Regarding protein-replacement therapy, factors worth considering include a short half-life, potential association with autoimmunity [194,195,196,197], the risk of overexpression of PGRN in the periphery and potential off-target effects [198,199,200], BBB permeability, and the possibility that the fusion protein may affect processing of PGRN in the lysosome. Here, GRN is linked to Autoimmunity.