Adeno-associated Virus (AAV) versus Immune Response

Abstract

Decades ago, Friedmann and Roblin postulated several barriers to gene therapy, including tissue targeting, delivery across the blood⁻brain barrier (BBB), and host immune responses. These issues remain pertinent till today. Since then, several advances have been made in elucidating structures of adeno-associated virus (AAV) serotypes, antibody epitopes, and ways to modify antibody-binding sites. AAVs capsid has also been engineered to re-direct tissue tropism, reduce ubiquitination, and promote passage across the BBB. Furthermore, the use of high(er) dose recombinant AAV (rAAV) has been accompanied by a better understanding of immune responses in both experimental animals and early clinical trials, and novel work is being performed to modulate the immune response. While the immune responses to rAAV remains a major challenge in translating experimental drugs to approved medicine, and will likely require more than a single solution, we now better understand the hurdles to formulate and test experimental solutions to surmount them.

Keywords: immune response; rAAV; rare diseases.

Figure 1

This cartoon describes two risks associated with adeno-associated virus (AAV) entrance in to a target cell. The innate immune repsonse is activated by TLR9 recognition of the externalization of the viral genome. This event is rapid and NF-kB will be activated resulting in proiinflammatory cytokine production. For the many virions that do not rapidly uncoat, a second risk exists—the slow degradation of the capsid. Proteasomes degradation of ubiquitinated AAV results in a small amount of capsid fragments being transported through the transporter associated with antigen processing (TAP), into the endoplasmic reticulum (ER), and innevitable attachment to major histocompatibility complex (MHC) class I molecules. These peptides will be displayed on the cell surface and eventually recognized by cytotoxic T cells.