Gene therapy of lysosomal storage disorders by lentiviral vectors

Lysosomal storage disorders (LSDs) comprise a class of inherited diseases characterized by disruption of normal lysosomal function and the consequent accumulation of incompletely degraded substrates. Most LSDs are caused by loss of function of specific lysosomal acid hydrolases, which act to degrade complex substrates that have been targeted for degradation after endocytosis or autophagy. The degradation occurs by a stepwise pathway, and if one step in the process fails, further degradation often ceases and the partially degraded substrate accumulates. The ensuing substrate accumulation in lysosomes affects the architecture and function of cells, tissues, and organs. In some cases, the accumulated substrate itself (as in Galactocerebrosidosis) or the product of an alternative metabolic route, which is upregulated by the accumulated primary substrate (as in the case of psycosine in Globoid Cell Leukodystrophy), is cytotoxic and leads to cell dysfunction or death. In other cases, the actual molecular mechanism triggered by the accumulated metabolite and leading to cellular toxicity and tissue pathology remains elusive.