Abstract
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.
| Language | English |
|---|---|
| Pages | 48-57 |
| Number of pages | 10 |
| Journal | Molecular Genetics and Metabolism |
| Volume | 89 |
| Issue number | 1-2 |
| DOIs | |
| Publication status | Published - 1 Sep 2006 |
Keywords
- Animal model
- Enzyme replacement
- Genetic disease
- Guinea-pig
- Lysosomal storage disease
- Therapy
- α-Mannosidase
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Biochemistry
- Molecular Biology
- Genetics
- Endocrinology
Cite this
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Enzyme replacement therapy in α-mannosidosis guinea-pigs. / Crawley, Allison C.; King, Barbara; Berg, Thomas; Meikle, Peter J.; Hopwood, John J.
In: Molecular Genetics and Metabolism, Vol. 89, No. 1-2, 01.09.2006, p. 48-57.Research output: Contribution to journal › Article
TY - JOUR
T1 - Enzyme replacement therapy in α-mannosidosis guinea-pigs
AU - Crawley, Allison C.
AU - King, Barbara
AU - Berg, Thomas
AU - Meikle, Peter J.
AU - Hopwood, John J.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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.
AB - 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.
KW - Animal model
KW - Enzyme replacement
KW - Genetic disease
KW - Guinea-pig
KW - Lysosomal storage disease
KW - Therapy
KW - α-Mannosidase
UR - http://www.scopus.com/inward/record.url?scp=33747008880&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2006.05.005
DO - 10.1016/j.ymgme.2006.05.005
M3 - Article
VL - 89
SP - 48
EP - 57
JO - Molecular Genetics and Metabolism
T2 - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 1-2
ER -