Gene transfer strategies for correction of lysosomal storage disorders

Lysosomal storage diseases (LSDs) represent a large group of monogenic disorders of metabolism, which affect approximately 1 in 5000 live births. LSDs result from a single or multiple deficiency of specific lysosomal hydrolases, the enzymes responsible for the luminal catabolization of macromolecular substrates. The consequent accumulation of undigested metabolites in lysosomes leads to polysystemic dysfunction, including progressive neurologic deterioration, mental retardation, visceromegaly, blindness, and early death. In general, the residual amount of functional enzyme in lysosomes determines the severity and age at onset of the clinical symptoms, implying that even modest increases in enzyme activity might affect a cure. A key feature on which therapy for LSDs is based is the ability of soluble enzyme precursors to be secreted by one cell type and reinternalize by neighboring cells via receptor-mediated endocytosis and routed to lysosomes, where they function normally. In principle, somatic gene therapy could be the preferred treatment for LSDs if the patient's own cells could be genetically modified in vitro or in vivo to constitutively express high levels of the correcting enzyme and become the source of the enzyme in the patient. Both ex vivo and in vivo gene transfer methods have been experimented with for gene therapy of lysosomal disorders. Several of these methods have proved efficient for the transfer of genetic material into deficient cells in culture and reconstitution of enzyme activity. However, the same methods applied to humans or animal models have been giving inconsistent results, the bases of which are not fully understood. A broader knowledge of disease pathogenesis, facilitated by available, faithful animal models of LSDs, coupled to the development of better gene transfer systems as well as the understanding of vector host interactions will make somatic gene therapy for these devastating and complex diseases the most suitable therapeutic approach.