Models of Lysosomal Storage Disorders Useful for the Study of Gene Therapy

Abstract

Lysosomal storage disorders are a group of monogenic inherited disorders that are caused by the deficiency of a catabolic enzyme. There is one exception, known as I-cell disease, where the defect is in an enzyme involved in the biosynthesis of the mannose-6-phosphate structure, required for the routing of most of the enzymes to the lysosome [1]. Localized within the organelle by a highly specialized transport system, the enzymes reside within the lysosome and are responsible for the degradation of macromolecular polymers or complex molecules that must be disposed of. Failure to degrade these molecules results in storage of the compounds and disease. The principle compounds involved in the lysosomal storage disorders are glycosaminoglycans (mucopolysaccharide), glycolipids and glycoproteins [2, 3]. Substrate accumulation is usually followed by cell dysfunction and death as well as the development of severe and often ultimately lethal symptoms in the patient, particularly when the central nervous system is involved. Many of these enzymatic deficiencies are found also in animals, (Tab. 2-1) [4–22] providing defined and controlled models for study. Bone marrow transplantation has been studied in some of these models and correlations have been drawn to the human diseases (Tab. 2-2). These results are useful in considering strategies designed to transfer genes to bone marrow stem cells [23, 24]. The majority of these animal models are found naturally, in domestic species, where selective inbreeding promotes the production of homozygotes for recessive mutant alleles. Many examples were discovered in pet and farm animals [25]. For diseases not yet discovered in animals, the advent of gene targeting in pluripotent mouse embryonic stem (ES) cells [26] has allowed the experimental development of at least three murine examples of human lysosomal storage conditions: glucocerebroside storage (Gaucher disease), cerebroside sulfatide storage (metachromatic leukodystrophy) and hexosaminidase A deficiency (Tay Sachs disease) [7–9] Additionally, gene targeted murine models of sphingomyelinase deficiency (Niemann-Pick disease), mucopolysaccharidosis VI and ceramide trihexosidase deficiency (Fabry disease) have been reported [10–12] but are not yet fully described in the published literature. Two animal models of lysosomal storage provide excellent examples of the types of studies that may be carried out with animal models of lysosomal storage diseases, as well as some of the problems associated with their use.