Cut the supply: a new treatment strategy for lysosomal storage diseases

Abstract

In patients with Sandhoff disease, certain glycosphingolipids (GSLs) fail to be degraded and accumulate in lysosomes owing to the insufficient activity of the lysosomal enzyme β-hexosaminidase. The accumulation of GSLs in neurons leads to the progressive neurodegeneration that characterizes Sandhoff disease. Currently, there is no cure for this disease; although intravenous administration of exogenous enzymes is being used to treat other lysosomal storage disorders, this approach is ineffective for Sandhoff disease because injected β-hexosaminidase is unable to cross the blood–brain barrier to reach the GSLs in the central nervous system (CNS).Recently, a new strategy called substrate deprivation has emerged as a promising avenue to treat lysosomal storage disorders that involve CNS complications. It is based upon inhibiting the enzymes that catalyze the initial steps of GSL biosynthesis. By slowing down the de novo synthesis of GSLs, the residual enzyme activity present (in cells, neurons or lysosomes) can catabolize the GSLs. In this paper, Jeyakumar et al.1xDelayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Jeyakumar, M. et al. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6388–6393Crossref | PubMed | Scopus (180)See all References1 have used the substrate-deprivation approach in a mouse model of Sandhoff disease. These mice undergo rapid, progressive neurodegeneration and die between four to five months of age. In these experiments, Sandhoff mice were treated with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of GSL biosynthesis. The treated mice had their life expectancy extended by ∼40% and had reduced GSL storage in the CNS and in peripheral tissues, such as the liver. Moreover, the NB-DNJ-treated mice performed significantly better than a control group in a variety of behavioral tests. However, the treatment was only effective when given at an early age (between three to six weeks of age). NB-DNJ administered after 11 weeks of age did not increase life expectancy, indicating that irreversible CNS damage had already occurred.The limiting factor in using substrate deprivation is that it requires a residual amount of enzyme activity to catabolize the reduced substrate levels that enter the lysosome. Thus substrate deprivation is expected to be most effective in adult- and juvenile-onset forms of the disease, where low-to-moderate levels of residual enzyme activity are present.