Lysosomal storage diseases (LSD) arise from mutations in the genes for lysosomal proteins that degrade and recycle macromolecules (Futerman and van Meer, 2004; Mach, 2002; Vellodi, 2005; Walkley, 2001). The undegraded waste products accumulate over time, resulting in derangement of cell physiology and eventually cell death. It follows, therefore, that delivery and expression of a wild-type copy of the defective gene to the affected cells should be preventive or therapeutic. For the lysosomal storage disorders, the challenges for gene therapy are to deliver the gene to the target tissue and to achieve reduction of lysosomal storage, thus preserving cellular function. Of the various strategies to achieve that goal, replication-deficient adenovirusderived vectors (Ad) are generally thought to be inappropriate because although Ad vectors mediate high levels of production of their transgene, expression is transient over a period of only a few weeks (Hackett and Crystal, 2003; Trapnell and Gorziglia, 1994; Wilson, 1996). This chapter provides a contrary and counterintuitive view, making the case for using Ad vectors to treat the lysosomal storage disorders. We do so by first providing an overview of the production and properties of Ad vectors and then discussing studies in which Ad has been used to treat animal models of lysosomal storage diseases. The intent of this analysis is to critically evaluate the applicability of Ad for the challenges provided by LSD, including the required spatial and temporal pattern of gene expression. We then discuss a novel hypothesis, which we call setting back the clock, which holds that, for some lysosomal storage diseases, transient overexpression of the deficient gene at high levels may be sufficient to completely reverse the storage defect and may give a substantial benefit, especially in diseases where the accumulation of the storage defect is slow.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)