Several strategies can be used to target
c-Rel, including small-molecule inhibitors and nucleic acid–based drugs.
28,33,35 Nucleic acid–based siRNA drugs have been utilized as therapeutic agents against various diseases.
36 To facilitate the delivery of siRNA drugs, a variety of non-viral and viral vectors have been developed over the past few decades. We have previously shown that nanopolymers loaded with
c-Rel–specific siRNA can efficiently prevent and treat autoimmune diseases including psoriasis, EAE, and RA. However, non-viral vectors have sometimes failed to show the expected therapeutic efficacy because of poor delivery efficiency to certain types of cells, especially T cells. In recent years, AAV-mediated gene transfer has been proving to be an effective treatment for immune-mediated inflammatory diseases of the eye.
37 AAV gene transfer has the advantages of efficient gene delivery and long-term transgene production after a single dose. Various AAV serotypes exhibit preferred tropism due to the use of different cellular surface receptors. For example, AAV8 and AAV9 are the most efficient AAV vectors to infect corneal cells,
37 but AAV6 is a vector with high infection efficiency for immune cells,
38 including T cells.
39 Gene transfer using AAV vectors has several advantages when treating ocular disease. The relatively small tissue area, accessibility of the eye for direct treatment, and overall ocular compartmentalization allow low doses of AAV vectors to produce therapeutic effects. In addition, low vector doses limit systemic exposure and thereby reduce the possibility of immune responses to the viral capsid or transgene.
40 In fact, two AAV therapeutics have been approved by the US Food and Drug Administration, including voretigene neparvovec (Luxturna) and nusinersen (Spinraza). In addition, 64 ocular clinical trials involving AAV gene therapy are currently listed in clinicaltrials.gov. In the current study, we demonstrated that AAV6 expressing
c-Rel–specific shRNA can efficiently reduce corneal transplant rejection in mice. It is worth noting that AAV6 can successfully transduce human but not mouse T cells. Although corneal transplant rejection is mainly mediated by T cells, inflammatory cytokines produced by macrophages and dendritic cells are also involved in the rejection of corneal graft either directly or through regulating T cell function. We suggest that AAV6-mediated targeting of c-Rel may reduce transplant rejection in mice by modulating the function of macrophage and dendritic cells.