Human Acid  -Glucosidase from Rabbit Milk Has Therapeutic Effect in Mice with Glycogen Storage Disease Type II

Bijvoet, Agnes G. A.; Hirtum, Hans Van; Kroos, Marian A.; Kamp, Esther H.M. van de; Schoneveld, Onard J.L.M.; Visser, Pim; Brakenhoff, Just P. J.; Weggeman, Miranda; Corven, E J van; Ploeg, Ans T. van der; Reuser, Arnold

doi:10.1093/hmg/8.12.2145

Cited by 117 publications

(89 citation statements)

References 21 publications

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“…19,26 Mutation analysis was performed on genomic DNA and cDNA, as described previously. 27 The functional effects of mutations were studied by assay of ␣-glucosidase synthesis and catalytic activity in transiently transfected COS cells.…”

Section: Biochemical-genetic Studiesmentioning

confidence: 99%

“…20 After cloning the human ␣-glucosidase gene, we have focused on production of the enzyme in Chinese hamster ovary (CHO) cells and milk of transgenic animals. 18,19,[21][22][23][24][25] The high yield of 2 g/L and the short reproduction time of rabbits has led to the pharmaceutical production of rhAGLU in milk of transgenic rabbits. The product's safety and efficacy were tested in phase I and phase II clinical studies.…”

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confidence: 99%

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Long-Term Intravenous Treatment of Pompe Disease With Recombinant Human α-Glucosidase From Milk

et al. 2004

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ABSTRACT. Objective. Recent reports warn that the worldwide cell culture capacity is insufficient to fulfill the increasing demand for human protein drugs. Production in milk of transgenic animals is an attractive alternative. Kilogram quantities of product per year can be obtained at relatively low costs, even in small animals such as rabbits. We tested the long-term safety and efficacy of recombinant human ␣-glucosidase (rhAGLU) from rabbit milk for the treatment of the lysosomal storage disorder Pompe disease. The disease occurs with an estimated frequency of 1 in 40 000 and is designated as orphan disease. The classic infantile form leads to death at a median age of 6 to 8 months and is diagnosed by absence of ␣-glucosidase activity and presence of fully deleterious mutations in the ␣-glucosidase gene. Cardiac hypertrophy is characteristically present. Loss of muscle strength prevents infants from achieving developmental milestones such as sitting, standing, and walking. Milder forms of the disease are associated with less severe mutations and partial deficiency of ␣-glucosidase.Methods. In the beginning of 1999, 4 critically ill patients with infantile Pompe disease (2.5-8 months of age) were enrolled in a single-center open-label study and treated intravenously with rhAGLU in a dose of 15 to 40 mg/kg/week.Results. Genotypes of patients were consistent with the most severe form of Pompe disease. Additional molecular analysis failed to detect processed forms of ␣-glucosidase (95, 76, and 70 kDa) in 3 of the 4 patients and revealed only a trace amount of the 95-kDa biosynthetic intermediate form in the fourth (patient 1). With the more sensitive detection method, 35 S-methionine incorporation, we could detect low-level synthesis of ␣-glucosidase in 3 of the 4 patients (patients 1, 2, and 4) with some posttranslation modification from 110 kDa to 95 kDa in 1 of them (patient 1). One patient (patient 3) remained totally deficient with both detection methods (negative for cross-reactive immunologic material [CRIM negative]). The ␣-glucosidase activity in skeletal muscle and fibroblasts of all 4 patients was below the lower limit of detection (<2% of normal). The rhAGLU was tolerated well by the patients during >3 years of treatment. AntirhAGLU immunoglobulin G titers initially increased during the first 20 to 48 weeks of therapy but declined thereafter. There was no consistent difference in antibody formation comparing CRIM-negative with CRIMpositive patients. Muscle ␣-glucosidase activity increased from <2% to 10% to 20% of normal in all patients during the first 12 weeks of treatment with 15 to 20 mg/kg/week. For optimizing the effect, the dose was increased to 40 mg/kg/week. This resulted, 12 weeks later, in normal ␣-glucosidase activity levels, which were maintained until the last measurement in week 72. Importantly, all 4 patients, including the patient without any endogenous ␣-glucosidase (CRIM negative), revealed mature 76-and 70-kDa forms of ␣-glucosidase on Western blot. Conversion of the 110-kDa precurs...

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Section: Biochemical-genetic Studiesmentioning

confidence: 99%

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confidence: 99%

Long-Term Intravenous Treatment of Pompe Disease With Recombinant Human α-Glucosidase From Milk

et al. 2004

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“…These patients eventually succumb to the multiple morbidities associated with respiratory insufficiency/failure. 4,5 To combat this devastating disease enzyme replacement therapy (ERT) attempts, using recombinant human acid-alpha glucosidase (rhGAA) produced from either transgenic rabbit milk 6,7 or Chinese hamster ovary rGAA producer cell lines, 8 have demonstrated promising results, with most of the infantile GSD-II patients treated in these trials surviving past the milestone of 1 year. However, the ERT approach is limited by the difficulties of large-scale enzyme production, and the need for repetitive, life-long enzyme injections.…”

Section: Introductionmentioning

confidence: 99%

Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model

Ding

Liao

et al. 2004

Gene Ther

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“…However, recombinant human GAA (rhGAA) has shown physiological activity both in animal disease models and in early clinical trials. [8][9][10][11][12][13][14][15] In 3 pilot studies in severely affected infants, rhGAA (purified from transgenic rabbit milk 11-14 or from Chinese hamster ovary [CHO] cell cultures 8 ) markedly ameliorated cardiomyopathy and prolonged all patients' survival beyond 1 year. One of 6 patients given rhGAA from rabbit milk (a preparation that is no longer available) and 1 of 3 patients given CHO cell-derived rhGAA walked independently and remained ventilator-free.…”

mentioning

confidence: 99%

Chinese hamster ovary cell-derived recombinant human acid α-glucosidase in infantile-onset Pompe disease

Kishnani

Nicolino

Voït

et al. 2006

The Journal of Pediatrics

273

237

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Objective-To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid α-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.Study design-We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echo-cardiograms, growth, and motor and cognitive function.Result-After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. Patients with infantile-onset Pompe disease typically present before 12 months of age with progressive, hypertrophic cardiomyopathy that may obstruct left ventricular outflow; profound muscle weakness and hypotonia; non-attainment or loss of motor milestones; difficulty feeding; and failure to thrive. These patients have a dramatically shortened life span. In patients who are not treated, the median age of death ranges from 6.0 to 8.7 months. 4,7 In the most rapidly progressive form, also termed "classic" infantile Pompe disease, the mortality rate is as high as 92% to 95% in the first year of life. 7 In an historical cohort of patients manifesting Pompe disease in the first year of life, irrespective of phenotype, 74% died by 1 year of age, 91% by 2 years of age, and 93% by 3 years of age. 7 Death generally results from cardiac and respiratory failure. 1,3,7No approved specific treatment for Pompe disease currently exists. However, recombinant human GAA (rhGAA) has shown physiological activity both in animal disease models and in early clinical trials. 8-15 In 3 pilot studies in severely affected infants, rhGAA (purified from transgenic rabbit milk 11-14 or from Chinese hamster ovary [CHO] cell cultures 8 ) markedly ameliorated cardiomyopathy and prolonged all patients' survival beyond 1 year. One of 6 patients given rhGAA from rabbit milk (a preparation that is no longer available) and 1 of 3 patients given CHO cell-derived rhGAA walked independently and remained ventilator-free. The remaining 7 patients from these 3 studies showed lesser degrees of motor improvement and eventually required ventilation. As of January 2006, 3 of the 9 patients in these pilot studies had died and 6 remained alive (unpublished data)...

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Human Acid -Glucosidase from Rabbit Milk Has Therapeutic Effect in Mice with Glycogen Storage Disease Type II

Cited by 117 publications

References 21 publications

Long-Term Intravenous Treatment of Pompe Disease With Recombinant Human α-Glucosidase From Milk

Long-Term Intravenous Treatment of Pompe Disease With Recombinant Human α-Glucosidase From Milk

Improved efficacy of gene therapy approaches for Pompe disease using a new, immune-deficient GSD-II mouse model

Chinese hamster ovary cell-derived recombinant human acid α-glucosidase in infantile-onset Pompe disease

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