Cardiac pathology in mucopolysaccharidosis I mice: Losartan modifies ERK1/2 activation during cardiac remodeling.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by mutations in the IDUA gene, that codifies the alpha-L-iduronidase enzyme, which deficiency leads to storage of glycosaminoglycans, with multiple clinical manifestations. One of the leading causes of death in MPS I patients are cardiac complications such as cardiac valve thickening, conduction abnormalities, myocardial dysfunction, and cardiac hypertrophy. The mechanism leading to cardiac dysfunction in MPS I is not entirely understood. In a previous study, we have demonstrated that losartan and propranolol improved the cardiac function in MPS I mice. Thus, we aimed to investigate whether the pathways influenced by these drugs may modulate the cardiac remodeling process in MPS I mice. According to our previous observation, losartan and propranolol restore the heart function, without altering valve thickness. MPS I mice presented reduced activation of AKT and ERK1/2, increased activity of cathepsins, but no alteration in metalloproteinase activity was observed. Animals treated with losartan showed a reduction in cathepsin activity and restored ERK1/2 activation. While both losartan and propranolol improved heart function, no mechanistic evidence was found for propranolol so far. Our results suggest that losartan or propranolol could be used to ameliorate the cardiac disease in MPS I and could be considered as adjuvant treatment candidates for therapy optimization.

Selective normalisation of regional brain bis(monoacylglycero)phosphate in the mucopolysaccharidosis 1 (Hurler) mouse.

Bis(monoacylglycero)phosphate (BMP) is a glycerophospholipid highly enriched in the lysosomal network and elevated in lysosomal diseases. To correct this elevation, BMP synthesis was manipulated by dietary fatty acid supplementation and the impact on subregional brain BMP and pathology assessed in the mouse model of mucopolysaccharidosis 1 (Hurler syndrome (HS)). There was widespread elevation of BMP in HS mice across all six sub-regions - brain stem, cortex, cerebellum, hippocampus, olfactory bulb and the sub-cortex - with 22:6/22:6 the most abundant species. Linoleic acid normalised total BMP in all regions except the cortex and cerebellum, although there were differences in fatty acid species; the major finding a decrease in 22:6- and a concomitant increase in 22:5-containing species. A battery of behaviour assessments showed that in the water cross maze both HS and wild type mice performed less well on the linoleic acid diet, and that both HS and wild type mice on the linoleic acid diet performed similarly and better in the exploratory open field test. This may be a consequence of differential subregional BMP composition in the brain. The effects of high fat and docosahexaenoic/eicosapentaenoic acid enriched diets were generally unremarkable. Although major pathologies were not completely abrogated, much of the neurobehavioural testing was confounded by skeletal pathology that did not resolve. This is the first detailed characterisation of subregional brain BMP species informing on the ability to manipulate this phospholipid in the brain, and as such, may hold promise as an adjunct therapy not only for HS but also for other lysosomal diseases.

Liver-directed neonatal gene therapy prevents cardiac, bone, ear, and eye disease in mucopolysaccharidosis I mice.

Mucopolysaccharidosis I (MPS I) due to deficient alpha-L-iduronidase (IDUA) activity results in accumulation of glycosaminoglycans in many cells. Gene therapy could program liver to secrete enzyme with mannose 6-phosphate (M6P), and enzyme in blood could be taken up by other cells via the M6P receptor. Newborn MPS I mice were injected with 10(9) (high dose) or 10(8) (low dose) transducing units/kg of a retroviral vector (RV) expressing canine IDUA. Most animals achieved stable expression of IDUA in serum at 1240 +/- 147 and 110 +/- 31 units/ml, respectively. At 8 months, untreated MPS I mice had aortic insufficiency, increased bone mineral density (BMD), and reduced responses to sound and light. In contrast, MPS I mice that received high-dose RV had normal echocardiograms, BMD, auditory-evoked brain-stem responses, and electroretinograms. This is the first report of complete correction of these clinical manifestations in any model of mucopolysaccharidosis. Biochemical and pathologic evaluation confirmed that storage was reduced in these organs. Mice that received low-dose RV and achieved 30 units/ml of serum IDUA activity had no or only partial improvement. We conclude that high-dose neonatal gene therapy with an RV reduces some major clinical manifestations of MPS I in mice, but low dose is less effective.

Cerebral MRI in two brothers with mucopolysaccharidosis type I and different clinical phenotypes.

We describe a cerebral MRI study of two brothers with mucopolysaccharidosis type I. They are of similar physical appearance, but the younger is severely mentally retarded while the elder is of normal intelligence. MRI shows characteristic abnormalities in the CNS, but it is not yet possible to establish a correlation between them and the mental retardation.