Abstract
Adeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases.
Highlights
Several clinical studies have shown long-term correction of the disease phenotype following gene transfer [1,2,3,4,5,6,7,8,9]
Therapeutic efficacy following associated virus (AAV) vector gene transfer was documented in several preclinical studies and, over the past decade, some of these results were successfully translated to the clinic, leading to some of the most exciting results in the field of gene therapy [11]
It has been shown that immune responses triggered by AAV vector-mediated gene transfer may constitute an important obstacle to long-term therapeutic efficacy and a safety concern
Summary
Several clinical studies have shown long-term correction of the disease phenotype following gene transfer [1,2,3,4,5,6,7,8,9]. Preclinical studies of intramuscular delivery of AAV vectors suggest that this approach carries a higher risk of triggering immune responses to the transgene [42] compared to other tissues such as the liver [43], and that the underlying disease-causing mutation is a major determinant of the risk of developing an immune response to the therapeutic transgene product following AAV-mediated gene transfer to the muscle [44].
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