Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice.

Abstract

The GM2 gangliosidoses are a group of severe, neurodegenerative conditions that include Tay-Sachs disease, Sandhoff disease, and the GM2 activator deficiency. Bone marrow transplantation (BMT) was examined as a potential treatment for these disorders using a Sandhoff disease mouse model. BMT extended the life span of these mice from approximately 4.5 mo to up to 8 mo and slowed their neurologic deterioration. BMT also corrected biochemical deficiencies in somatic tissues as indicated by decreased excretion of urinary oligosaccharides, and lower glycolipid storage and increased levels of beta-hexosaminidase activity in visceral organs. Even with neurologic improvement, neither clear reduction of brain glycolipid storage nor improvement in neuronal pathology could be detected, suggesting a complex pathogenic mechanism. Histological analysis revealed beta-hexosaminidase-positive cells in the central nervous system and visceral organs with a concomitant reduction of colloidal iron-positive macrophages. These results may be important for the design of treatment approaches for the GM2 gangliosidoses.

Early deficits in motor coordination and cognitive dysfunction in a mouse model of the neurodegenerative lysosomal storage disorder, Sandhoff disease

“…4C) indicative of increased "anxiety-like" behavior in the hexb−/−mice. We have employed a behavioral test battery to assess a mouse model of Sandhoff disease that we backbred onto the C57BL/6J background.We demonstrated deficits in motor activity, and coordination consistent with those previously reported [1,7,8,13,14,16,18,20,22,25,27,28] suggesting no significant effect of genetic background. However, we were also able to detect deficits as early as 66 days using the balance beam test.…”

“…However, we were also able to detect deficits as early as 66 days using the balance beam test. Importantly, we have now extended the range of behavioral assays to include tests of cognitive function which demonstrate memory deficits and increased "anxiety-like" behavior.Although we cannot rule out peripheral factors that could affect motor performance [13,22,25], we suggest this is not primary cause of the poor coordination in the balance beam and rotarod that we demonstrate here. The mice did not have abnormal grip (hexb−/ −8.6 ± 1.4 s and hexb+/+ 13.3 ± 2.5 s) and exhibited voluntary activity and exploration within normal ranges at the time points tested.…”

“…The Sandhoff models have engendered much research directed at overcoming the challenges [1,2,4,11,14,15,18,20]. The knockout model [25] presented here displays ataxia, tremor, muscle wasting, and deficits in motor reflex, coordination and balance [1,4,7,8,13,14,16,18,20,22,25,27,28]. However, systematic studies examining cognitive or affective outcomes are lacking [25].…”

“…Both latency (time to cross the beam from end to end) and number of slips (each time a paw fell under the beam midline) were assessed as measures of motor coordination. In the rotarod test, latency to fall from a rotating rod (acceleration increased by 0.5 cm/s every 5 s) was scored automatically with infrared sensors in a Rotamex 5 rotarod (Columbus Inst, Ohio) with four trials per day over 2 days.Behavioral tests were primarily conducted on mice of 79(±2) days old, an age that in most previous assays showed no deficits, but were also performed on some at 66(± 2) and 97(± 2) days when had been typically reported as normal or displaying deficits, respectively [1,4,7,8,13,14,16,18,20,22,25,27,28]. All data are shown as mean ± S.E.M.…”

Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations

“…However, in other lipid storage disorders such as Gaucher's disease low amounts of substituted enzyme are sufficient to reverse glucocerebroside storage, and upon BMT in mice with Sandhoff's disease the amount of gangliosides in the liver was substantially reduced although only 40% of normal ␤-hexosaminidase activity was reached in this organ. 19,20 Thus, compared with other lipid storage diseases stored sulfatide or ASA may have particular properties requiring comparatively large amounts of enzyme for amelioration of storage. The lysosomal deposition of sulfatide is paralleled by an enrichment of this sphingolipid in the cytoplasmic membrane and such membranes display physicochemical characteristics distinct from normal membranes.…”