Pompe's disease - RePub - Erasmus Universiteit Rotterdam

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Introduction Acid α-glucosidase production in CHO cells Chinese Hamster Ovary cells (CHO) are commonly used for the production of recombinant enzymes and are therefore a logical option for the production of human recombinant acid αglucosidase. Several gene promoters can be used for this purpose. They are usually linked to the cDNA in a suitable vector system. Fuller et al. used the promotor of the human elongation factor 1α gene (140). A CMV promoter driven expression vector was used by van Hove et al. containing a DHFR gene in tandem with the acid α-glucosidase cDNA (141). This type of vector allows for metrotrexate-induced amplifi cation of the construct. Under maximal stimulation and optimal circumstances, a production capacity of 91.4 µgr/ml secreted acid α-glucosidase over a period of 24 hours was reached in a laboratory setting. The enzyme collected was in all aspects very similar to the recombinant human acid α-glucosidase reported by Fuller et al. (140). The uptake in fi broblasts was mannose 6-phosphate dependent (141). The enzyme was also tested in the quail model for Pompe’s disease. Normal levels of acid α-glucosidase activity were reached in the spleen with either a high (14 mg/kg) or a low (4.2 mg/kg) dose (142). Martiniuk et al. also reported the production of recombinant human acid α-glucosidase in CHO cells but did not harvest the enzyme from the medium but from the cells (143). Fibroblasts of patients with Pompe’s disease were corrected by the administration of the enzyme to the culture medium. Intra-peritoneal administration of the enzyme preparation to KO mice (6 neo /6 neo ) resulted in an increase of acid α-glucosidase activity to heterozygous levels in skeletal-muscle, heart, and diaphragm after two intra-peritoneal infusions over 10 days in a dose of approximately 1 mg/kg. After three infusions improvement of motor activity was reported (143). Production in transgenic animals Investigations into the large-scale production of acid α-glucosidase in transgenic animals started with the expression of cDNA encoded acid α-glucosidase in the milk of transgenic mice (144). To regulate expression of the acid α-glucosidase gene constructs, they were placed under control of a bovine casein gene promoter. This way a high expression was expected in the epithelial cells of the mammary gland. The gene constructs were injected into the pronucleus of fertilised oocytes and the embryos were transferred to the uterus of foster mothers to further develop into transgenic animals. The transgenic females produce acid α-glucosidase in the mammary gland during lactation and the product is secreted in the milk from which it can be extracted. The expression was demonstrated to be mammary gland specifi c. The mouse milk contained two acid α-glucosidase isoforms of 110 and 76 kD, and the therapeutic potential was tested in fi broblasts and KO mice (144, 145). The 110 kD precursor was taken up in a mannose 6-phosphate dependent manner and cleared lysosomal glycogen from cultured fi broblasts of patients with Pompe’s disease. On the way to large scale production and clinical testing, the recombinant human acid αglucosidase was produced in the milk of transgenic rabbits using the same bovine αS1 casein expression cassette as in the mouse model (146). The procedure was very successful. The rabbits produced up to 8-gr recombinant human acid α-glucosidase per litre milk. The 110 kD product was effective in the long-term treatment of KO mice with Pompe’s disease (13 neo / 13 neo ). The stored glycogen was degraded in a variety of tissues including the target organs (heart, skeletal muscle and smooth muscle). But the therapeutic enzyme did not reach the brain (146). While these pre-clinical studies in the mouse model were ongoing, the Dutch biotechnology company Pharming B.V. developed a safe product for clinical testing. After completion of the toxicology studies in animals and phase I studies in healthy volunteers, the fi rst clinical trial of enzyme replacement therapy for Pompe’s disease started in 1999 in the Sophia Children’s hospital. 23
Chapter 1 1.7 Scope The studies described in this thesis were aimed to further develop enzyme replacement therapy for Pompe’s disease. The potential effi cacy of this therapy had been demonstrated in knockout mice but not yet in patients. Four patients with the infantile form of Pompe’s disease were included in the fi rst clinical trial that started in 1999. The purpose of this trial was to study the long-term safety and effi cacy of repeated intravenous administrations of recombinant human acid α-glucosidase from rabbit milk. Survival was chosen as the primary clinical end point and several clinical and morphological investigations were done at regular intervals to monitor the effect of treatment. Chapter 3 describes the three-year follow up of the patients and Chapter 4 presents in more detail the morphological changes that occurred in muscle tissue in the fi rst 72 weeks of treatment. The mouse model of Pompe’s disease was employed to investigate the cause of hearing loss (Chapter 5) that was detected serendipitously when the infants were clinically examined before inclusion. Chapter 2 gives a detailed description of the cardiac pathophysiology in knock-out mice. These latter investigations were undertaken to develop a non-invasive method to follow the effect of therapeutic interventions in mice. During the clinical studies in humans questions arose about the height of the dose and the optimal dosing regimen. These molecular aspects of enzyme replacement therapy were also studied in the knockout mouse model and are described in Chapter 6. The combined studies described in this thesis encourage the further development of enzyme replacement therapy for Pompe’s disease and illustrate how the mouse model can be used to explore ways to improve the effect of treatment. References 1. De Duve, C., et al., Tissue fractionation studies. 6. Intracellular distribution patterns of enzymes in rat-liver tissue. Biochem. J., 1955. 60: p. 604-617. 2. Hers, H.G., α-Glucosidase defi ciency in generalized glycogen storage disease (Pompe’s disease). Biochem. J., 1963. 86: p. 11-16. 3. Walkley, S.U., Cellular pathology of lysosomal storage disorders. Brain Pathol., 1998. 8: p. 175-193. 4. Gieselmann, V., Lysosomal storage diseases. Biochim. Biophys. Acta, 1995. 1270: p. 103-136. 5. d’Azzo, A.A., G;Strisciuglio, P.; Galjaard, H., Galactosialidosis in The Metabolic & Inherited Bases of Inherited Disease, ed. C.R.B. Scriver, A.L.; Valle, D.; Sly, W. 2001, New York: McGraw-Hill. 6. Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium. Cell, 1995. 82(6): p. 949-57. 7. Huie, M.L., et al., Glycogen storage disease type II: identifi cation of four novel missense mutations (D645N, G648S, R672W, R672Q) and two insertions/deletions in the acid alpha-glucosidase locus of patients of differing phenotype. Biochem Biophys Res Commun, 1998. 244(3): p. 921-7. 8. Huie, M.L., et al., Increased occurrence of cleft lip in glycogen storage disease type II (GSDII): exclusion of a contiguous gene syndrome in two patients by presence of intragenic mutations including a novel nonsense mutation Gln58Stop. Am J Med Genet, 1999. 85(1): p. 5-8. 9. Walter, P., I. Ibrahimi, and G. Blobel, Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein. J Cell Biol, 1981. 91(2 Pt 1): p. 545-50. 10. Walter, P. and G. Blobel, Translocation of proteins across the endoplasmic reticulum. II. Signal recognition protein (SRP) mediates the selective binding to microsomal membranes of in-vitro-assembled polysomes synthesizing secretory protein. J Cell Biol, 1981. 91(2 Pt 1): p. 551-6. 11. Walter, P. and G. Blobel, Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specifi c arrest of chain elongation that is released by microsomal membranes. J Cell Biol, 1981. 91(2 Pt 1): p. 557-61. 12. Kornfeld, R. and S. Kornfeld, Assembly of asparagine-linked oligosaccharides. Annu Rev Biochem, 1985. 54: p. 631-64. 13. Elbein, A.D., Inhibitors of the biosynthesis and processing of N-linked oligosaccharides. CRC Crit Rev Biochem, 1984. 16(1): p. 21-49. 14. Fuhrmann, U., E. Bause, and H. Ploegh, Inhibitors of oligosaccharide processing. Biochim Biophys Acta, 1985. 825(2): p. 95-110. 15. Ellis, R.J. and S.M. Hemmingsen, Molecular chaperones: proteins essential for the biogenesis of some macromolecular structures. Trends Biochem Sci, 1989. 14(8): p. 339-42. 24
Page 2 and 3: Pompe’s disease The mouse as mode
Page 4 and 5: Pompe’s disease The mouse as mode
Page 6: Contents Chapter 1 Introduction 11
Page 10: 1Introduction
Page 13 and 14: Chapter 1 In lysosomal storage diso
Page 15 and 16: Chapter 1 Network are associated wi
Page 17 and 18: Chapter 1 the indirect approach can
Page 19 and 20: Chapter 1 Diagnosis Clinical Diagno
Page 21 and 22: Chapter 1 Fig. 3. Targeting vectors
Page 23: Chapter 1 muscles in approximately
Page 27 and 28: Chapter 1 47. Rudolph, C., et al.,
Page 29 and 30: Chapter 1 112. Dorling, P.R., J.M.
Page 32: 2 Cardiac Remodeling and Contractil
Page 35 and 36: Chapter 2 Experimental groups The a
Page 37 and 38: Chapter 2 Macroscopy The wet weight
Page 39 and 40: Chapter 2 Pooling of all individual
Page 41 and 42: Chapter 2 Hemodynamics during isofl
Page 43 and 44: Chapter 2 Discussion The major fi n
Page 45 and 46: Chapter 2 References 1. Bharati S,
Page 48: 3 Long Term Intravenous Treatment o
Page 51 and 52: Chapter 3 gene, we have focused on
Page 53 and 54: Chapter 3 pattern of alpha-glucosid
Page 55 and 56: Chapter 3 Alpha-glucosidase activit
Page 57 and 58: Chapter 3 and 4, respectively. The
Page 59 and 60: Chapter 3 For patient 1 the mental
Page 61 and 62: Chapter 3 R.M. Koppenol, T. de Vrie
Page 64: 4 Morphological Changes in Muscle T
Page 67 and 68: Chapter 4 Therapeutic regimen Pharm
Page 69 and 70: Chapter 4 Fig. 2. Pre treatment var
Page 71 and 72: Chapter 4 Fig. 4. Effect of ERT on
Page 73 and 74: Chapter 4 Table 2. Patients scores
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Chapter 4 enzyme. Moreover, when th
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5Hearing loss in Infantile Pompe’
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Chapter 5 Methods Patients Seven pa
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Chapter 5 revealed a hearing loss o
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Chapter 5 Fig. 3. Threshold levels
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Chapter 5 Discussion Hearing loss i
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6 Both Low and High Uptake Forms of
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Chapter 6 healthy volunteers, we st
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Chapter 6 was extracted from human
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Chapter 6 from bovine testes (bAGLU
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Chapter 6 Fig. 5. Immunocytochemica
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Chapter 6 glucuronidase, and is obv
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Chapter 6 van Deel MSc for technica
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7Discussion
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Chapter 7 Cardiac function The mous
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Chapter 7 After the fi rst three mo
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Chapter 7 in 2004. This is 40 years
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Chapter 7 the skeletal muscle. The
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Chapter 7 46. Baudhuin, P., H.G. He
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age are ventilator dependent and wh
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om de morfologie van de spieren te
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naar de ziekte van Pompe bij kinder
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Publications Cardiac remodeling and
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Dankwoord Of ‘Mice and men’ zou
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