Huntingtin Aggregate-Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6/2 Mice

The accumulation of mutant huntingtin (mHTT) aggregates drives the pathology of Huntington's disease (HD), yet therapies capable of distinguishing toxic species from wild-type proteins remain elusive. Here, a synthetic gene circuit, termed ARAA, was engineered to couple the preferential recognition of aggregated polyQ species to the on-demand activation of autophagy. Utilizing a repurposed bacterial NarX-NarL system fused with a conformation-sensitive intrabody, the circuit detects pathological polyQ conformers and triggers the transcriptional expression of the master autophagy regulator TFEB. To enable systemic application, the ARAA plasmid is encapsulated in CD98-targeted immunoliposomes (LIP-CD98) that facilitate efficient blood-brain barrier crossing via receptor-mediated transcytosis. In the R6/2 HD mouse model, ARAA treatment significantly reduces mHTT burden, attenuates neuroinflammation, and rescues synaptic deficits. This closed-loop intervention improves motor function and extends lifespan. Together, these findings provide proof-of-concept evidence that aggregate-responsive regulation of autophagy can mitigate disease-associated phenotypes in exon 1-based HD models.