Researchers from University of Rochester Medicine and the University of Copenhagen reported a delivery strategy intended to overcome two persistent gene therapy hurdles—blood-brain barrier crossing and off-target exposure—by pairing engineered AAV vectors with glymphatic targeting in mice. In a Nature Biotechnology paper, the team described engineered AAV capsids and a delivery approach aimed at preferentially transducing glial cell lineages. The platform used engineered AAV5 variants screened in mice with transplanted human glial progenitor cells, tracking infection in human glial progenitor descendants including astrocytes and oligodendrocytes. The authors argue that human-cell molecular signatures and in vivo brain behavior differ from in vitro systems, motivating the in vivo screening approach. The work is positioned for future neurological indications where glial dysfunction is considered a major disease driver, including conditions like Huntington’s disease and multiple sclerosis.