Adeno‐associated virus (AAV) vectors in gene therapy: immune challenges and strategies to circumvent them

Abstract

AAV-based gene transfer protocols have shown remarkable success when directed to immune-privileged sites such as for retinal disorders like Lebers congenital amaurosis. In contrast, AAV-mediated gene transfer into liver or muscle tissue for diseases such as hemophilia B, α1 anti-trypsin deficiency and muscular dystrophy has demonstrated a decline in gene transfer efficacy over time. It is now known that in humans, AAV triggers specific pathways that recruit immune sensors. These factors initiate an immediate reaction against either the viral capsid or the vector encoded protein as part of innate immune response or to produce a more specific adaptive response that generates immunological memory. The vector-transduced cells are then rapidly destroyed due to this immune activation. However, unlike other viral vectors, AAV is not immunogenic in murine models. Its immunogenicity becomes apparent only in large animal models and human subjects. Moreover, humans are natural hosts to AAV and exhibit a high seroprevalence against AAV vectors. This limits the widespread application of AAV vectors into patients with pre-existing neutralising antibodies or memory T cells. To address these issues, various strategies are being tested. Alternate serotype vectors (AAV1-10), efficient expression cassettes, specific tissue targeting, immune-suppression and engineered capsid variants are some approaches proposed to minimise this immune stimulation. In this review, we have summarised the nature of the immune response documented against AAV in various pre-clinical and clinical settings and have further discussed the strategies to evade them.

Hyper-IL-15 suppresses metastatic and autochthonous liver cancer by promoting tumour-specific CD8+ T cell responses

“…At this time point, the tumours might not be well-established in the liver. In addition, the AAV itself may have triggered specific pathways to induce innate and adaptive immune responses against both viruses and tumours [27], complicating the interpretation of these experiments with respect to the effects of IL-15/IL-15Rα. Here, we show the impressive therapeutic effect of hyper-IL-15 to well-established tumours in the liver 10 days after transplantation.…”

Regulation of hepatocyte identity and quiescence

“…Apparently, this effect only required transduction of a modest fraction of hepatocytes, and improvement in hepatic function began within 48 h after infection and lasted at least for 100 days [207]. Nevertheless, administration of AAV vectors to patients with chronic liver disease is not exempt from risks [208], and also strategies to avoid the immune response to AAVs found in humans need to be optimized [209].…”

Monitoring Endoplasmic Reticulum Calcium Homeostasis Using a <em>Gaussia</em> Luciferase SERCaMP

“…This range is 4-400 times lower than reported in previous work utilizing firefly luciferasebased viral injections of the liver 19 . At higher concentrations, we observed a loss of detectable expression over time, which is possibly due to an immune response of the animal to the transgene 22 . Higher titers of virus should be avoided when possible due to increased likelihood of signal loss.…”