported that the expression of endogenous proteins in animals lessens the development of their immunorejection. Kay et al 35 demonstrated, furthermore, the effect of CTLA4Ig, a costimulatory signal inhibitor between T lymphocytes and antigen-presenting cells. With the use of CTLA4Ig, persistent adenoviral gene expression was obtained in mice without long-term immunosuppression.…”

Section: Correspondence: T Takeuchi Department Of Molecular Medicinementioning

confidence: 99%

Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

Tamemoto

Shibata

et al. 1998

Gene Ther

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To utilize hepatocytes for insulin-producing surrogate cells, also observed with glucagon and IBMX. Production was we devised a regulatory secretion system by placing proinaugmented two-fold by the addition of wortmannin, a sulin DNA under the regulatable promoter for phosphoenolphosphatidylinositol (PI)-3-kinase inhibitor, suggesting pyruvate carboxykinase (PEPCK). The expression of that inhibitory insulin signaling to the PEPCK promoter PEPCK is down-regulated by insulin, and up-regulated by may be mediated through PI-3-kinase. Addition of cAMP and glucagon. To express insulin in hepatocytes, we exogenous insulin to the culture decreased insulin constructed an adenoviral insulin expression system. After mRNA expression remarkably on Northern blot. Thus, infection, the hepatocytes secreted immunoreactive insulin by using a PEPCK promoter for insulin expression, we (IRI) at an increasing rate. IRI secretion increased over were able to up-regulate insulin production from hepatofour-fold upon stimulation with 300 M cAMP and 500 M cytes with cAMP and glucagon, and down-regulate with of the cAMP-dependent phosphodiesterase inhibitor 3-insulin itself. isobutyl-1-methylxanthine (IBMX). This increase was

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Section: Correspondence: T Takeuchi Department Of Molecular Medicinementioning

confidence: 99%

Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

Tamemoto

Shibata

et al. 1998

Gene Ther

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“…General immune suppression may be induced in mice by inhibiting the CD28-B7 costimulatory signals by systemic administration of a recombinant chimeric protein, CTLA4-Ig, which consists of an immunoglobulin fused to CTLA4. 32 Kay et al 33 have demonstrated, in mice, that administration of muCTLA4-Ig, consisting of murine immunoglobulin C␥2a fused to murine CTLA4, extends the duration of adenovirus-mediated gene expression in the liver. They have also recently demonstrated that constitutive expression of murine CTLA4Ig from the viral vector also prolongs transgene expression.…”

Section: U Adrl In Pbs) the Results Indicate Transduction Of Rpe Cementioning

confidence: 99%

Co-injection of adenovirus expressing CTLA4-Ig prolongs adenovirally mediated lacZ reporter gene expression in the mouse retina

et al. 1998

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There is growing interest in gene delivery to the eye in describes a strategy for prolonging gene expression by order to develop gene therapy for the many ocular disblocking the B7-CD28 interactions between antigen orders which may be amenable to this approach. To date, presenting cells (APC) and T cells in order to prevent the recombinant adenoviruses (AV) have been the main vector costimulatory signals required for T cell survival and proused for gene delivery to anterior and posterior segments liferation. This was achieved by the co-injection of AV in animal models. As with delivery to other organs, immune encoding a secreted immunomodulatory molecule (CTLA4-responses to vector and transgene limit the duration of Ig) which consists of the extra-cellular domain of mouse expression in the eye. Using an E1-deleted adenoviral vec-CTLA4 fused to the Fc region of human IgG. Subretinal cotor carrying a lacZ reporter gene, we have previously deminjection of AV encoding ␤ galactosidase with AV encoding onstrated that a T cell-mediated immune response reduces CTLA4-Ig results in prolonged expression in retinal cells the level of intra-ocular transgene expression over time compared with subretinal injection of only adenovirus and limits it to around 3 weeks in mice. This report encoding ␤ galactosidase. Keywords: gene therapy; immune response; photoreceptor; eyeThere is growing interest in gene transfer into various tissues of the eye since there are many ocular disorders which may be amenable to gene therapy. 1 Of these, there is particular interest in developing gene therapy for inherited retinal degenerations, some of which are due to single gene defects in photoreceptor-specific genes. These disorders may ultimately be treated by gene replacement strategies which require gene transfer to photoreceptors or by strategies which prevent these cells entering the apoptotic pathway. The latter might be achieved, for instance, by the delivery of genes encoding neurotrophic growth factors to the adjacent retinal pigment epithelium (RPE) cells or to cells in the anterior chamber. A number of vectors, including those based on herpes simplex virus (HSV), 2 lentivirus 3 and adeno-associated virus (AAV) [4][5][6][7] have been used for ocular gene transfer but, to date, the most widely reported system is that based on adenoviral (AV) vectors. [8][9][10][11][12][13][14][15][16][17][18][19] Studies in either the rabbit or more often the mouse, using these AV vectors carrying a lacZ reporter gene, have demonstrated that cells in the anterior segment, including the corneal endothelium, iris pigment epithelium, ciliary body, trabecular meshwork and Schlemms canal, may be efficiently transduced by intra-cameral injection. Subretinal injection is required for efficient targeting of the RPE and also results in the transduction of a small proportion of photoreceptors. Host immune responses to vector and transgene currently present a general problem for long-term gene delivery. There has been particular concern about the immunogenicity of A...

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“…However, most of them present secondary complications and/or their use in human patients is questionable. These strategies include macrophage depletion, 39,40 use of immunosuppressive agents (cyclosporin A, cyclophosphamide, dexamethasone, FK506, Interleukin-12 and deoxypergualin), [41][42][43][44][45][46] use of antibodies to deplete CTLs, 47,48 blockade of costimulatory interactions between APCs, T and B cells, [49][50][51][52] intrathymic administration of adenovirus, 53 oral tolerization, 54 use of vectors derived from non-crossreacting serotypes, 55,56 use of adenoviruses from other species 57,58 and coating vectors with inert chemicals like polyethylene glycol (PEG). [59][60][61] Diverse in vivo studies in mice suggested that, in the absence of an immune response, first-generation adenoviral vector DNA is maintained as a stable episome in the host cell.…”

Section: Gutless Adenovirus and Immune Responsementioning

confidence: 99%

Gutless adenovirus: last-generation adenovirus for gene therapy

2005

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Last-generation adenovirus vectors, also called helper-dependent or gutless adenovirus, are very attractive for gene therapy because the associated in vivo immune response is highly reduced compared to first-and second-generation adenovirus vectors, while maintaining high transduction efficiency and tropism. Nowadays, gutless adenovirus is administered in different organs, such as the liver, muscle or the central nervous system achieving high-level and long-term transgene expression in rodents and primates. However, as devoid of all viral coding regions, gutless vectors require viral proteins supplied in trans by a helper virus. To remove contamination by a helper virus from the final preparation, different systems based on the excision of the helper-packaging signal have been generated. Among them, Cre-loxP system is mostly used, although contamination levels still are 0.1-1% too high to be used in clinical trials. Recently developed strategies to avoid/reduce helper contamination were reviewed. Gene Therapy (2005) 12, S18-S27.

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Long–term hepatic adenovirus–mediated gene expression in mice following CTLA4Ig administration

Cited by 274 publications

References 29 publications

Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

Regulatable production of insulin from primary-cultured hepatocytes: insulin production is up-regulated by glucagon and cAMP and down-regulated by insulin

Co-injection of adenovirus expressing CTLA4-Ig prolongs adenovirally mediated lacZ reporter gene expression in the mouse retina

Gutless adenovirus: last-generation adenovirus for gene therapy

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