Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with <i>N</i> -butyldeoxynojirimycin

TLDR

Sandhoff disease, caused by HEXB mutations, leads to GM2 ganglioside buildup in lysosomes and currently has no CNS‑targeted therapies, making substrate deprivation a promising strategy. The study investigates whether N‑butyldeoxynojirimycin can treat CNS‑involved lysosomal storage diseases. The authors treated a Sandhoff disease mouse model with N‑butyldeoxynojirimycin, an inhibitor that balances glycosphingolipid synthesis with impaired catabolism to prevent storage. Treatment delayed symptom onset, reduced brain and peripheral storage, and extended life expectancy, supporting substrate deprivation as a general therapy for CNS‑involved lysosomal storage diseases.

Abstract

Sandhoff disease is a neurodegenerative disorder resulting from the autosomal recessive inheritance of mutations in the HEXB gene, which encodes the β-subunit of β-hexosaminidase. G M2 ganglioside fails to be degraded and accumulates within lysosomes in cells of the periphery and the central nervous system (CNS). There are currently no therapies for the glycosphingolipid lysosomal storage diseases that involve CNS pathology, including the G M2 gangliosidoses. One strategy for treating this and related diseases is substrate deprivation. This would utilize an inhibitor of glycosphingolipid biosynthesis to balance synthesis with the impaired rate of catabolism, thus preventing storage. One such inhibitor is N -butyldeoxynojirimycin, which currently is in clinical trials for the potential treatment of type 1 Gaucher disease, a related disease that involves glycosphingolipid storage in peripheral tissues, but not in the CNS. In this study, we have evaluated whether this drug also could be applied to the treatment of diseases with CNS storage and pathology. We therefore have treated a mouse model of Sandhoff disease with the inhibitor N -butyldeoxynojirimycin. The treated mice have delayed symptom onset, reduced storage in the brain and peripheral tissues, and increased life expectancy. Substrate deprivation therefore offers a potentially general therapy for this family of lysosomal storage diseases, including those with CNS disease.