Non Viral Gene Transfer Approaches for Lysosomal Storage Disorders

Abstract

The lysosomal storage disorders (LSDs) are a group of almost 50 genetic diseases, characterized by mutations and loss of activity of lysosomal enzymes or, less frequently, non-lysosomal proteins that are involved in protein maturation or lysosomal biogenesis (Meikle et al, 2004). Most LSDs have an autosomal recessive inheritance, with some exceptions as Hunter syndrome (X-linked recessive), Danon disease (X-linked dominant) and Fabry disease (X-linked with a high proportion of heterozygous affected females). Storage of distinct undegraded or partially degraded material, usually the substrate of the defective enzyme, occurs in the lysosome. The substrate type is used to group the LSDs into general categories (table 1), including mucopolysaccharidoses (characterized by the storage of mucopolysaccharides, also called glycosaminoglycans), lipidoses (storage of lipids), glycogenoses (storage of glycogen) and oligosaccharidoses (storage of small sugar chains). Despite this categorization, many clinical similarities are observed between groups as well as within each group. Generally these diseases are multisystemic, and clinical features of many LSDs include organomegaly, central nervous system dysfunction and coarse hair and faces. Most LSDs are characterized by their progressive course with high morbidity and increased mortality, although there are significant variations between different diseases, and even among patients with the same disease (Walkley 2009). Lysosomal enzymes are ubiquitously distributed, but substrate storage is usually restricted to cells, tissues and organs with higher substrate turnover. Recently, it has been suggested that the primary gene defect and substrate storage are triggers of a complex cascade of events that lead to many of the disease manifestations (Bellettato & Scarpa, 2010). In this context, secondary substrate storage, perturbations of Calcium homeostasis and lipid trafficking would contribute to disease pathogenesis. Other manifestations, related to the lysosome’s role in vescicle trafficking, including antigen presentation, innate immunity, and signal transduction would cause inflammatory and auto-immune disturbances observed in the LSD (Parkinson-Lawrence et al., 2010). In addition, general mechanisms such as unfolded protein response, reticulum stress, oxidative stress and autophagy blockade would also play a role in the pathogenesis (Vitner et al., 2010). The incidence and prevalence of these diseases varies from different countries and regions. For example, the overall incidence of GM1 Gangliosidosis is considered to be 1:100,000-