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Clinical outcomes in idursulfase-treated patients with MPS II: 3-year data from the Hunter Outcome Survey (HOS)
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
Introduction: Niemann-Pick disease type C (NPD-C) is an autosomal recessive inborn of cholesterol trafficking, with an estimated incidence of 1:150,000. The progressive storage of unesterified cholesterol inside the lysosomes, together with secondary pathogenic mechanisms still not well understood, leads to progressive visceral and neurological manifestations, with reduced life expectancy. Objective: The purpose of this study was to evaluate a Brazilian sample of NPD-C patients, regarding selected characteristics, including treatment with miglustat, disease duration and survival. Methods: Retrospective study based in chart reviews of Brazilian NPD-C patients treated or not with miglustat. The variables ascertained were: date of birth, age at diagnosis, age at onset of neurological manifestations, age at death. The information related to miglustat treatment was recorded. Results and Conclusions: Fifty one patients were included, with a mean age of 15.1 years, being 27 female and 24 male (53%/47%). Of the 51 patients, 27 were diagnosed before the age of 6 years, 4 between 6 and 11 years, 7 between 12 and 18 years and 13 after 18 years. The majority of patients (30/51, or 59%) presented the first neurological manifestations before 6 years of age. A significant number of patients (33/51) received treatment with miglustat, with a mean treatment duration of 3.09 ± 2.36 years. Preliminary data indicate that the treated patients had a mean disease duration (from diagnosis until death, or until survey date) of 10.12 ± 5.12 years, while the untreated had a mean disease duration of 5.11 ± 5.14 years. In the 12/51 patients who already died, disease duration was 3.40 ± 1.51 years in the treated patients (n = 5) and 2.50 ± 1.61 years in the untreated (n = 7). Although these data should be further evaluated in more detail, they indicate a potential effect of miglustat treatment on the survival of NPD-C patients. doi:10.1016/j.ymgme.2015.12.271
114 Clinical outcomes in idursulfase-treated patients with MPS II: 3-year data from the Hunter Outcome Survey (HOS) Roberto Giugliania, Joseph Muenzerb, Maurizio Scarpac, Anna TylkiSzymańskad, Virginie Jegoe, Michael Beckf, aMedical Genetics Service/ HCPA, Porto Alegre, Brazil, bUniversity of North Carolina at Chapel Hill, Chapel Hill, NC, United States, cHorst Schmidt Clinic, Wiesbaden, Germany, d Child Memorial Health Institute, Warsaw, Poland, eCytel, Inc., Geneva, Switzerland, fUniversity Medical Center, Johannes Gutenberg University, Mainz, Germany The Hunter Outcome Survey (HOS) is a global, multicentre, longitudinal, observational registry that collects real-world information on the natural history of mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) and the response to idursulfase treatment. Clinical outcomes following 3 years of idursulfase treatment were investigated in a broad population of patients with MPS II. As of July 2015, 620 patients (excluding female patients, individuals who had received a bone marrow transplant and those enrolled in the TKT018/ TKT024 clinical trials) followed prospectively in HOS had received idursulfase for at least 6 months. Clinical parameters were assessed using the subpopulation of patients with a measurement at baseline and at least one further measurement. Median age at first treatment was 6.2 years; median treatment duration from HOS entry to last visit was 40.4 months. Urinary glycosaminoglycan (uGAG) levels and palpable liver size were reduced following 3 years of treatment (median [10th, 90th percentiles] change from baseline: -69.6 [-88.9, -26.9] % [n = 72] and -50.0 [-78.3, 0.0] % [n = 31], respectively). Improvements in 6minute walk test distance (6MWT), left ventricular mass index (LVMI) and pulmonary function (measured by absolute forced vital capacity and absolute forced expiratory volume in 1 second) were also observed after
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3 years (median change from baseline: 10.0 [-33.6, 50.8] % [n = 17], -11.1 [-55.9, 14.4] % [n = 25], 18.8 [-6.3, 65.0] % [n = 11] and 7.9 [-13.2, 51.6] % [n = 11], respectively). In addition, no new or unexpected safety concerns were identified in patients who were treatment-naïve at HOS entry. These findings suggest that 3 years of idursulfase treatment has a positive effect upon uGAG levels, 6MWT results, palpable liver size, LVMI and pulmonary function. Funding information: Shire sponsors the Hunter Outcome Survey and funds medical writing support. doi:10.1016/j.ymgme.2015.12.272
115 Caveole-mediated uptake of α-galactosidase A in Fabry disease in vitro systems Ozlem Goker-Alpana,b, Chidima Ioanoua,b, Erk Changsilaa, Chandni Sejpala,b, Margarita Ivanovaa, aLDRTC, Fairfax, VA, United States, bO&O Alpan LLC, Fairfax VA, Fairfax, VA, United States Fabry disease (FD) is lysosomal disorder due to alpha-galactosidase A enzyme deficiency, resulting in cardiac, renal and cerebrovascular injury. Two human recombinant α-galactosidase A (rh-αGAL-A) preparations are available as enzyme replacement therapy (ERT), however only agalsidase beta (Fabrazyme), has been approved in the USA. Despite of ERT, there is still a significant mortality associated with FD, suggested to be a result of lack of delivery of rh-αGAL-A to different cell types with similar efficiency. Mannose-6-phosphate receptor (M6PR) dependent endocytosis is major pathway for intracellular processing of rh-αGAL-A, other mechanisms mediated by megalin, sortilin, and even passive diffusion have been implicated in different cells. We investigated the uptake and intracellular transport of rh-αGAL-A in vitro in cell types affected in FD, including primary fibroblasts and podocytes derived from patients and healthy controls, embryonic kidney cells (HEK293), mainly focusing on M6PRdependent endocytosis. Enzyme uptake was measured by α-galactosidase assay and microscopy. M6PR inhibitor (mannose-6-phosphatase), caveolae inhibitor (Filipin) and the microtubule depolymerization inhibitor (Nocodazole) were used to study the endocytosis. Results: efficiency of enzyme uptake and maximum capacity is cell type specific. The time to maximum enzyme load was 1 h for HEK293 and control fibroblast vs 3 h for Fabry fibroblasts and all podocytes. The enzyme uptake capacity in Fabry fibroblasts exceeded by 70-fold compared to 15-fold for podocytes and 6-fold for HEK293. Enzyme uptake efficiency depends on endogenous enzyme concentration and low concentration of endogenous enzyme results in more efficient uptake. Initial enzyme uptake into lysosomes is achieved by caveolaemediated endocytosis, as evidenced by the inhibition in presence of Filipin. Microtubule depolymerazation partially blocked the uptake of rh-αGAL-A in HEK293, fibroblasts and control podocytes. However, Fabry podocytes were more sensitive for Nocodazole treatments. Initial αGAL-A uptake is achieved by caveolae-mediated endocytosis. Functional microtubule polymerization is crucial for αGAL-A uptake in primary podocytes. doi:10.1016/j.ymgme.2015.12.273
116 Clinical-pathological correlation in Fabry nephropathy in Mexican children based on ISGFN Circe Gómez-Tenorioa, Virgilia Soto-Abrahamb, Carmen Díaz-Leal Ca, Juan Antonio García-Belloa, Karen Ordaz-Lópeza, Norma E. GuerraHernándeza, Miguel Arturo Márquez-Gutierreza, Sergio Franco-Ornelasa,
Introduction: Niemann-Pick disease type C (NPD-C) is an autosomal recessive inborn of cholesterol trafficking, with an estimated incidence of 1:150,000. The progressive storage of unesterified cholesterol inside the lysosomes, together with secondary pathogenic mechanisms still not well understood, leads to progressive visceral and neurological manifestations, with reduced life expectancy. Objective: The purpose of this study was to evaluate a Brazilian sample of NPD-C patients, regarding selected characteristics, including treatment with miglustat, disease duration and survival. Methods: Retrospective study based in chart reviews of Brazilian NPD-C patients treated or not with miglustat. The variables ascertained were: date of birth, age at diagnosis, age at onset of neurological manifestations, age at death. The information related to miglustat treatment was recorded. Results and Conclusions: Fifty one patients were included, with a mean age of 15.1 years, being 27 female and 24 male (53%/47%). Of the 51 patients, 27 were diagnosed before the age of 6 years, 4 between 6 and 11 years, 7 between 12 and 18 years and 13 after 18 years. The majority of patients (30/51, or 59%) presented the first neurological manifestations before 6 years of age. A significant number of patients (33/51) received treatment with miglustat, with a mean treatment duration of 3.09 ± 2.36 years. Preliminary data indicate that the treated patients had a mean disease duration (from diagnosis until death, or until survey date) of 10.12 ± 5.12 years, while the untreated had a mean disease duration of 5.11 ± 5.14 years. In the 12/51 patients who already died, disease duration was 3.40 ± 1.51 years in the treated patients (n = 5) and 2.50 ± 1.61 years in the untreated (n = 7). Although these data should be further evaluated in more detail, they indicate a potential effect of miglustat treatment on the survival of NPD-C patients. doi:10.1016/j.ymgme.2015.12.271
114 Clinical outcomes in idursulfase-treated patients with MPS II: 3-year data from the Hunter Outcome Survey (HOS) Roberto Giugliania, Joseph Muenzerb, Maurizio Scarpac, Anna TylkiSzymańskad, Virginie Jegoe, Michael Beckf, aMedical Genetics Service/ HCPA, Porto Alegre, Brazil, bUniversity of North Carolina at Chapel Hill, Chapel Hill, NC, United States, cHorst Schmidt Clinic, Wiesbaden, Germany, d Child Memorial Health Institute, Warsaw, Poland, eCytel, Inc., Geneva, Switzerland, fUniversity Medical Center, Johannes Gutenberg University, Mainz, Germany The Hunter Outcome Survey (HOS) is a global, multicentre, longitudinal, observational registry that collects real-world information on the natural history of mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) and the response to idursulfase treatment. Clinical outcomes following 3 years of idursulfase treatment were investigated in a broad population of patients with MPS II. As of July 2015, 620 patients (excluding female patients, individuals who had received a bone marrow transplant and those enrolled in the TKT018/ TKT024 clinical trials) followed prospectively in HOS had received idursulfase for at least 6 months. Clinical parameters were assessed using the subpopulation of patients with a measurement at baseline and at least one further measurement. Median age at first treatment was 6.2 years; median treatment duration from HOS entry to last visit was 40.4 months. Urinary glycosaminoglycan (uGAG) levels and palpable liver size were reduced following 3 years of treatment (median [10th, 90th percentiles] change from baseline: -69.6 [-88.9, -26.9] % [n = 72] and -50.0 [-78.3, 0.0] % [n = 31], respectively). Improvements in 6minute walk test distance (6MWT), left ventricular mass index (LVMI) and pulmonary function (measured by absolute forced vital capacity and absolute forced expiratory volume in 1 second) were also observed after
S51
3 years (median change from baseline: 10.0 [-33.6, 50.8] % [n = 17], -11.1 [-55.9, 14.4] % [n = 25], 18.8 [-6.3, 65.0] % [n = 11] and 7.9 [-13.2, 51.6] % [n = 11], respectively). In addition, no new or unexpected safety concerns were identified in patients who were treatment-naïve at HOS entry. These findings suggest that 3 years of idursulfase treatment has a positive effect upon uGAG levels, 6MWT results, palpable liver size, LVMI and pulmonary function. Funding information: Shire sponsors the Hunter Outcome Survey and funds medical writing support. doi:10.1016/j.ymgme.2015.12.272
115 Caveole-mediated uptake of α-galactosidase A in Fabry disease in vitro systems Ozlem Goker-Alpana,b, Chidima Ioanoua,b, Erk Changsilaa, Chandni Sejpala,b, Margarita Ivanovaa, aLDRTC, Fairfax, VA, United States, bO&O Alpan LLC, Fairfax VA, Fairfax, VA, United States Fabry disease (FD) is lysosomal disorder due to alpha-galactosidase A enzyme deficiency, resulting in cardiac, renal and cerebrovascular injury. Two human recombinant α-galactosidase A (rh-αGAL-A) preparations are available as enzyme replacement therapy (ERT), however only agalsidase beta (Fabrazyme), has been approved in the USA. Despite of ERT, there is still a significant mortality associated with FD, suggested to be a result of lack of delivery of rh-αGAL-A to different cell types with similar efficiency. Mannose-6-phosphate receptor (M6PR) dependent endocytosis is major pathway for intracellular processing of rh-αGAL-A, other mechanisms mediated by megalin, sortilin, and even passive diffusion have been implicated in different cells. We investigated the uptake and intracellular transport of rh-αGAL-A in vitro in cell types affected in FD, including primary fibroblasts and podocytes derived from patients and healthy controls, embryonic kidney cells (HEK293), mainly focusing on M6PRdependent endocytosis. Enzyme uptake was measured by α-galactosidase assay and microscopy. M6PR inhibitor (mannose-6-phosphatase), caveolae inhibitor (Filipin) and the microtubule depolymerization inhibitor (Nocodazole) were used to study the endocytosis. Results: efficiency of enzyme uptake and maximum capacity is cell type specific. The time to maximum enzyme load was 1 h for HEK293 and control fibroblast vs 3 h for Fabry fibroblasts and all podocytes. The enzyme uptake capacity in Fabry fibroblasts exceeded by 70-fold compared to 15-fold for podocytes and 6-fold for HEK293. Enzyme uptake efficiency depends on endogenous enzyme concentration and low concentration of endogenous enzyme results in more efficient uptake. Initial enzyme uptake into lysosomes is achieved by caveolaemediated endocytosis, as evidenced by the inhibition in presence of Filipin. Microtubule depolymerazation partially blocked the uptake of rh-αGAL-A in HEK293, fibroblasts and control podocytes. However, Fabry podocytes were more sensitive for Nocodazole treatments. Initial αGAL-A uptake is achieved by caveolae-mediated endocytosis. Functional microtubule polymerization is crucial for αGAL-A uptake in primary podocytes. doi:10.1016/j.ymgme.2015.12.273
116 Clinical-pathological correlation in Fabry nephropathy in Mexican children based on ISGFN Circe Gómez-Tenorioa, Virgilia Soto-Abrahamb, Carmen Díaz-Leal Ca, Juan Antonio García-Belloa, Karen Ordaz-Lópeza, Norma E. GuerraHernándeza, Miguel Arturo Márquez-Gutierreza, Sergio Franco-Ornelasa,