Fig. (2).

Transport of a lysosomal enzyme in a normal cell, correction of storage in the cell of a patient with Mucopolysaccharidosis, and basis for ‘cross-correction’. The M6P recognition signal is added to the lysosomal enzyme precursor in the late-Golgi compartments, where enzyme modified by M6P binds to M6P receptors. The enzyme–receptor complex is packaged into a transport carrier vesicle and delivered to early endosomes in which low pH promotes the dissociation of the enzyme from the receptor. The enzyme is then delivered to the mature lysosome, and the M6P receptor is recycled to the Golgi apparatus. A small amount of the M6P–modified enzyme escapes capture by the M6P receptors and is released into the extra-cellular space. This enzyme can be recaptured by binding to a M6P receptor in a clathrin-coated pit on the cell surface. In a patient who has undergone hematopoietic stem-cell transplantation, enzyme released from a donor-derived stem cell can be taken up by a Mucopolysaccharidosis cell, which corrects aberrant glycosaminoglycan storage (from [Muenzer, J. & Fisher, A. (2004) Advances in the treatment of Mucopolysaccharidosis type I. New England Journal of Medicine 350(19):1932–4] Massachusetts Medical Society. All rights reserved, with permission of the editor).