Enzyme replacement therapy in feline mucopolysaccharidosis I

Enzyme replacement therapy (ERT) has long been considered an approach to tr eating lysosomal storage disorders caused by deficiency of lysosomal enzyme s. ERT is currently used to treat Graucher disease and is being developed f or several lysosomal storage disorders now that recombinant sources of the enzymes have become available. We have continued development of ERT for muc opolysaccharidosis I (MPS I) using the feline model, Recombinant alpha -L-i duronidase was administered intravenously at low dose (similar to0.1 mg/kg or 25,000 units/kg) to four cats and high dose (0.5 mg/kg or 125,000 units/ kg) to two cats on a weekly basis for 3- or g-month terms, Clinical examina tions showed distinct clearing of corneal clouding in one cat although clin ical effects in the others were not evident. Biochemical studies of the cat s showed that the enzyme was distributed to a variety of tissues although t he liver and spleen contained the highest enzyme activities. Glycosaminogly can storage was decreased in liver and spleen, and the histologic appearanc e improved in liver, spleen, and renal cortex. Enzyme was not consistently detected in cerebral cortex, brainstem, or cerebellum and the histologic ap pearance and ganglioside pro files did not improve. A variety of other tiss ues showed low variable uptake of enzyme and no distinct improvement, IgG; antibodies to alpha -L-iduronidase were observed in five cats with higher t iters noted when higher doses were administered. Mild complement activation occurred in three cats, Enzyme replacement therapy was effective in revers ing storage in some tissues at the biochemical and histologic level in MPS I cats but an improved tissue distribution and prevention of a significant immune response could make the therapy more effective. (C) 2001 Academic Pr ess.