Overview of different therapy strategies on the 2 major hurdles in MPS. Patients treated with current standard treatments, ERT and HCT, still experience significant disease progression. Two major hurdles in the failure of these treatments in specific tissues are the presence of a physical barrier, such as the BBB or the BRB, and the vascularity of the tissue. Connective tissues, in which most disease progression is seen and which are avascular, are isolated from the circulation. Thus, they completely depend on diffusion of monocytes and free enzyme. For the epiphyseal plate for instance, the distance to overcome is 4.5 mm, which is too far; therefore, enzyme availability in the epiphyseal plate is still zero, despite treatment. Only increasing the available amount of enzyme in the circulation, like in the GT strategies, will most likely not solve this problem. Furthermore, it is unknown whether monocytes migrate past the BRB into the retina like it is assumed in the central nervous system. Progression of retinal degeneration insinuates that the available amount of enzyme is insufficient, at the least. Therefore, the route to cure MPS disease is to focus on increasing enzyme availability in these “hard-to-reach” tissues.