Pilot clinical trials of bone marrow transplantation (BMT) for lysosomal storage diseases have demonstrated that (1) this potential therapeutic modality is an effective means of introducing large amounts of enzyme-producing cells on a continuous basis into patients with enzyme deficiency diseases; (2) long-term engraftment by normal donor cells results in metabolic correction as demonstrated by cessation, or reversal, of substrate accumulation and by disappearance of the pathomorphologic and pathophysiologic correlates; and (3) central nervous system disease appears to be accessible to treatment by this means. The goal of this study is to extend these observations thereby permitting broader generalization, and defining the efficacy of this therapeutic modality. These studies will characterize the extent, the degree, and the rate of metabolic correction in the prototypic mucopolysaccharidosis (MPS) disease, Hurler syndrome, and will compare the response in a limited number of other patients representing the broader spectrum of MPS disorders. Assays of lysosomal enzymatic activity will be used to confirm the diagnosis of a specific MPS disease, to determine the homozygote/heterozygote genotype of sibling donors, and to follow the course of engraftment. Special modifications of these assays will be used to study small increments of enzyme activity in nonhematologic tissues and fluids (eg, liver, cerebrospinal fluid, tears) after stem cell engraftment. Highly sensitive methodologies for measuring tissue glycosaminoglycan substrates will be used to follow the response and will be correlated with quantitative morphometric analysis of lysosomal inclusion morphology. This proposal assumes that trials of BMT for MPS disease are best accomplished at a facility with extensive experience in marrow of each disease entity. We describe a program committed to the longitudinal evaluation of 8 new patients per year, in each of 5 years, to quantitate parameters of metabolic correction and to assess corresponding effects at specific pathophysiologic sites, especially the central nervous system. Important issues to be studied by this project are a) the age at which BMT must be accomplished to be effective, b) which tissues and organs are responsive to treatment, and which are not, and c) description of the biochemical and morphologic parameters which are most helpful in monitoring the progress of metabolic correction. These studies will further delineate the potentially broad application of BMT for inborn errors of metabolism, and will be crucial in defining the requisites for future attempts at gene therapy.
