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01.11.2013 | Original Article

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

verfasst von: L. Borgwardt, C. I. Dali, J. Fogh, J. E. Månsson, K. J. Olsen, H. C. Beck, K. G. Nielsen, L. H. Nielsen, S. O. E. Olsen, H. M. F. Riise Stensland, O. Nilssen, F. Wibrand, A. M. Thuesen, T. Pearl, U. Haugsted, P. Saftig, J. Blanz, S. A. Jones, A. Tylki-Szymanska, N. Guffon-Fouiloux, M. Beck, A. M. Lund

Erschienen in: Journal of Inherited Metabolic Disease | Ausgabe 6/2013

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Abstract

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.

ATS committee on profiency standards for clinical pulmonary function laboratories (2002) ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 166(1):111–117CrossRef

Balfour-Lynn IM, Prasad SA, Laverty A, Whitehead BF, Dinwiddie R (1998) A step in the right direction: assessing exercise tolerance in cystic fibrosis. Pediatr Pulmonol 25(4):278–284PubMedCrossRef

Beydon N, Davis SD, Lombardi E et al (2007) An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med 175(12):1304–1345PubMedCrossRef

Blanz J, Stroobants S, Lullmann-Rauch R et al (2008) Reversal of peripheral and central neural storage and ataxia after recombinant enzyme replacement therapy in alpha-mannosidosis mice. Hum Mol Genet 17(22):3437–3445PubMedCrossRef

Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E (1995) Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 26(3):231–245PubMedCrossRef

Bolton JW, Weiman DS, Haynes JL, Hornung CA, Olsen GN, Almond CH (1987) Stair climbing as an indicator of pulmonary function. Chest 92(5):783–788PubMedCrossRef

Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130PubMedCrossRef

Colletti L, Zoccante L (2008) Nonverbal cognitive abilities and auditory performance in children fitted with auditory brainstem implants: preliminary report. Laryngoscope 118(8):1443–1448PubMedCrossRef

Crawley AC, Walkley SU (2007) Developmental analysis of CNS pathology in the lysosomal storage disease alpha-mannosidosis. J Neuropathol Exp Neurol 66(8):687–697PubMedCrossRef

Crawley AC, Jones MZ, Bonning LE, Finnie JW, Hopwood JJ (1999) Alpha-mannosidosis in the guinea pig: a new animal model for lysosomal storage disorders. Pediatr Res 46(5):501–509PubMedCrossRef

Deitz JC, Kartin D, Kopp K (2007) Review of the Bruininks-Oseretsky test of motor proficiency, second edition (BOT-2). Phys Occup Ther Pediatr 27(4):87–102PubMedCrossRef

Eng CM, Banikazemi M, Gordon RE et al (2001a) A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies. Am J Hum Genet 68(3):711–722PubMedCrossRef

Eng CM, Guffon N, Wilcox WR et al (2001b) Safety and efficacy of recombinant human alpha-galactosidase A–replacement therapy in Fabry’s disease. N Engl J Med 345(1):9–16PubMedCrossRef

Giovannoni G, Nath A (2011) After the storm: neurofilament levels as a surrogate endpoint for neuroaxonal damage. Neurology 76(14):1200–1201PubMedCrossRef

Grubb JH, Vogler C, Levy B, Galvin N, Tan Y, Sly WS (2008) Chemically modified beta-glucuronidase crosses blood–brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 105(7):2616–2621PubMedCrossRef

Harmatz P, Giugliani R, Schwartz IV et al (2008) Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase. Mol Genet Metab 94(4):469–475PubMedCrossRef

Hessl D, Nguyen DV, Green C et al (2009) A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. J Neurodev Disord 1(1):33–45PubMedCrossRef

Holden DA, Rice TW, Stelmach K, Meeker DP (1992) Exercise testing, 6-min walk, and stair climb in the evaluation of patients at high risk for pulmonary resection. Chest 102(6):1774–1779PubMedCrossRef

Malm D, Nilssen O (2008) Alpha-mannosidosis. Orphanet J Rare Dis doi:10.1186/1750-1172-3-21

Malm D, Nilssen O (2010) Alpha-Mannosidosis—GeneReviews—NCBI Bookshelf. University of Washington, Seattle

Malm D, Tollersrud OK, Tranebjaerg L, Mansson JE (1995) Alpha-mannosidosis. Tidsskr Nor Laegeforen 115(5):594–597PubMed

Malm D, Pantel J, Linaker OM (2005) Psychiatric symptoms in alpha-mannosidosis. J Intellect Disabil Res 49(Pt 11):865–871PubMedCrossRef

Mattsson N, Savman K, Osterlundh G, Blennow K, Zetterberg H (2010) Converging molecular pathways in human neural development and degeneration. Neurosci Res 66(3):330–332PubMedCrossRef

Mattsson N, Portelius E, Rolstad S et al (2012) Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment. J Alzheimers Dis 30(4):767–778PubMed

Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA 281(3):249–254PubMedCrossRef

Mynarek M, Tolar J, Albert MH et al (2012) Allogeneic hematopoietic SCT for alpha-mannosidosis: an analysis of 17 patients. Bone Marrow Transplant 47(3):352–359PubMedCrossRef

Myrelid A, Bergman S, Elfvik SM et al (2010) Late effects of early growth hormone treatment in Down syndrome. Acta Paediatr 99(5):763–769PubMed

Nilssen O, Berg T, Riise HM et al (1997) alpha-Mannosidosis: functional cloning of the lysosomal alpha-mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet 6(5):717–726PubMedCrossRef

Pastores GM (2008) Laronidase (Aldurazyme): enzyme replacement therapy for mucopolysaccharidosis type I. Expert Opin Biol Ther 8(7):1003–1009PubMedCrossRef

Pastores GM, Boyd E, Crandall K, Whelan A, Piersall L, Barnett N (2007) Safety and pharmacokinetics of agalsidase alfa in patients with Fabry disease and end-stage renal disease. Nephrol Dial Transplant 22(7):1920–1925PubMedCrossRef

Roces DP, Lullmann-Rauch R, Peng J et al (2004) Efficacy of enzyme replacement therapy in alpha-mannosidosis mice: a preclinical animal study. Hum Mol Genet 13(18):1979–1988PubMedCrossRef

Rosengren LE, Ahlsen G, Belfrage M, Gillberg C, Haglid KG, Hamberger A (1992) A sensitive ELISA for glial fibrillary acidic protein: application in CSF of children. J Neurosci Methods 44(2–3):113–119PubMedCrossRef

Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C (1996) Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 67(5):2013–2018PubMedCrossRef

Salzer J, Svenningsson A, Sundstrom P (2010) Neurofilament light as a prognostic marker in multiple sclerosis. Mult Scler 16(3):287–292PubMedCrossRef

Scarpa M, Bird T, Pagon R, Dolan C, Stephens K & Adam M (1993) Mucopolysaccharidosis type II. GeneReviews. University of Washington, Seattle

Thomas GH (2001) Disorder of glycoprotein degradation, the metabolic & molecular bases of inherited disease, 8th edn

Tsatsanis KD, Dartnall N, Cicchetti D, Sparrow SS, Klin A, Volkmar FR (2003) Concurrent validity and classification accuracy of the Leiter and Leiter-R in low-functioning children with autism. J Autism Dev Disord 33(1):23–30PubMedCrossRef

Yoon DY, Scott K, Hill MN, Levitt NS, Lambert EV (2006) Review of three tests of motor proficiency in children. Percept Mot Skills 102(2):543–551PubMedCrossRef

Zymenex A/S (2012) Investigator’s brochure for LAMAZYM, information for clinical investigators

Titel: Enzyme replacement therapy for alpha-mannosidosis: 12 months follow-up of a single centre, randomised, multiple dose study
verfasst von: L. Borgwardt
C. I. Dali
J. Fogh
J. E. Månsson
K. J. Olsen
H. C. Beck
K. G. Nielsen
L. H. Nielsen
S. O. E. Olsen
H. M. F. Riise Stensland
O. Nilssen
F. Wibrand
A. M. Thuesen
T. Pearl
U. Haugsted
P. Saftig
J. Blanz
S. A. Jones
A. Tylki-Szymanska
N. Guffon-Fouiloux
M. Beck
A. M. Lund
Publikationsdatum: 01.11.2013
Verlag: Springer Netherlands
Erschienen in: Journal of Inherited Metabolic Disease / Ausgabe 6/2013
Print ISSN: 0141-8955
Elektronische ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-013-9595-1

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