Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of aspartylglycosaminuria mice

Abstract

Aspartylglycosaminuria (AGU) is a lysosomal storage disease caused by deficient activity of glycosylasparaginase (AGA), and characterized by motor and mental retardation. Enzyme replacement therapy (ERT) in adult AGU mice with AGA removes the accumulating substance aspartylglucosamine from and reverses pathology in many somatic tissues, but has only limited efficacy in the brain tissue of the animals. In the current work, ERT of AGU mice was initiated at the age of 1 week with three different dosage schedules of recombinant glycosylasparaginase. The animals received either 3.4 U of AGA/kg every second day for 2 weeks (Group 1), 1.7 U/kg every second day for 9 days followed by an enzyme injection once a week for 4 weeks (Group 2) or 17 U/kg at the age of 7 and 9 days (Group 3). In the Group 1 and Group 3 mice, ERT reduced the amount of aspartylglucosamine by 34 and 41% in the brain tissue, respectively. No therapeutic effect was observed in the brain tissue of Group 2 mice. As in the case of adult AGU mice, the AGA therapy was much more effective in the somatic tissues than in the brain tissue of the newborn AGU mice. The combined evidence demonstrates that a high dose ERT with AGA in newborn AGU mice is up to twofold more effective in reducing the amount of the accumulated storage material from the brain tissue than ERT in adult AGU animals, indicating the importance of early detection and treatment of the disease.

Chronic enzyme replacement therapy ameliorates neuropathology in alpha‐mannosidosis mice

“…Further uptake studies, using different preparations of recombinant enzymes that are commercially available are therefore necessary to elucidate whether modification of the glycan structure and/or a low phosphorylation content in general, or only in the case of specific enzymes can improve brain uptake. Furthermore, it should be investigated if an earlier onset of treatment might result in improved efficacy of ERT, as described for other preclinical ERT in murine LSD models 41, 42, 43, 44. Impairment of the blood–brain barrier integrity in LSDs represents another pathway of how an enzyme can reach the brain 14.…”

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

“…For example, a-mannosidosis (OMIM 248500), caused by mutations in the a-mannosidase (MAN2B1, EC 3.2.1.24, 609458) gene, has been described in cats, cattle, guinea pigs, humans, and knockout mice (Auclair and Hopwood 2007;Blanz et al 2008;Crawley and Walkley 2007;Damme et al 2011;Stinchi et al 1999;Vite et al 2001) and has somewhat different neurological manifestations and neuropathological characteristics depending on the species. Aspartylglucosaminuria (AGU, OMIM 208400) (Dunder et al 2010;Jalanko et al 1998;Kaartinen et al 1996) is caused by mutations in the gene for glycosylasparaginase (AGA, EC 3.5.1.26, 613228), the enzyme necessary for hydrolysis of the proteinoligosaccharide linkage in N-linked glycoproteins. Glycosylasparaginase deficiency results in accumulation of glycoasparagines, such as aspartylglucosamine (GlcNAc-Asn), a small molecule that may be analogous to Man(b1-4)GlcNAc.…”

“…Cognitive or behavioral deficits have been identified in a-mannosidosis and AGU knockout mice, and correlate with CNS pathology. Both animal models have been used successfully to explore therapeutic strategies to improve brain function (Blanz et al 2008;Damme et al 2011;Dunder et al 2010).…”

Brain MRI findings in aspartylglucosaminuria

“…From the MR examinations, twelve parameters were evaluated. These included thalamic (1) and pulvinar nuclei SI changes (2), periventricular (3) and other white matter SI abnormalities (4), GM/WM differentiation (5), PVS dilatation (6), widening of cerebral sulci (7) and cerebellar fissures (8), enlargement of ventricles (9), abnormalities of the corpus callosum (10), cystic changes (11) and the presence of cavum variations (12). …”

“…Lysosomal storage disorders that primarily affect the central nervous system have no known treatment available to cure or slow down the progression of the disease. Mouse model studies investigating virus-mediated gene therapy and enzyme replacement therapy in AGU have shown some metabolic correction and decreased storage in the brain [8][9][10]. Previous brain MRI studies at 1.0 and 1.5 T have shown thalamic T2 SI decrease, delayed myelination and increased T2 SI in the periventricular WM in AGU [1,11,12].…”