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Cloaking vector genomes
Adeno-associated viral (AAV) vectors are frequently used in gene therapy, but they trigger an immune response through Toll-like receptor 9 (TLR9), a receptor that senses foreign DNA. Chan and colleagues incorporated short noncoding DNA sequences into the AAV genome to directly antagonize TLR9 activation and “cloak” the much larger AAV DNA sequence from detection. In mice and pigs, administration of these modified AAV vectors resulted in reduced innate immune and T cell activation with improved gene expression. In macaques, intravitreal injection of the modified vector delayed but did not fully prevent development of uveitis. Incorporation of these cloaking sequences may improve the success of AAV-based gene therapies.
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