Immunogenicity and toxicity of AAV gene therapy

Abstract

Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses. Although it was initially thought that AAV vectors induce only marginal innate responses below the threshold of systemic symptoms recent trials have shown that complement activation can results in serious adverse events. Dorsal root ganglia toxicity has also been identified as a complication of high vector doses as has severe hepatotoxicity. Most of the critical complications occur in patients who are treated with very high vector doses indicating that the use of more efficient AAV vectors to allow for dose sparing or giving smaller doses repeatedly, the latter in conjunction with antibody or B cell depleting measures, should be explored.

Keywords: AAV; B cell responses; T cell responses; innate immune responses; serious adverse events.

Figure 1

Immune responses and toxicity to AAV vectors. The graph shows the different type of immune responses that are elicited upon injection of AAV vectors. Toxicities are underlined and listed next to the components of the immune responses that contribute or may (?)contribute to the adverse events. The following abbreviations are used within the figure: CpG, unmethylated CpG motifs; C1 and C3, complement factors 1 or 3; DCs, dendritic cells; DRG, Dorsal root ganglia, dsRNA, double stranded RNA; MAC, membrane attack complex; MHC, major histocompatibility complex; NK cells, natural killer cells, TMA, thrombotic microangiopathy,? – remains to be tested in more detail.