Persistent transgene expression in the hypothalamus following stereotaxic delivery of a recombinant adenovirus: suppression of the immune response with cyclosporin.

Abstract

Replication deficient, recombinant adenoviruses (Ads) have been used successfully to transfect several forebrain and brainstem nuclei, but have yet to be demonstrated as useful vectors for transgene delivery in the structurally diverse and highly vascularised nuclei of the hypothalamus. In the present study we have assessed the ability of an Ad expressing the lac-Z gene to transfect cells of the paraventricular nucleus (PVN) of the hypothalamus in vivo. We show that: (1) we can achieve stable expression of the lacZ gene in cells of the magnocellular PVN for at least 2 months; (2) there were no obvious differences in the level of AVP mRNA in the PVNs injected with Ad compared with those injected with vehicle suggesting that Ad treatment is not disrupting normal cellular function in the injection region; (3) the introduction of Ads results in a limited immune response; (4) systemic treatment with cyclosporin dramatically reduces its magnitude. We conclude that Ad vectors represent useful tools for neuroendocrinological and gene therapeutic studies of the hypothalamus.

cAMP Responsive Element-Binding Protein Phosphorylation Is Necessary for Perirhinal Long-Term Potentiation and Recognition Memory

“…The comparisons were made between animals that had been injected with A-CREB and control adenoviral vectors, so that the transduction itself may be excluded from being responsible for the behavioral, Fos, pCREB, and plasticity impairments. Previous studies have also shown that adenoviral vectors elicit a negligible immune response when measured several weeks after injection at the titers used in the present study (Byrnes et al, 1995;Geddes et al, 1996;Gerdes et al, 2000). The behavioral effects clearly originate in the perirhinal cortex and/or Te2, because that is the region that was virally transduced and the region in which differential Fos and pCREB expression was disrupted.…”

Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient mice

“…8 However, since these vectors also deliver large amounts of viral sequences they often cause host immune reactions and tissue damage, an affect which can be prevented by immunosuppressants including glucocorticoids. 12,13,16 The lack of any detectable inflammation in the adrenal following intra-adrenal injection of the adenoviral constructs suggests that in contrast to other tissues, the high levels of endogenous steroids in this tissue may have a protective effect preventing inflammatory responses. This makes the adrenal an immune privileged organ and an ideal candidate for gene therapy.…”

Somatic gene transfer: implications for cardiovascular control

“…Survival of the transgene delivered by adenoviruses can be limited by both the spontaneous elimination of the episomal viral DNA and the immune response to the viral antigens produced by transfected cells. While the immune response limits the value of the adenoviruses for gene delivery into peripheral tissues, this response is less intense in the brain and can be suppressed by cyclosporin (Geddes et al 1996). Geddes et al (1996 demonstrated that the lacZ gene introduced using adenoviruses into the paraventricular nucleus of the hypothalamus persisted for at least 2 months.…”