What is the greatest challenge to increasing AAV potency in human tissues today—delivery to the target cell, cellular entry, intracellular processing, vector genome expression, or our inability to predict these processes from preclinical models?

How could capsid, route of administration and target tissue be co-optimized rather than developed as largely independent variables?

What will define success for the next generation of capsids: increased potency/reduced dose, target-cell selectivity, reduced off-target biodistribution, immune evasion—or some combination of these characteristics?

To what degree can we realistically solve the challenge of immunogenicity through vector engineering as opposed to dose reduction and pharmacological immune management?

What experimental evidence might increase confidence that a capsid optimized in animals would perform similarly in humans—and should human tissues, organoids and other human-based models play a much earlier role in vector selection?