Enzyme replacement therapy in α-mannosidosis guinea-pigs

α-Mannosidosis is a lysosomal storage disorder caused by deficient activity of lysosomal α-mannosidase and is characterised by massive accumulation of mannose-containing oligosaccharides in affected individuals. Patients develop behaviour and learning difficulties, skeletal abnormalities, immune deficiency and hearing impairment. Disease in α-mannosidosis guinea-pigs resembles the clinical, histopathological, biochemical and molecular features of the human disease. We have used the guinea-pig model to investigate efficacy of enzyme replacement therapy as a treatment for α-mannosidosis. Intravenous recombinant human lysosomal α-mannosidase, administered at a dose of 1 mg/kg, was cleared from circulation with a half-life of 53 h, with significant enzyme activity (1.4× normal levels) detected in circulation one week post-injection. α-Mannosidase administered to α-mannosidosis guinea-pigs at 1 mg/kg (onset at birth or ∼30 days) and 10 mg/kg (at birth) was distributed widely amongst tissues, including to capillary depleted brain. By monitoring with tandem mass spectrometry, enzyme replacement therapy was found to be effective in reducing stored substrates in peripheral tissues at both dose rates, and in brain by up to 39% at the 10 mg/kg dose, compared with untreated α-mannosidosis controls. Reductions of up to 60% of urinary mannose containing oligosaccharides were also observed. No histological improvements were seen in the brain at either dose, however marked decreases in lysosomal vacuolation in liver, kidney, spleen and endocrine pancreas, as well as a significant reduction in trigeminal ganglion neurons were observed. Multiple injections of 1 mg/kg recombinant enzyme in α-mannosidosis guinea-pigs induced a very rapid humoral immune response precluding long-term intravenous treatment.