Immune response following intraocular delivery of recombinant viral vectors

Abstract

There has been significant progress in the last few years in demonstrating the utility of recombinant viral vectors in treating a variety of ocular diseases. The field has moved beyond 'proof-of-principle' and, in fact, has entered the phase where some of these vectors/paradigms are being or soon will be evaluated in human clinical trials. For this reason and also, to increase the understanding of immunological effects of transgenes/viral vectors on the eye, it is important to summarize what is known about these effects. Here, the biology of and immune responses to intraocular injection of three different recombinant viral vectors -adenovirus, adeno-associated virus (AAV), and lentivirus -are summarized. Perhaps, in part because of the unique immunological environment of the eye, the immunological effects of these viruses appear to be fairly benign. Nevertheless, a significant cell-mediated immune response can develop after intraocular administration of adenovirus. The magnitude of this response is affected by the nature of the intraocular compartment to which this virus is administered. Neither AAV nor lentivirus, however, elicit a cell-mediated response and are thus promising vectors for treatment of chronic ocular (retinal) diseases. Gene Therapy (2003) 10, 977-982.

Adenoviral capsid modulates secretory compartment organization and function in acinar epithelial cells from rabbit lacrimal gland

“…Adeno-associated virus (AAV) has also been extensively considered as an alternative to Ad-mediated gene therapy, largely due to its considerably decreased immunogenicity. 13 Recent findings suggest that AAV utilizes mechanisms comparable to Ad5 to enter host cells, including receptormediated endocytosis through a v integrin binding, and MT-based trafficking within the endosomal pathway. 49 These findings suggest some shared interactions between Ad and AAV capsid proteins and host cells, leading to the possibility that AAV capsid proteins may likewise influence epithelial secretory functions.…”

“…Even the conventional E1-, E3-deleted Ad vectors in current use have been reported to express adenoviral coding sequences at a level sufficient to elicit a robust Class I immune response against transduced cells in vivo, exhibit cytotoxicity at high doses, and have been responsible for the only reported instance of a fatality associated with a clinical gene therapy trial to date. [7][8][9][10][11][12][13] A particularly attractive feature of the eye within the context of Ad-mediated gene therapy is its relatively 'immuneprivileged' status, although some examples of immunogenicity associated with Ad-mediated ocular gene therapy have been reported. 12,13 Although the potential for therapeutic gene transfer by replication-deficient Ad has resulted in extensive investigations of its toxicity and immunogenicity, less information is available on the cellular effects associated with Ad binding, internalization and trafficking to the nucleus, particularly in epithelial cells that represent normal targets for Ad infection.…”

“…[7][8][9][10][11][12][13] A particularly attractive feature of the eye within the context of Ad-mediated gene therapy is its relatively 'immuneprivileged' status, although some examples of immunogenicity associated with Ad-mediated ocular gene therapy have been reported. 12,13 Although the potential for therapeutic gene transfer by replication-deficient Ad has resulted in extensive investigations of its toxicity and immunogenicity, less information is available on the cellular effects associated with Ad binding, internalization and trafficking to the nucleus, particularly in epithelial cells that represent normal targets for Ad infection. In addition to the use of Ad-based viral vectors, such information is relevant to feasibility and safety studies for next-generation gene therapy vectors, which attempt to overcome issues associated with viral immunogenicity and toxicity by incorporating Ad capsid proteins into nonviral gene delivery systems.…”

Virale und nichtvirale Gentherapieansätze zur Behandlung von Netzhauterkrankungen

“…In par al le len An sät zen forschten an de re Grup pen an re kom bi nan ten Ade no vi ren zur Trans duk ti on, doch schon bald zeig te sich, dass die ser Vi rus pro blema ti sche Ne ben wir kun gen zeig te und somit für gen the ra peu ti sche Fra gen un ge eignet ist. Dies konn te mit der Ent wick lung des re kom bi nan ten ade no as so zi ier ten Virus (rAAV), ei nem nicht pa tho ge ner Parvo vi rus, zum größ ten Teil um gan gen werden [2,4]. Ob wohl auch rAAV star ke An tikör per pro duk tio nen im Kör per aus lö sen, sind die se im mu no lo gisch harm los.…”

Virology and immunology of gene therapy, or virology and immunology of high MOI infection with defective viruses

“…5,12,13 Of further importance to the field, this issue explores how inflammatory and immune responses will vary, even for the same vector, depending on the target organ being injected and transduced. 6,11,13 Thus, this special issue examines immune responses to vectors infecting different tissues, that is, muscle, 9 liver, 10 eye, 11 and brain. 6 Main themes of this issue include early inflammatory responses and signaling pathways activated by viral vectors; 4 how viral vectors stimulate the release of inflammatory mediators, cytokines, and 9 the mechanisms by which the innate and/or adaptive arm of the immune response can inhibit transgene expression (or eliminate transduced cells).…”