Comparative Therapeutic Effects of Velaglucerase Alfa and Imiglucerase in a Gaucher Disease Mouse Model
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{"title"=>"Comparative therapeutic effects of velaglucerase Alfa and imiglucerase in a gaucher disease mouse model", "type"=>"journal", "authors"=>[{"first_name"=>"You Hai", "last_name"=>"Xu", "scopus_author_id"=>"7406450523"}, {"first_name"=>"Ying", "last_name"=>"Sun", "scopus_author_id"=>"55737744200"}, {"first_name"=>"Sonya", "last_name"=>"Barnes", "scopus_author_id"=>"7202713702"}, {"first_name"=>"Gregory A.", "last_name"=>"Grabowski", "scopus_author_id"=>"7102555492"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"20505772", "issn"=>"19326203", "doi"=>"10.1371/journal.pone.0010750", "pui"=>"359515560", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "scopus"=>"2-s2.0-77956289133", "sgr"=>"77956289133"}, "id"=>"7ef4b956-9afb-3686-a120-ad3ded87efa7", "abstract"=>"Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid beta-glucosidase (GCase). Regular infusions of purified recombinant GCase are the standard of care for reversing hematologic, hepatic, splenic, and bony manifestations. Here, similar in vitro enzymatic properties, and in vivo pharmacokinetics and pharmacodynamics (PK/PD) and therapeutic efficacy of GCase were found with two human GCases, recombinant GCase (CHO cell, imiglucerase, Imig) and gene-activated GCase (human fibrosarcoma cells, velaglucerase alfa, Vela), in a Gaucher mouse, D409V/null. About 80+% of either enzyme localized to the liver interstitial cells and <5% was recovered in spleens and lungs after bolus i.v. injections. Glucosylceramide (GC) levels and storage cell numbers were reduced in a dose (5, 15 or 60 U/kg/wk) dependent manner in livers (60-95%) and in spleens ( approximately 10-30%). Compared to Vela, Imig (60 U/kg/wk) had lesser effects at reducing hepatic GC (p = 0.0199) by 4 wks; this difference disappeared by 8 wks when nearly WT levels were achieved by Imig. Anti-GCase IgG was detected in GCase treated mice at 60 U/kg/wk, and IgE mediated acute hypersensitivity and death occurred after several injections of 60 U/kg/wk (21% with Vela and 34% with Imig). The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions.", "link"=>"http://www.mendeley.com/research/comparative-therapeutic-effects-velaglucerase-alfa-imiglucerase-gaucher-disease-mouse-model", "reader_count"=>31, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>3, "Student > Bachelor"=>5}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>3, "Student > Bachelor"=>5}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>5, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>7, "Pharmacology, Toxicology and Pharmaceutical Science"=>2}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>7}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>2}}, "reader_count_by_country"=>{"Netherlands"=>1, "United States"=>2, "Spain"=>1}, "group_count"=>4}

Scopus | Further Information

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  • {"files"=>["https://ndownloader.figshare.com/files/849929"], "description"=>"<p>(<b>A</b>) GCase activities in liver were assessed at 20 min to 42 h post-injection of Vela (▴, solid lines) or Imig (•, dashed lines). The results are referenced to average WT activity (fold change, WT = 1). The disappearance of Vela and Imig activities in liver were also plotted as the percentage of the 20-min peak values (% peak activity panels). The GCase activities in liver from saline-injected mice were 7.2% (SE = ±0.006) of WT (<b>X</b>, solid line at the bottom). The disappearances of the Vela and Imig protein (CRIM panels) up to 42 h post-injection were analyzed by immunoblots (bottom panels, arrows). To control for potential differential recognition by the rabbit anti-human GCase antibody, known amounts of Vela or Imig protein (0.5–2 ng) were loaded on each blot for quantification of Vela or Imig protein in liver against their respective standards. CRIM-SA is the specific activity per unit (ng) of CRIM determined by corresponding immunoblots. Each data point represents the mean ± SE from duplicate assays of three mice in each cohort. (<b>B</b>) Immunofluorescence of injected Vela or Imig in liver. Frozen liver sections from 9 V/null mice at 20 min post-injection of saline (left), Vela (middle), or Imig (right) were processed by immunofluorescence staining with rabbit anti-hGCase antibodies/goat anti-rabbit IgG-FITC. The hGCase signals (green) were located mainly in the periportal region of the liver acinus in the interstitial spaces between hepatocyte arrays. The magnification was 200×, scale bar  = 50 µm.</p>", "links"=>[], "tags"=>["vela", "imig", "20-wk", "5-wk"], "article_id"=>520387, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g002", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fate_and_distribution_of_Vela_and_Imig_in_liver_of_20_wk_or_5_wk_9_V_null_mice_/520387", "title"=>"Fate and distribution of Vela and Imig in liver of 20-wk or 5-wk 9 V/null mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:26:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/850585"], "description"=>"A<p>The recovery of injected Vela or Imig was calculated as the percentage (% ± SE) of total serum or whole organ activity at the peak of enzyme activity following a bolus of 60 U/kg injection.</p>B<p>The peak activity in serum was 2 min post injection.</p>C<p>The peak activity in liver and lung was 20 min post injection.</p>D<p>The peak activity in spleen was at 40 min in 5-wk mice and 20 min in 20-wk mice post injection.</p>", "links"=>[], "tags"=>["vela", "imig", "serum", "organs"], "article_id"=>521046, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.t004", "stats"=>{"downloads"=>7, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Recovery_of_Vela_or_Imig_activity_in_serum_and_organs_of_9_V_null_mice_A_/521046", "title"=>"Recovery of Vela or Imig activity in serum and organs of 9 V/null mice<sup>A</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:29:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/850388"], "description"=>"<p>(<b>A</b>) 9 V/null mice that received Vela (solid bars) or Imig (open bars) were bled prior to every second injection, and mouse anti-human GCase IgG levels were assessed by ELISA. The OD 490 nm (Y-axis) readings from each mouse (X-axis) are presented. The number of tested (n) in each group is listed below the graph with the number of mice that died indicated as (-n), e.g., (n = 15, −1) means that 15 mice were assayed and that one mouse in that group had died from the injection related reaction, and the empty lane on the graph represents the death of those mice from which no serum was obtained. Assays were in triplicate; control samples were from saline-injected (hatched bars) mice and were conducted in parallel. The standards (grey bars) were determined with mouse anti-human GCase antiserum (3–10×10<sup>3</sup> dilutions) and were used as a reference. (<b>B</b>) Total serum IgE levels in Vela- or Imig-treated mice that experienced acute immunological/anaphylactic reactions. Shown are results from serum samples from three mice that died with apparent anaphylactic reactions following 4 or 5 injections of Vela (solid bars) or Imig (open bars) with a 60 U/kg/wk dose. The values were quantified using pure mouse IgE protein as a standard and plotted as ng IgE/ml. Assays were conducted in triplicate; control samples were from saline-injected mice (hatched bars) and were conducted in parallel.</p>", "links"=>[], "tags"=>["gcase", "igg", "ige", "vela-", "imig-treated"], "article_id"=>520839, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g007", "stats"=>{"downloads"=>7, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Anti_human_GCase_IgG_A_and_IgE_B_in_Vela_or_Imig_treated_9_V_null_mice_/520839", "title"=>"Anti-human GCase IgG (A) and IgE (B) in Vela- or Imig-treated 9 V/null mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:28:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/850143"], "description"=>"<p>9 V/null mice were injected with 5, 15, or 60 U/kg/wk of Vela (▴) or Imig (•) for 4 wks (top panels) or 8 wks (bottom panels). GC liver levels were quantified by LC/MS and expressed as the percentage of the saline-injected group. WT mice (♦) are provided for reference. GC values in accompanying data tables represent the mean ± SE from 5–13 mice in each cohort. Liver GC values for Vela- or Imig-treated mouse cohorts were analyzed by <i>t</i>-test.</p>", "links"=>[], "tags"=>["vela", "imig", "gc", "levels"], "article_id"=>520599, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g004", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Vela_or_Imig_on_GC_levels_in_liver_/520599", "title"=>"Effect of Vela or Imig on GC levels in liver.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:27:11"}
  • {"files"=>["https://ndownloader.figshare.com/files/850038"], "description"=>"<p>GCase activities in spleen were determined from 20 min to 42 h post-injection and represented as fold of WT (WT = 1) as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010750#pone-0010750-g002\" target=\"_blank\">Figure 2</a>. The disappearances of Vela or Imig activities were plotted as fold WT (activity panels) or from the 20-min (20-wk) or 40-min (5-wk) peak values (% peak activity panels). The GCase activities in spleen from saline-injected mice were 8.1% (SE = ±0.017) of WT (<b>X</b>, solid line at the bottom of top panels). Disappearances of Vela or Imig proteins (CRIM panels) up to 42 h post-injection were analyzed by immunoblots as per <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010750#pone-0010750-g002\" target=\"_blank\">Figure 2</a>.</p>", "links"=>[], "tags"=>["vela", "imig", "spleen", "20-wk", "5-wk"], "article_id"=>520492, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g003", "stats"=>{"downloads"=>1, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Disappearance_of_Vela_or_Imig_in_spleen_of_20_wk_left_or_5_wk_right_9_V_null_mice_/520492", "title"=>"Disappearance of Vela or Imig in spleen of 20-wk (left) or 5-wk (right) 9 V/null mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:26:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/850521"], "description"=>"A<p>mean ± SE, Active sites are expressed as mole ratios of 2,4-DNP released and enzyme protein.</p>", "links"=>[], "tags"=>["imig", "sites"], "article_id"=>520977, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.t001", "stats"=>{"downloads"=>2, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Vela_and_Imig_active_sites_and_specific_activities_/520977", "title"=>"Vela and Imig active sites and specific activities.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:29:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/850552"], "description"=>"A<p>9 V/null mice were injected with 60 U/kg of Vela or Imig, once a week for 8 weeks; the mouse death number and percentage (%) of total injected mice in 8-wk courses are presented.</p>B<p>Oxygen chamber was applied for minimum 20 min to the mice receiving Vela or Imig.</p>C<p>The number of injected mice in each cohort;</p>D<p>The number and percentage of dead mice from total injected mice.</p>", "links"=>[], "tags"=>["Biochemistry", "genetics and genomics/disease models", "genetics and genomics/genetics of disease"], "article_id"=>521010, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.t005", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Injection_related_deaths_A_/521010", "title"=>"Injection-related deaths<sup>A</sup>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:29:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/850452"], "description"=>"<p>Vela or Imig activities were assayed as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010750#s4\" target=\"_blank\">Methods</a>. The <i>t</i><sub>½</sub> was the time at which GCase activity decreased to 50% of initial values. n = 3 to 6 for all assays.</p>", "links"=>[], "tags"=>["enzyme"], "article_id"=>520915, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.t003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Thermostability_of_Enzyme_Activity_/520915", "title"=>"Thermostability of Enzyme Activity.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:28:53"}
  • {"files"=>["https://ndownloader.figshare.com/files/850491"], "description"=>"<p>*K<sub>i</sub> values for all, except Conduritol B epoxide. Equal amounts of Vela or Imig protein (8 pmol) were used. SE in all measurements was ≤20%.</p>", "links"=>[], "tags"=>["gcase", "inhibitors", "vela"], "article_id"=>520950, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.t002", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Ki_and_IC_50_values_of_GCase_inhibitors_for_Vela_and_Imig_/520950", "title"=>"Ki and IC<sub>50</sub> values of GCase inhibitors for Vela and Imig.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-21 01:29:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/850208"], "description"=>"<p>The graphs contain the GC values (mean ± SE) from 7–16 mice in each dosing cohort relative to the values from saline injected mice. The symbols and analysis methods are the same as in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0010750#pone-0010750-g004\" target=\"_blank\">Figure 4</a>.</p>", "links"=>[], "tags"=>["vela", "imig", "gc", "levels", "spleen"], "article_id"=>520663, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g005", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_Vela_or_Imig_on_GC_levels_in_Spleen_A_and_Lung_B_/520663", "title"=>"Effect of Vela or Imig on GC levels in Spleen (A) and Lung (B).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:27:32"}
  • {"files"=>["https://ndownloader.figshare.com/files/850303"], "description"=>"<p>Liver storage cell quantification was done after administration of various doses of Vela or Imig for 4 or 8 wks. Liver H&E sections from these mice were examined by light microscopy, and storage cells in 10 independent fields from each section were counted. The mean (±SE) values are shown in the data tables. Liver sections from saline-treated mice (▾) were processed in parallel. Storage cells in Vela (▴) or Imig (•) treated mice (n = 6–14 mice) in each cohort were analyzed by <i>t</i>-test.</p>", "links"=>[], "tags"=>["cells", "vela", "imig"], "article_id"=>520760, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g006", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduction_of_liver_storage_cells_with_Vela_or_Imig_administration_/520760", "title"=>"Reduction of liver storage cells with Vela or Imig administration.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:28:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/849804"], "description"=>"<p>GCase activities in serum were measured at 2–60 min post-injection of Vela (▴, solid line) or Imig (•, dashed line). The values are referenced to the 2-min peak values. Serum disappearances of injected Vela and Imig proteins (CRIM panels) up to 60 min were analyzed by immunoblots (immunoblot panels). Known amounts of Vela or Imig protein (0.5–6 ng) were loaded on each blot as a reference for quantification of serum Vela or Imig protein for the respective GCases. CRIM-SA was the specific activity based on the amount of CRIM determined by corresponding immunoblots (CRIM-SA panels). Each data point represents the mean ± SE from duplicate assays of three mice in each cohort.</p>", "links"=>[], "tags"=>["disappearance", "vela", "imig", "20-wk", "5-wk"], "article_id"=>520250, "categories"=>["Biochemistry", "Genetics"], "users"=>["You-Hai Xu", "Ying Sun", "Sonya Barnes", "Gregory A. Grabowski"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0010750.g001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Serum_disappearance_of_Vela_or_Imig_in_20_wk_left_or_5_wk_right_9_V_null_mice_/520250", "title"=>"Serum disappearance of Vela or Imig in 20-wk (left) or 5-wk (right) 9 V/null mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 01:25:17"}

PMC Usage Stats | Further Information

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Relative Metric

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