Pompe's disease - RePub - Erasmus Universiteit Rotterdam

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Introduction The 6 neo /6 neo and ∆6/∆6 models turned out to be similar with respect to the acid α-glucosidase activity in skin, liver, and heart, and the lysosomal glycogen storage in skeletal muscle, heart and diaphragm. In an open-fi eld setting, the 6 neo /6 neo mice were less active than the ∆6/∆6 mice (36% and 91 %, respectively, compared to heterozygous littermates; ∆6/+ mice). The heterozygous 6 neo /+ mice were reported to perform at the 50-70 % level of the heterozygous ∆6/+ mice(120). Based on the combination of all fi ndings it was concluded that the two strategies for knocking out exon 6 had been equally deleterious. The difference in performance was ascribed to the different genetic background of the mice. To further investigate the infl uence of the genetic background on the phenotype of KO mice with Pompe’s disease, yet another model was created (121). Exon 14 was replaced by a neo cassette (∆14 neo /∆14 neo ). The resulting mice with a 129/C57Bl/6 background were in all aspects very similar to the 6 neo /6 neo mice. Unfortunately the inbred C57Bl/6 were not available for testing. Table 2 summarises the age of onset of clinical symptoms in the various models. Notably, there does not seem to be a signifi cant difference in age of onset when comparing the 6 neo / 6 neo , ∆6/∆6 and ∆14 neo /∆14 neo mice with the earlier published 13 neo /13 neo mice. Table 2. Onset of clinical symptoms in three mouse models of Pompe’s disease Strain Background Males (months) Females (months) 13 neo /13 neo FVB inbred 7.4 (n = 8) 7.4 (n=8) 6neo /6neo 129xC57Bl/6 8.1 ± 0.3 (n = 19) 7.1 ± 0.3 (n = 29) ∆6/∆6 129xC57Bl/6xFVB 9.8 ± 0.4 (n = 11) 9.0 ± 0.6 (n = 13) ∆14neo /∆14neo 129xC57Bl/6 8.3 ± 0.8 (n = 14) 6.6 ± 0.4 (n = 14) The relatively slow progression of clinical signs in these four mouse models is not ideal for experimental purposes. Therefore, it was attempted to improve the model by crossing the 6 neo /6 neo KO mice with transgenic mice overexpressing either the human GlutI glucose transporter or the enzyme glycogen synthase (GS). These transgenic mice have a signifi cantly elevated level of cytoplasmic glucose (GlutI) or glycogen (GS) compared to wild type mice (125, 126). The knockout mice with either the GS or GlutI transgene have an increased lysosomal glycogen storage and develop clinical symptoms at the age of 4-5 months. By 9 months of age their phenotype is clinically indistinguishable from the knockout mice without the Glut I or GS transgene (127). Another potential improvement of the KO mouse model of Pompe’s disease was the introduction of an α-glucosidase transgene with very low expression, exclusively in the liver (128). The purpose of this modifi cation was to prevent an antibody response against recombinant human acid α-glucosidase in experiments related to the application of enzyme replacement therapy. As anticipated, the response was markedly diminished. 1.6 Therapy for Pompe’s disease With present day knowledge, the therapeutic options for Pompe’s disease are limited. Bone marrow transplantation was attempted but the results of the experiments were disappointing. No increase of acid α-glucosidase activity was detected in the muscles of treated patients, and the method is no longer applied for the treatment of Pompe’s disease (129, 130). There are several reports in which a high protein diet with branched chain amino acids or a supplement of L-alanine is advised to help restore the net protein balance and thereby prevent muscle breakdown. The studies report improvement of function of respiratory and skeletal 21
Chapter 1 muscles in approximately 25% of cases (93, 131-133). Daily exercise may also improve the condition of the patient but should not be exhaustive. The variation of disease severity and clinical course of patients with Pompe’s disease complicates the evaluation of the effect of any form of therapy. At present ERT is the most promising as the preliminary results of the clinical trials suggest that patients with both the early as well as the late onset form of disease can benefi t from this type of therapy. The application of gene therapy is still in the pre-clinical phase and dependent on the production of safe and effective vectors for gene delivery. Gene therapy Amalfi tano et al. and Pauly et al. (134, 135) showed that a single intravenous injection of a modifi ed adenoviral vector, expressing human acid α-glucosidase, resulted in effi cient hepatic transduction and expression of acid α-glucosidase. High levels of acid α-glucosisdase activity were also found in the plasma of the treated animals. The plasma enzyme secreted by the hepatocytes can potentially restore the enzyme defi ciency in other tissues via endocytosis. Local administration of adenoviral gene constructs by intra-muscular injection in three days old mice led to a 50-fold elevation of acid α-glucosidase activity in the muscles at the site of injection. Importantly the vector RNA was also detected in the hind limb muscle, the heart and the liver for as long as 6 months (136). A similar experiment was performed in acid maltase defi cient quails (137) and the results were more or less the same. Intra-muscular and intra-cardial delivery of acid α-glucosidase gene constructs with a recombinant adeno-associated vector resulted in near normal enzyme activities and at least a partial restoration of muscle strength in the soleus muscle of KO mice up to 6 months after treatment (138). Martin-Touaux et al. performed a similar experiment injecting an acid αglucosidase expressing adenoviral vector in the gastrocnemius muscle of KO mouse neonates. Strong expression was detected at the site of injection but activity was also found in heart and more distant skeletal muscles. All gene therapy studies use a single injection while expression of the gene is still transient. The problem of immune response arising with repeated dosing, especially when using adenovirus-derived vectors, has to be overcome. Enzyme replacement therapy The studies towards enzyme replacement therapy in Pompe’s disease were aimed to use the mannose 6-phosphate receptor to target the acid α-glucosidase to the muscle and heart (139). Once the proof of principle was obtained, efforts were devoted to the large-scale production of recombinant human enzyme. The two production systems that were successfully developed are described in the following paragraphs. One uses Chinese Hamster Ovary (CHO) cells, the other uses transgenic technology to produce recombinant human acid α-glucosidase in the milk of mammals (Fig.4). Fig. 4. α-glucosidase production systems DNA 22 CHO cell fertilised oocyte harvest medium collect milk extract α-glucosidase
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: Chapter 1 Fig. 3. Targeting vectors
Page 25 and 26: Chapter 1 1.7 Scope The studies des
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
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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
Page 129:
Dit proefschrift had er niet zo uit
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