Key result
rAAV vectors containing miR142-binding sites efficiently repressed costimulatory signals in DCs, blunted the cytotoxic T cell response, and allowed for sustained transgene expression in mice.
Why the study?
rAAV gene delivery is limited by host immune responses against the transgene, and the mechanisms underlying miRNA-mediated detargeting from antigen presenting cells to modulate anti-transgene immunity are not fully understood.
Incorporating APC-specific miRNA binding sites into rAAV vectors effectively reduces transgene-specific immune responses, holding promise for safe gene delivery.
Supports miR142 detargeting in rAAV for reduced immunogenicity in mice; human translation and safety remain untested.
Recombinant adeno-associated virus (rAAV)-mediated gene delivery can efficiently target muscle tissues to serve as "biofactories" for secreted proteins in prophylactic and therapeutic scenarios. Nevertheless, efficient rAAV-mediated gene delivery is often limited by host immune responses against the transgene product. The development of strategies to prevent anti-transgene immunity is therefore crucial. The employment of endogenous microRNA (miRNA)-mediated regulation to detarget transgene expression from antigen presenting cells (APCs) has shown promise for reducing immunogenicity. However, the mechanisms underlying miRNA-mediated modulation of anti-transgene immunity by APC detargeting are not fully understood. Using the highly immunogenic ovalbumin (OVA) protein as a proxy for foreign antigens, we show that rAAV vectors containing miR142 binding sites efficiently repress co-stimulatory signals in dendritic cells, significantly blunt the cytotoxic T cell response, allow for sustained transgene expression in skeletal myoblasts, and attenuate clearance of transduced muscle cells in mice. Furthermore, the blunting of humoral immunity against circulating OVA correlates with detargeting of OVA expression from APCs. This demonstrates that incorporating APC-specific miRNA binding sites into rAAV vectors provides an effective strategy for reducing transgene-specific immune response. This approach holds promise for clinical applications where the safe and efficient delivery of a prophylactic or therapeutic protein is desired.
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Xiao et al. (2019) studied Transgene immunity in rAAV gene therapy. rAAV vectors containing miR142-binding sites (rAAV1.OVA.miR142BS) vs. rAAV vectors without miR142-binding sites (rAAV1.OVA) was evaluated on Sustained transgene (OVA) expression and immune response attenuation. rAAV vectors containing miR142-binding sites efficiently repressed costimulatory signals in DCs, blunted the cytotoxic T cell response, and allowed for sustained transgene expression in mice.
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