Sandhoff disease is an incurable
neurodegenerative disorder caused by mutations in the lysosomal
hydrolase β-
hexosaminidase. Deficiency in this
enzyme leads to excessive accumulation of
ganglioside GM2 and its asialo derivative, GA2, in brain and visceral tissues. Small molecule inhibitors of
ceramide-specific
glucosyltransferase, the first committed step in
ganglioside biosynthesis, reduce storage of GM2 and GA2. Limited brain access or adverse effects have hampered the therapeutic efficacy of the clinically approved substrate reduction molecules,
eliglustat tartrate and the imino
sugar NB-DNJ (
Miglustat). The novel
eliglustat tartrate analog, 2-(2,3-dihydro-1H-inden-2-yl)-N-((1R,2R)-1-(2,3-dihydrobenzo[b][1, 4]
dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)
acetamide (EtDO-PIP2, CCG-203586 or "3h"), was recently reported to reduce
glucosylceramide in murine brain. Here we assessed the therapeutic efficacy of 3h in juvenile Sandhoff (Hexb-/-) mice. Sandhoff mice received
intraperitoneal injections of
phosphate buffered saline (PBS) or 3h (60 mg/kg/day) from postnatal day 9 (p-9) to postnatal day 15 (p-15). Brain weight and brain water content was similar in 3h and PBS-treated mice. 3h significantly reduced total
ganglioside sialic acid, GM2, and GA2 content in cerebrum, cerebellum and liver of Sandhoff mice. Data from the liver showed that 3h reduced the key upstream
ganglioside precursor (
glucosylceramide), providing evidence for an on target mechanism of action. No significant differences were seen in the distribution of
cholesterol or of neutral and acidic
phospholipids. These data suggest that 3h can be an effective alternative to existing substrate reduction molecules for
ganglioside storage diseases.