The meeting brought together a multi-disciplinary group of experts in the field of CNS-directed gene-targeted therapy delivery from academia, industry, advocacy, and the government. The group was charged with identifying the key challenges and gaps in this evolving field, as well as suggesting potential solutions.
“Strategies to evade an immune response
Workshop participants discussed concerns over the immune response to AAV vector DNA sequences and methods to avoid it. Toll-like receptor 9 (TLR9) functions to detect foreign DNA and stimulates immune responses. TLR9 binds to unmethylated CpG motifs, which are frequently enriched in codon-optimized transgenes and strong ubiquitous promoters. Modification of AAV vector sequences to decrease CpG motifs can reduce innate immune responses and help with long-term transgene expression in the mouse skeletal muscle (Faust et al., 2013). Also, AAV vector sequences can be engineered to include short DNA oligonucleotides that inhibit TLR9 activation, reducing immune responses in the mouse liver, muscle, and retinas, as well as in pig retinas.”
