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Gaucher disease is associated with lymph node reactive follicular hyperplasia with tangible body (M2) macrophages
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Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
6 males with Fabry disease (age 31 [18-46]) were studied by electron microscopy. Total GL-3 volume and volume density per PEC and podocyte were estimated by unbiased stereology. Total GL-3 volume reduced 3.7 fold from baseline (2792 ± 2104 μm3) to 1 year (752 ± 292 μm3; p = 0.03) in podocytes, vs. 1.6 fold in PEC (201 ± 201 μm3 at baseline, 122 ± 124 μm3 at 1 year; p = 0.08). In contrast, GL-3 volume density didn't change in podocytes, but reduced in PEC (0.45 ± 0.14 at baseline, 0.27 ± 0.19 at 1 year; p = 0.03). This was due to podocyte cytoplasmic shrinkage proportional to GL-3 loss from baseline (4152 ± 4074 μm3) to 1 year (1863 ± 1016 μm3), while PEC volume didn’t change. Percent reduction in total GL-3 volume in PEC and podocytes from baseline to 1 year ERT were correlated (r = 0.8; p = 0.05). GL-3 inclusions in PEC were predominantly in round aggregates of irregularly-shaped smaller inclusions, which were not identified in podocytes. Typical myelin figures were fewer in PEC than in podocytes. In conclusion, PEC, similar to podocytes do not completely clear from GL-3 within 1 year of ERT. ERTinduced GL-3 loss is less in PEC than in podocytes. Different morphology of GL-3 inclusions in PEC suggests that GL-3 production or trafficking varies with cellular phenotype. PEC may be a novel treatment target in FN. doi:10.1016/j.ymgme.2015.12.218
61 Gaucher disease is associated with lymph node reactive follicular hyperplasia with tangible body (M2) macrophages Erk Changsilaa, Ozlem Goker-Alpana,b, Renuka Pudi Limgalaa,b, Suzanne Duttab, Michelle Hoardb, Chidima Iaonoua,b, Ariel Badgera, Margarita Ivanovaa, aLDRTC, Fairfax, VA, United States, bO&O Alpan LLC, Fairfax, VA, United States In Gaucher disease (GD), the deficiency of the lysosomal enzyme glucocerebrosidase and accumulation of its substrate in macrophages leads to inappropriate immune activation and dysfunction of the reticuloendothelial system organs including the liver, spleen and lymph nodes. While lymphadenopathy is often observed in GD, the underlying mechanisms are unknown. We have previously shown that pseudotumors or Gaucheromas consist of M2 or tumor-associated macrophages (TAM), major players in cancer-related inflammation, tumor growth, and propagation. In this study, the role of M2 macrophages in lymph node hyperplasia is further explored. A 46-year old female with GD (N370S/RecNciI GBA mutation) on enzyme replacement therapy presented with a large (4x6 cm) submandibular lymphadenopathy. Excisional biopsy showed reactive follicular hyperplasia with intrafollicular monotypic plasma cells (IgG kappa), preserved architecture, as well as variably-sized follicles in polarized germinal centers with tingible body macrophages. To assess cell proliferation and the role of macrophage expansion, we performed immunostaining using antibodies against markers for cell proliferation (Ki67), tumor (VEGF), M1 (iNos) and M2 macrophages (CD163, CD68). In the patient, 26% of cells in the center of follicles were Ki67+ as opposed to 3% in the controls. Ki67 staining was most pronounced in cortical centers, where 16% of the cells were CD68+/Ki67+, doubled in number compared to the controls. The dual-labeling of macrophages with M2 marker and Ki67 indicates proliferative activity or an activation state of M2 macrophages. This was an unexpected finding since macrophages are post-mitotic cells and therefore, are considered to be unable to express such markers. Based on this data, we hypothesize that reactive follicular hyperplasia in GD is due to a higher amount of M2 macrophages with a cell proliferation capability characteristic of tumors. doi:10.1016/j.ymgme.2015.12.219
62 Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis I Agnes Chena, Patricia Dicksona, Elsa Shapirob, Julie Eisengartb, Igor Nestrasilb, Paul Harmatzc, aLos Angeles Biomedical Research Institute, Torrance, CA, United States, bUniversity of Minnesota, Minneapolis, MN, United States, cUCSF Benioff Children's Hospital Oakland, Oakland, CA, United States Patients with attenuated MPS I have been found to suffer from progressive decline in memory and intelligence which is inadequately treated with intravenous enzyme replacement therapy (ERT). This study investigates intrathecal (IT) ERT with recombinant human alphaL-iduronidase (formulated as laronidase) as a treatment for cognitive decline. This study is a twenty-four month open label prospective randomized study in 8 MPS I patients, ages between ten and fifty years. Subjects receive baseline neuropsychological, clinical, radiological, and biochemical evaluations and then are monitored for change in these parameters during first monthly, then quarterly IT ERT. The study randomizes subjects to a treatment and a control group for 12 months, and then all subjects receive treatment on a 12 month open label continuation. The study has recently closed to enrollment. Adverse events possibly related to IT ERT include low back pain, groin pain, neck stiffness, headache, and transient blurry vision. The only serious adverse event possibly related to treatment is a headache that required an extra hospital day of monitoring after treatment. The intrathecal approach to treating cognitive decline in MPS I appears to be safe. Clinical, neuropsychological, biochemical, and radiological changes will be reported. A five-year extension study of subjects who have completed this two-year pilot study has begun. The pilot study was funded by the Lysosomal Disease Network (NIH/NINDS #U54NS065768), UCLA Clinical and Translational Science Institute at Harbor-UCLA Medical Center (1UL1-RR033176), the Ryan Foundation, Genzyme Corporation, and BioMarin Pharmaceutical Inc. doi:10.1016/j.ymgme.2015.12.220
63 Long-term efficacy and safety results of taliglucerase alfa through 5 years in adult treatment-naïve patients with Gaucher disease Raul Chertkoffa, Ari Zimranb, Gloria Duranc, Pilar Giraldod, Hanna Rosenbaume, Fiorina Gionaf, Milan Petakovg, Sergio Eduardo SolorioMezah, Peter A. Cooperi, Sheeba Varughesei, Sari Alona, Einat BrillAlmona, aProtalix BioTherapeutics, Carmiel, Israel, bGaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel, cPontificia Universidad Catolica de Chile, Santiago, Chile, dCIBERER, Hospital Universitario Miguel Servet, Zaragoza, Spain, eRambam Medical Center, Haifa, Israel, fSapienza University, Rome, Italy, gBelgrade University Medical School, Belgrade, Serbia, hHospital de Especialidades No1, Leon, Mexico, iUniversity of the Witwatersrand & Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa Taliglucerase alfa is an enzyme replacement therapy approved for treatment of adult and pediatric patients with type 1 Gaucher disease (GD) in several countries and the first plant cell-expressed recombinant therapeutic protein approved by the US FDA for humans. This extension study of the long-term efficacy and safety of taliglucerase alfa in adult treatment-naïve patients enrolled 19 patients with GD (8 patients received 30 U/kg; 9 patients received 60 U/kg; 2 patients initially received 30 U/kg but had their doses adjusted to 45 and 60 U/kg after 27 total months and who were analyzed separately). Seventeen patients completed the study and received taliglucerase alfa for
Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124
6 males with Fabry disease (age 31 [18-46]) were studied by electron microscopy. Total GL-3 volume and volume density per PEC and podocyte were estimated by unbiased stereology. Total GL-3 volume reduced 3.7 fold from baseline (2792 ± 2104 μm3) to 1 year (752 ± 292 μm3; p = 0.03) in podocytes, vs. 1.6 fold in PEC (201 ± 201 μm3 at baseline, 122 ± 124 μm3 at 1 year; p = 0.08). In contrast, GL-3 volume density didn't change in podocytes, but reduced in PEC (0.45 ± 0.14 at baseline, 0.27 ± 0.19 at 1 year; p = 0.03). This was due to podocyte cytoplasmic shrinkage proportional to GL-3 loss from baseline (4152 ± 4074 μm3) to 1 year (1863 ± 1016 μm3), while PEC volume didn’t change. Percent reduction in total GL-3 volume in PEC and podocytes from baseline to 1 year ERT were correlated (r = 0.8; p = 0.05). GL-3 inclusions in PEC were predominantly in round aggregates of irregularly-shaped smaller inclusions, which were not identified in podocytes. Typical myelin figures were fewer in PEC than in podocytes. In conclusion, PEC, similar to podocytes do not completely clear from GL-3 within 1 year of ERT. ERTinduced GL-3 loss is less in PEC than in podocytes. Different morphology of GL-3 inclusions in PEC suggests that GL-3 production or trafficking varies with cellular phenotype. PEC may be a novel treatment target in FN. doi:10.1016/j.ymgme.2015.12.218
61 Gaucher disease is associated with lymph node reactive follicular hyperplasia with tangible body (M2) macrophages Erk Changsilaa, Ozlem Goker-Alpana,b, Renuka Pudi Limgalaa,b, Suzanne Duttab, Michelle Hoardb, Chidima Iaonoua,b, Ariel Badgera, Margarita Ivanovaa, aLDRTC, Fairfax, VA, United States, bO&O Alpan LLC, Fairfax, VA, United States In Gaucher disease (GD), the deficiency of the lysosomal enzyme glucocerebrosidase and accumulation of its substrate in macrophages leads to inappropriate immune activation and dysfunction of the reticuloendothelial system organs including the liver, spleen and lymph nodes. While lymphadenopathy is often observed in GD, the underlying mechanisms are unknown. We have previously shown that pseudotumors or Gaucheromas consist of M2 or tumor-associated macrophages (TAM), major players in cancer-related inflammation, tumor growth, and propagation. In this study, the role of M2 macrophages in lymph node hyperplasia is further explored. A 46-year old female with GD (N370S/RecNciI GBA mutation) on enzyme replacement therapy presented with a large (4x6 cm) submandibular lymphadenopathy. Excisional biopsy showed reactive follicular hyperplasia with intrafollicular monotypic plasma cells (IgG kappa), preserved architecture, as well as variably-sized follicles in polarized germinal centers with tingible body macrophages. To assess cell proliferation and the role of macrophage expansion, we performed immunostaining using antibodies against markers for cell proliferation (Ki67), tumor (VEGF), M1 (iNos) and M2 macrophages (CD163, CD68). In the patient, 26% of cells in the center of follicles were Ki67+ as opposed to 3% in the controls. Ki67 staining was most pronounced in cortical centers, where 16% of the cells were CD68+/Ki67+, doubled in number compared to the controls. The dual-labeling of macrophages with M2 marker and Ki67 indicates proliferative activity or an activation state of M2 macrophages. This was an unexpected finding since macrophages are post-mitotic cells and therefore, are considered to be unable to express such markers. Based on this data, we hypothesize that reactive follicular hyperplasia in GD is due to a higher amount of M2 macrophages with a cell proliferation capability characteristic of tumors. doi:10.1016/j.ymgme.2015.12.219
62 Intrathecal enzyme replacement for cognitive decline in mucopolysaccharidosis I Agnes Chena, Patricia Dicksona, Elsa Shapirob, Julie Eisengartb, Igor Nestrasilb, Paul Harmatzc, aLos Angeles Biomedical Research Institute, Torrance, CA, United States, bUniversity of Minnesota, Minneapolis, MN, United States, cUCSF Benioff Children's Hospital Oakland, Oakland, CA, United States Patients with attenuated MPS I have been found to suffer from progressive decline in memory and intelligence which is inadequately treated with intravenous enzyme replacement therapy (ERT). This study investigates intrathecal (IT) ERT with recombinant human alphaL-iduronidase (formulated as laronidase) as a treatment for cognitive decline. This study is a twenty-four month open label prospective randomized study in 8 MPS I patients, ages between ten and fifty years. Subjects receive baseline neuropsychological, clinical, radiological, and biochemical evaluations and then are monitored for change in these parameters during first monthly, then quarterly IT ERT. The study randomizes subjects to a treatment and a control group for 12 months, and then all subjects receive treatment on a 12 month open label continuation. The study has recently closed to enrollment. Adverse events possibly related to IT ERT include low back pain, groin pain, neck stiffness, headache, and transient blurry vision. The only serious adverse event possibly related to treatment is a headache that required an extra hospital day of monitoring after treatment. The intrathecal approach to treating cognitive decline in MPS I appears to be safe. Clinical, neuropsychological, biochemical, and radiological changes will be reported. A five-year extension study of subjects who have completed this two-year pilot study has begun. The pilot study was funded by the Lysosomal Disease Network (NIH/NINDS #U54NS065768), UCLA Clinical and Translational Science Institute at Harbor-UCLA Medical Center (1UL1-RR033176), the Ryan Foundation, Genzyme Corporation, and BioMarin Pharmaceutical Inc. doi:10.1016/j.ymgme.2015.12.220
63 Long-term efficacy and safety results of taliglucerase alfa through 5 years in adult treatment-naïve patients with Gaucher disease Raul Chertkoffa, Ari Zimranb, Gloria Duranc, Pilar Giraldod, Hanna Rosenbaume, Fiorina Gionaf, Milan Petakovg, Sergio Eduardo SolorioMezah, Peter A. Cooperi, Sheeba Varughesei, Sari Alona, Einat BrillAlmona, aProtalix BioTherapeutics, Carmiel, Israel, bGaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel, cPontificia Universidad Catolica de Chile, Santiago, Chile, dCIBERER, Hospital Universitario Miguel Servet, Zaragoza, Spain, eRambam Medical Center, Haifa, Israel, fSapienza University, Rome, Italy, gBelgrade University Medical School, Belgrade, Serbia, hHospital de Especialidades No1, Leon, Mexico, iUniversity of the Witwatersrand & Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa Taliglucerase alfa is an enzyme replacement therapy approved for treatment of adult and pediatric patients with type 1 Gaucher disease (GD) in several countries and the first plant cell-expressed recombinant therapeutic protein approved by the US FDA for humans. This extension study of the long-term efficacy and safety of taliglucerase alfa in adult treatment-naïve patients enrolled 19 patients with GD (8 patients received 30 U/kg; 9 patients received 60 U/kg; 2 patients initially received 30 U/kg but had their doses adjusted to 45 and 60 U/kg after 27 total months and who were analyzed separately). Seventeen patients completed the study and received taliglucerase alfa for