Substrate Reduction Therapy for Sandhoff Disease through Inhibition of Glucosylceramide Synthase Activity.
Neuronopathic glycosphingolipidoses are a sub-group of lysosomal storage disorders for which there are presently no effective therapies. Here, we evaluated the potential of substrate reduction therapy (SRT) using an inhibitor of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide (GL1) and related glycosphingolipids. The substrates that accumulate in Sandhoff disease (e.g., ganglioside GM2 and its nonacylated derivative, lyso-GM2) are distal to the drug target, GCS. Treatment of Sandhoff mice with a GCS inhibitor that has demonstrated CNS access (Genz-682452) reduced the accumulation of GL1 and GM2, as well as a variety of disease-associated substrates in the liver and brain. Concomitant with these effects was a significant decrease in the expression of CD68 and glycoprotein non-metastatic melanoma B protein (Gpnmb) in the brain, indicating a reduction in microgliosis in the treated mice. Moreover, using in vivo imaging, we showed that the monocytic biomarker translocator protein (TSPO), which was elevated in Sandhoff mice, was normalized following Genz-682452 treatment. These positive effects translated in turn into a delay (∼28 days) in loss of motor function and coordination, as measured by rotarod latency, and a significant increase in longevity (∼17.5%). Together, these results support the development of SRT for the treatment of gangliosidoses, particularly in patients with residual enzyme activity.
['Marshall|John|J|', 'Nietupski|Jennifer B|JB|', 'Park|Hyejung|H|', 'Cao|James|J|', 'Bangari|Dinesh S|DS|', 'Silvescu|Cristina|C|', 'Wilper|Terry|T|', 'Randall|Kristen|K|', 'Tietz|Drew|D|', 'Wang|Bing|B|', 'Ying|Xiaoyou|X|', 'Leonard|John P|JP|', 'Cheng|Seng H|SH|']
D000818:Animals D001921:Brain D002219:Carbamates D004195:Disease Models, Animal D004791:Enzyme Inhibitors D005260:Female D005964:Glucosyltransferases D008024:Ligands D008099:Liver D008297:Male D013058:Mass Spectrometry D051379:Mice D018345:Mice, Knockout D057054:Molecular Imaging D011812:Quinuclidines D018079:Receptors, GABA D012497:Sandhoff Disease D013107:Sphingolipids D054821:beta-Hexosaminidase beta Chain
substrate reduction therapy Sandhoff disease glucosylceramide synthase lysosomal storage disorder glycosphingolipid in vivo imaging GM2 gangliosidosis tissue mass spectrometry imaging