Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study

• Published in: Journal of inherited metabolic disease Vol. 36; no. 6; pp. 1015 - 1024
• Main Authors: Borgwardt, L., Dali, C. I., Fogh, J., Månsson, J. E., Olsen, K. J., Beck, H. C., Nielsen, K. G., Nielsen, L. H., Olsen, S. O. E., Riise Stensland, H. M. F., Nilssen, O., Wibrand, F., Thuesen, A. M., Pearl, T., Haugsted, U., Saftig, P., Blanz, J., Jones, S. A., Tylki-Szymanska, A., Guffon-Fouiloux, N., Beck, M., Lund, A. M.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.11.2013; Springer; Blackwell Publishing Ltd
• Subjects: Adolescent; alpha-Mannosidase - administration & dosage; alpha-Mannosidase - adverse effects; alpha-Mannosidase - immunology; alpha-Mannosidase - pharmacokinetics; alpha-Mannosidosis - drug therapy; Biochemistry; Biological and medical sciences; Carbohydrates (enzymatic deficiencies). Glycogenosis; Child; Cognition - drug effects; Dose-Response Relationship, Drug; Enzyme Replacement Therapy - adverse effects; Enzyme Replacement Therapy - methods; Errors of metabolism; Exercise Test; Follow-Up Studies; Human Genetics; Humans; Internal Medicine; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Original Article; Pediatrics; Psychomotor Performance - drug effects; Recombinant Proteins - administration & dosage; Recombinant Proteins - adverse effects; Recombinant Proteins - immunology; Recombinant Proteins - pharmacokinetics; Treatment Outcome; Enzyme Replacement Therapy; Force Vital Capacity; Pulmonary Function Test; Intellectual Disability; Haematopoietic Stem Cell Transplantation; Replacement therapy; Nutrition; Enzyme; Single dose; Metabolic diseases; Enzymopathy; Genetic disease; Multiple dose; Mucolipidosis; Chemotherapy; Randomization; Treatment; Surveillance; Follow up study; Genetics; Carbohydrate; Mannosidosis
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-013-9595-1

Background Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. Methods This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7–17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. Results Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6 % (CI −92.0 −85.2, p  < 0.001), 54.1 % (CI −69.5- −38.7, p  < 0,001), and 25.7 % (CI −44.3- −7.1, p  < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15 %, p  < 0.009) and 32.5, p  < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p  < 0.01) and in 6MWT (60.4 m (CI −8.9 −51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI −0.2-0.8, NS). Conclusions These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.