Each vector system faces its own set of immunological hurdles for gene therapy, some more related to innate immunity, others to adaptive immunity (including memory and pre-existing immunity). Nonetheless, similar to transplantation biologists, gene therapists are learning to circumvent, manipulate, or suppress unwanted immune responses. Advances in vector engineering (such as capsid engineering, miRNA-regulated expression cassettes, etc) and delivery techniques, administration to immune privileged sites, taking advantage of organ-specific immune responses, immune suppression and modulation regimens represent promising strategies to overcome immunological hurdles. While translation of knowledge gained from preclinical studies in animal models to human therapeutics in gene therapy is not always straightforward, immune modulation protocols are nonetheless being refined and tailored towards specific vector/target tissue/disease combination.
With reference to AAV, more clinical results are expected to emerge in the near future from ongoing or yet to be initiated clinical trials. These will help us understand the effect of target organ (e.g. brain, central nervous system, eye, muscle, liver) on T cell responses to capsid and its consequences for long term expression. Interestingly, a recent paper describes a patient that received IM AAV1-mediated gene transfer and continued to express the transgene despite a detectable CD8 response to capsid.68
However a different study suggested transient expression as a result of capsid-specific response in muscle.21
More human data are required to resolve these issues.
In the case of AAV and Ad, continued engineering of capsids should establish whether pre-existing NAB/cross-reactive antibodies to the vector can be avoided without loss of gene transfer in humans.69
Ad vectors have been an excellent model for obtaining a detailed understanding of innate immune responses to DNA viruses. A fairly complete picture of the interactions between Ad and the innate immune system is emerging. These vectors remain attractive vaccine carriers and new vaccines based on human and primate serotypes are being developed. With regard to using Ad vector for treatment of genetic disease, limited doses and local delivery of gutted vectors will likely be required to avoid immunotoxicity.
Results from LV based treatment of genetic disease in large animal models are expected to be produced in the near future. It will be of interest to compare efficacy and immune responses using optimized envelope and miRNA regulated expression cassettes to current data from rodent models. Effective de-targeting of professional APCs will decrease immune responses to LV gene transfer. In general, additional clinical experience with viral vectors combined with advances in the laboratory should generate a more complete assessment of immune responses to these gene transfer vectors and their transgene products.