Enzyme replacement therapy: efficacy and limitations.

Enzyme replacement therapy (ERT) is available for mucopolysaccharidosis (MPS) I, MPS II, MPS VI, and MPS IVA. The efficacy of ERT has been evaluated in clinical trials and in many post-marketing studies with a long-term follow-up for MPS I, MPS II, and MPS VI. While ERT is effective in reducing urinary glycosaminoglycans (GAGs) and liver and spleen volume, cartilaginous organs such as the trachea and bronchi, bones and eyes are poorly impacted by ERT probably due to limited penetration in the specific tissue. ERT in the present formulations also does not cross the blood-brain barrier, with the consequence that the central nervous system is not cured by ERT. This is particularly important for severe forms of MPS I and MPS II characterized by cognitive decline. For severe MPS I patients (Hurler), early haematopoietic stem cell transplantation is the gold standard, while still controversial is the role of stem cell transplantation in MPS II. The use of ERT in patients with severe cognitive decline is the subject of debate; the current position of the scientific community is that ERT must be started in all patients who do not have a more effective treatment. Neonatal screening is widely suggested for treatable MPS, and many pilot studies are ongoing. The rationale is that early, possibly pre-symptomatic treatment can improve prognosis. All patients develop anti-ERT antibodies but only a few have drug-related adverse reactions. It has not yet been definitely clarified if high-titre antibodies may, at least in some cases, reduce the efficacy of ERT.