Pharmacokinetic and Pharmacodynamic Investigations of ION-353382, a Model Antisense Oligonucleotide: Using Alpha-2-Macroglobulin and Murinoglobulin Double-Knockout Mice
To investigate the pharmacokinetics (PKs) and pharmacodynamics (PDs) for ION-353382, an antisense oligonucleotide (ASO) targeting scavenger receptor class B type I (SRB1) mRNA, using alpha-2-macroglobulin (A2M), murinoglobulin double-knockout (DKO), and wild-type mice. Wild-type and DKO homozygous m...
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| Veröffentlicht in: | Nucleic acid therapeutics 2016-08, Vol.26 (4), p.223-235 |
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| creator | Shemesh, Colby S. Yu, Rosie Z. Gaus, Hans J. Seth, Punit P. Swayze, Eric E. Bennett, Frank C. Geary, Richard S. Henry, Scott P. Wang, Yanfeng |
| description | To investigate the pharmacokinetics (PKs) and pharmacodynamics (PDs) for ION-353382, an antisense oligonucleotide (ASO) targeting scavenger receptor class B type I (SRB1) mRNA, using alpha-2-macroglobulin (A2M), murinoglobulin double-knockout (DKO), and wild-type mice. Wild-type and DKO homozygous mice were administered a single subcutaneous injection of ION-353382 at 0, 5, 15, 30, and 60 mg/kg. Mice were sacrificed at 72 h with plasma and organs harvested. Both liquid chromatography–mass spectrometry (LC-MS) and enzyme-linked immunosorbent assay (ELISA) were used to determine ASO exposure with real-time PCR for SRB1 expression. Immunohistochemistry was evaluated to explore hepatic uptake of ASOs. The total plasma protein binding and profiling was assessed. Finally, two-dimensional gel electrophoresis identified protein expression differences. PK exposures were comparable between wild-type and DKO mice in plasma, liver, and kidney, yet a near twofold reduction in EC
50
was revealed for DKO mice based on an inhibitory effect liver exposure response model. Total plasma protein binding and profiling revealed no major dissimilarities between both groups. Plasma proteome fingerprinting confirmed protein expression variations related to A2M. Histological examination revealed enhanced ASO distribution into hepatocytes and less nonparenchymal uptake for DKO mice compared to wild-type mice. Knocking out A2M showed improved PD activities without an effect on total plasma and tissue exposure kinetics. Binding to A2M could mediate ASOs to nonproductive compartments, and thus, decreased binding of ASOs to A2M could potentially improve ASO pharmacology. |
| doi_str_mv | 10.1089/nat.2016.0607 |
| format | Article |
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50
was revealed for DKO mice based on an inhibitory effect liver exposure response model. Total plasma protein binding and profiling revealed no major dissimilarities between both groups. Plasma proteome fingerprinting confirmed protein expression variations related to A2M. Histological examination revealed enhanced ASO distribution into hepatocytes and less nonparenchymal uptake for DKO mice compared to wild-type mice. Knocking out A2M showed improved PD activities without an effect on total plasma and tissue exposure kinetics. Binding to A2M could mediate ASOs to nonproductive compartments, and thus, decreased binding of ASOs to A2M could potentially improve ASO pharmacology.</description><identifier>ISSN: 2159-3337</identifier><identifier>EISSN: 2159-3345</identifier><identifier>DOI: 10.1089/nat.2016.0607</identifier><identifier>PMID: 27031383</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Animals ; Antisense oligonucleotides ; Binding ; Disease ; Electrophoresis ; Enzyme-Linked Immunosorbent Assay ; Exposure ; Fingerprinting ; Gel electrophoresis ; Gene Expression Regulation - drug effects ; Genetic Therapy ; Hepatocytes ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Humans ; Immunohistochemistry ; Kidneys ; Ligands ; Liquid chromatography ; Liver ; Liver - drug effects ; Liver - metabolism ; Mass spectrometry ; Mass spectroscopy ; Mice ; Mice, Knockout ; mRNA ; Oligonucleotides, Antisense - genetics ; Oligonucleotides, Antisense - pharmacokinetics ; Oligonucleotides, Antisense - pharmacology ; Organs ; Original Papers ; Peptide mapping ; Pharmaceuticals ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Pregnancy-Associated alpha 2-Macroglobulins - antagonists & inhibitors ; Pregnancy-Associated alpha 2-Macroglobulins - genetics ; Proteins ; Proteomes ; Scavenger receptors ; Scavenger Receptors, Class B - antagonists & inhibitors ; Scavenger Receptors, Class B - genetics ; Serum Globulins - antagonists & inhibitors ; Serum Globulins - genetics ; α2-Macroglobulin</subject><ispartof>Nucleic acid therapeutics, 2016-08, Vol.26 (4), p.223-235</ispartof><rights>2016, Mary Ann Liebert, Inc.</rights><rights>Copyright 2016, Mary Ann Liebert, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-85cf781b909dc858fe9723cab0deeb5df0f149d1677bad6b93284e530bbd826d3</citedby><cites>FETCH-LOGICAL-c431t-85cf781b909dc858fe9723cab0deeb5df0f149d1677bad6b93284e530bbd826d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27031383$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shemesh, Colby S.</creatorcontrib><creatorcontrib>Yu, Rosie Z.</creatorcontrib><creatorcontrib>Gaus, Hans J.</creatorcontrib><creatorcontrib>Seth, Punit P.</creatorcontrib><creatorcontrib>Swayze, Eric E.</creatorcontrib><creatorcontrib>Bennett, Frank C.</creatorcontrib><creatorcontrib>Geary, Richard S.</creatorcontrib><creatorcontrib>Henry, Scott P.</creatorcontrib><creatorcontrib>Wang, Yanfeng</creatorcontrib><title>Pharmacokinetic and Pharmacodynamic Investigations of ION-353382, a Model Antisense Oligonucleotide: Using Alpha-2-Macroglobulin and Murinoglobulin Double-Knockout Mice</title><title>Nucleic acid therapeutics</title><addtitle>Nucleic Acid Ther</addtitle><description>To investigate the pharmacokinetics (PKs) and pharmacodynamics (PDs) for ION-353382, an antisense oligonucleotide (ASO) targeting scavenger receptor class B type I (SRB1) mRNA, using alpha-2-macroglobulin (A2M), murinoglobulin double-knockout (DKO), and wild-type mice. Wild-type and DKO homozygous mice were administered a single subcutaneous injection of ION-353382 at 0, 5, 15, 30, and 60 mg/kg. Mice were sacrificed at 72 h with plasma and organs harvested. Both liquid chromatography–mass spectrometry (LC-MS) and enzyme-linked immunosorbent assay (ELISA) were used to determine ASO exposure with real-time PCR for SRB1 expression. Immunohistochemistry was evaluated to explore hepatic uptake of ASOs. The total plasma protein binding and profiling was assessed. Finally, two-dimensional gel electrophoresis identified protein expression differences. PK exposures were comparable between wild-type and DKO mice in plasma, liver, and kidney, yet a near twofold reduction in EC
50
was revealed for DKO mice based on an inhibitory effect liver exposure response model. Total plasma protein binding and profiling revealed no major dissimilarities between both groups. Plasma proteome fingerprinting confirmed protein expression variations related to A2M. Histological examination revealed enhanced ASO distribution into hepatocytes and less nonparenchymal uptake for DKO mice compared to wild-type mice. Knocking out A2M showed improved PD activities without an effect on total plasma and tissue exposure kinetics. Binding to A2M could mediate ASOs to nonproductive compartments, and thus, decreased binding of ASOs to A2M could potentially improve ASO pharmacology.</description><subject>Animals</subject><subject>Antisense oligonucleotides</subject><subject>Binding</subject><subject>Disease</subject><subject>Electrophoresis</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Exposure</subject><subject>Fingerprinting</subject><subject>Gel electrophoresis</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genetic Therapy</subject><subject>Hepatocytes</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Kidneys</subject><subject>Ligands</subject><subject>Liquid chromatography</subject><subject>Liver</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>mRNA</subject><subject>Oligonucleotides, Antisense - genetics</subject><subject>Oligonucleotides, Antisense - pharmacokinetics</subject><subject>Oligonucleotides, Antisense - pharmacology</subject><subject>Organs</subject><subject>Original Papers</subject><subject>Peptide mapping</subject><subject>Pharmaceuticals</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Pregnancy-Associated alpha 2-Macroglobulins - antagonists & inhibitors</subject><subject>Pregnancy-Associated alpha 2-Macroglobulins - genetics</subject><subject>Proteins</subject><subject>Proteomes</subject><subject>Scavenger receptors</subject><subject>Scavenger Receptors, Class B - antagonists & inhibitors</subject><subject>Scavenger Receptors, Class B - genetics</subject><subject>Serum Globulins - antagonists & inhibitors</subject><subject>Serum Globulins - genetics</subject><subject>α2-Macroglobulin</subject><issn>2159-3337</issn><issn>2159-3345</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkUtvEzEURi0EolXpki2yxBYHP8YzHnZRyyOiISzoeuTHndStYwfbg9R_xM9kQtqyxJtrfTr6rq4OQq8ZXTCq-vdR1wWnrF3QlnbP0ClnsidCNPL50190J-i8lFs6P0lpo-RLdMI7KphQ4hT9_n6j807bdOcjVG-xjg4_Zu4-6t2creIvKNVvdfUpFpxGvNp8I0IKofg7rPE6OQh4GasvEAvgTfDbFCcbIFXv4AO-Lj5u8TLsbzThZK1tTtuQzBR8_LtwPWUf_0WXaTIByNeY7F2aKl57C6_Qi1GHAucP8wxdf_r44-ILudp8Xl0sr4htBKtESTt2ipme9s4qqUboOy6sNtQBGOlGOrKmd6ztOqNda3rBVQNSUGOc4q0TZ-jtsXef089pPnu4TVOO88qBM94wznrWzRQ5UvMlpWQYh332O53vB0aHg5phVjMc1AwHNTP_5qF1MjtwT_SjiBkQR-AQ6xiDBwO5_qf2D76bnMA</recordid><startdate>20160801</startdate><enddate>20160801</enddate><creator>Shemesh, Colby S.</creator><creator>Yu, Rosie Z.</creator><creator>Gaus, Hans J.</creator><creator>Seth, Punit P.</creator><creator>Swayze, Eric E.</creator><creator>Bennett, Frank C.</creator><creator>Geary, Richard S.</creator><creator>Henry, Scott P.</creator><creator>Wang, Yanfeng</creator><general>Mary Ann Liebert, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QL</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope></search><sort><creationdate>20160801</creationdate><title>Pharmacokinetic and Pharmacodynamic Investigations of ION-353382, a Model Antisense Oligonucleotide: Using Alpha-2-Macroglobulin and Murinoglobulin Double-Knockout Mice</title><author>Shemesh, Colby S. ; Yu, Rosie Z. ; Gaus, Hans J. ; Seth, Punit P. ; Swayze, Eric E. ; Bennett, Frank C. ; Geary, Richard S. ; Henry, Scott P. ; Wang, Yanfeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c431t-85cf781b909dc858fe9723cab0deeb5df0f149d1677bad6b93284e530bbd826d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antisense oligonucleotides</topic><topic>Binding</topic><topic>Disease</topic><topic>Electrophoresis</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Exposure</topic><topic>Fingerprinting</topic><topic>Gel electrophoresis</topic><topic>Gene Expression Regulation - 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Wild-type and DKO homozygous mice were administered a single subcutaneous injection of ION-353382 at 0, 5, 15, 30, and 60 mg/kg. Mice were sacrificed at 72 h with plasma and organs harvested. Both liquid chromatography–mass spectrometry (LC-MS) and enzyme-linked immunosorbent assay (ELISA) were used to determine ASO exposure with real-time PCR for SRB1 expression. Immunohistochemistry was evaluated to explore hepatic uptake of ASOs. The total plasma protein binding and profiling was assessed. Finally, two-dimensional gel electrophoresis identified protein expression differences. PK exposures were comparable between wild-type and DKO mice in plasma, liver, and kidney, yet a near twofold reduction in EC
50
was revealed for DKO mice based on an inhibitory effect liver exposure response model. Total plasma protein binding and profiling revealed no major dissimilarities between both groups. Plasma proteome fingerprinting confirmed protein expression variations related to A2M. Histological examination revealed enhanced ASO distribution into hepatocytes and less nonparenchymal uptake for DKO mice compared to wild-type mice. Knocking out A2M showed improved PD activities without an effect on total plasma and tissue exposure kinetics. Binding to A2M could mediate ASOs to nonproductive compartments, and thus, decreased binding of ASOs to A2M could potentially improve ASO pharmacology.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>27031383</pmid><doi>10.1089/nat.2016.0607</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Nucleic acid therapeutics, 2016-08, Vol.26 (4), p.223-235 |
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| subjects | Animals Antisense oligonucleotides Binding Disease Electrophoresis Enzyme-Linked Immunosorbent Assay Exposure Fingerprinting Gel electrophoresis Gene Expression Regulation - drug effects Genetic Therapy Hepatocytes Hepatocytes - drug effects Hepatocytes - metabolism Humans Immunohistochemistry Kidneys Ligands Liquid chromatography Liver Liver - drug effects Liver - metabolism Mass spectrometry Mass spectroscopy Mice Mice, Knockout mRNA Oligonucleotides, Antisense - genetics Oligonucleotides, Antisense - pharmacokinetics Oligonucleotides, Antisense - pharmacology Organs Original Papers Peptide mapping Pharmaceuticals Pharmacodynamics Pharmacokinetics Pharmacology Pregnancy-Associated alpha 2-Macroglobulins - antagonists & inhibitors Pregnancy-Associated alpha 2-Macroglobulins - genetics Proteins Proteomes Scavenger receptors Scavenger Receptors, Class B - antagonists & inhibitors Scavenger Receptors, Class B - genetics Serum Globulins - antagonists & inhibitors Serum Globulins - genetics α2-Macroglobulin |
| title | Pharmacokinetic and Pharmacodynamic Investigations of ION-353382, a Model Antisense Oligonucleotide: Using Alpha-2-Macroglobulin and Murinoglobulin Double-Knockout Mice |
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