This is the case when neither endogenous expression, nor over-expression can effectively reach the CNS, but improved routing of lysosomal enzymes significantly enhances efficacy, as has been shown for mucopolysaccharidosis type II (Hunter disease) using apolipoprotein E (ApoE)-tags [137], or for Pompe disease using insulin-like growth factor 2 (IGF2) tags [138]. Here, APOE is linked to mucopolysaccharidosis type 2.