Adenovirus-mediated gene transfer: influence of transgene, mouse strain and type of immune response on persistence of transgene expression

Abstract

E1-deleted adenovirus (Ad) vectors expressing the human to the induction of a cellular immune response to the lacZ coagulation factor IX (hFIX) or the bacterial ␤-galactoantigen. In contrast, absence of detectable levels of serum sidase (lacZ) were injected intravenously into various hFIX in immunocompetent animals was not associated with strains of immunocompetent (C57Bl/6, BALB/c, CD1, a loss of viral DNA but was strictly correlated with the CBA/J, C3H) and immunodeficient (BALB/c-nu/nu, induction of anti-hFIX antibodies. Surprisingly, anti-hFIX C57Bl/6-nu/nu, SCID, NIH-bg-nu-xid) mice. Regular analyantibodies were never detected in C57Bl/6 mice, leading sis of mouse sera and tissues showed a persistent to prolonged detection of hFIX. These results suggest that expression of both transgenes in immunodeficient mice, cellular immunity to viral antigens plays a minor role in the while detection diminished very rapidly in immunocompetearly extinction of transgene expression and illustrate the ent mice. The mechanisms responsible for the transient influence of the cellular (eg lacZ) or humoral (eg hFIX) detection of the two transgenes were however not identimmunity to transgene-encoded products on the persistical. Rapid decline of lacZ expression was correlated with a ence of transgene expression. rapid decrease of viral DNA sequences, and consequently

Direct intramuscular injection with recombinant AAV vectors results in sustained expression in a dog model of hemophilia

“…In contrast, human F.IX specifically induces antibody formation in BALB/c mice, but has evaded antibody formation in C57Bl/6 mice. 20 The relative antigenicity of a recombinant protein in any given in vivo application appears to involve a complex interplay of the particular transgene, vector, animal strain and tissue targeted. 21,22 While these results support the safe transduction of the target muscle by rAAV vectors leading to human factor IX expression, we cannot rule out from our studies that expressed factor IX may be bound locally, and thus sequestered from efficient delivery into the circulation.…”

Creation of immune ‘stealth’ genes for gene therapy through fusion with the Gly-Ala repeat of EBNA-1

“…Indeed, prolonged transgene expression was detected in mice treated with rAd5-GAr-LacZ, consistent with the prominent role of the cellular immunity to transgene-encoded products on the persistence of transgene expression. 3 Nonetheless, we did not achieve persistent transgene expression in vivo, which is likely to be the result of the use of the first-generation E1-deleted adenoviral vectors. These vectors are notorious for their immunogenicity due to the leaky expression of viral genes residing in the vector.…”

“…These vectors are notorious for their immunogenicity due to the leaky expression of viral genes residing in the vector. 3,48 The GAr provides a powerful and specific tool to inhibit the presentation of transgene-derived antigens to CD8 þ CTL. Provided that the GAr is also functional in human cells, it may be exploited in gene-therapy applications involving expression of new antigenic proteins, for example, in hereditary protein deficiencies, in enzyme/prodrug or 'suicide' strategies that employ bacterial or viral enzymes, and in hiding bacterial transcription-regulating proteins, that is, those used in the tetracycline-regulated gene-expression systems.…”

“…One of the limitations imposed onto gene therapy is the immune response directed against vector and/or transgene product. [1][2][3][4] While beneficial for the development of recombinant vaccines against infectious agents 5,6 and tumor cells, 7,8 it significantly impedes the development of those gene-therapy approaches where persistent expression of the transgenes encoding neoantigens is required. Long-term humoral and cellular immunity against several viral-vector systems prevails in a large part of the population, or may be induced upon the first vector administration.…”

Intracerebral injection of adenovirus harboring the HSVtk gene combined with ganciclovir administration: toxicity study in nonhuman primates

“…30 Recent experiments, however, have shown the importance of the immunogenicity of the (non-self) transgene- encoded protein rather than the viral proteins in eliciting this inflammatory reaction. [44][45][46][47] Taking the different experiments together, Morral et al 46 stressed the importance of the concomitant response to adenoviral and foreign proteins. In cancer gene therapy, the intra-tumor induction of a strong immune response directed against viral and/or transgene encoded proteins may be favorable.…”