Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency
We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lip...
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| Veröffentlicht in: | Molecular therapy 2018-03, Vol.26 (3), p.801-813 |
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| creator | Prieve, Mary G. Harvie, Pierrot Monahan, Sean D. Roy, Debashish Li, Allen G. Blevins, Teri L. Paschal, Amber E. Waldheim, Matt Bell, Eric C. Galperin, Anna Ella-Menye, Jean-Rene Houston, Michael E. |
| description | We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.
In this issue of Molecular Therapy, Prieve et al. describe a novel, targeted mRNA delivery system that corrects a rare liver disease in a murine model of ornithine transcarbamylase deficiency having a single enzyme defect. This non-viral delivery method allows multi-dose, systemic administration for treatment of inherited metabolic diseases. |
| doi_str_mv | 10.1016/j.ymthe.2017.12.024 |
| format | Article |
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In this issue of Molecular Therapy, Prieve et al. describe a novel, targeted mRNA delivery system that corrects a rare liver disease in a murine model of ornithine transcarbamylase deficiency having a single enzyme defect. This non-viral delivery method allows multi-dose, systemic administration for treatment of inherited metabolic diseases.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2017.12.024</identifier><identifier>PMID: 29433939</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Ammonia ; Animal models ; Animals ; Deoxyribonucleic acid ; Disease ; Disease Models, Animal ; DNA ; Enzymes ; Genetic Therapy - methods ; Hepatocytes ; Histopathology ; hybrid mRNA technology delivery system ; i-ERT ; inherited metabolic disorder ; intracellular enzyme replacement therapy ; lipid nanoparticle ; Lipids ; Liver ; LNP ; Male ; Metabolic Networks and Pathways ; Mice ; Mice, Knockout ; Micelles ; mRNA ; mRNA delivery ; Nanoparticles ; Nanotechnology ; Nuclease ; Original ; Ornithine ; Ornithine Carbamoyltransferase - genetics ; Ornithine Carbamoyltransferase - metabolism ; Ornithine Carbamoyltransferase Deficiency Disease - genetics ; Ornithine Carbamoyltransferase Deficiency Disease - metabolism ; Ornithine Carbamoyltransferase Deficiency Disease - therapy ; ornithine transcarbamylase deficiency ; Orotic acid ; OTCD ; Otcspf -ash mice ; Particle size ; Polyethylene glycol ; Polymer solubility ; Polymers ; Protein biosynthesis ; Proteins ; RNA, Messenger - administration & dosage ; RNA, Messenger - genetics ; RNA, Small Interfering - genetics ; Software ; Studies ; Urea - metabolism ; Vectors (Biology)</subject><ispartof>Molecular therapy, 2018-03, Vol.26 (3), p.801-813</ispartof><rights>2018 The American Society of Gene and Cell Therapy</rights><rights>Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.</rights><rights>2018. The American Society of Gene and Cell Therapy</rights><rights>2018 The American Society of Gene and Cell Therapy. 2018 The American Society of Gene and Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-df5f6ad9cf8cc9ea85f0e96555d749194231cb7e3a1107decaf6a718d64c1b423</citedby><cites>FETCH-LOGICAL-c487t-df5f6ad9cf8cc9ea85f0e96555d749194231cb7e3a1107decaf6a718d64c1b423</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910669/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910669/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29433939$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Prieve, Mary G.</creatorcontrib><creatorcontrib>Harvie, Pierrot</creatorcontrib><creatorcontrib>Monahan, Sean D.</creatorcontrib><creatorcontrib>Roy, Debashish</creatorcontrib><creatorcontrib>Li, Allen G.</creatorcontrib><creatorcontrib>Blevins, Teri L.</creatorcontrib><creatorcontrib>Paschal, Amber E.</creatorcontrib><creatorcontrib>Waldheim, Matt</creatorcontrib><creatorcontrib>Bell, Eric C.</creatorcontrib><creatorcontrib>Galperin, Anna</creatorcontrib><creatorcontrib>Ella-Menye, Jean-Rene</creatorcontrib><creatorcontrib>Houston, Michael E.</creatorcontrib><title>Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.
In this issue of Molecular Therapy, Prieve et al. describe a novel, targeted mRNA delivery system that corrects a rare liver disease in a murine model of ornithine transcarbamylase deficiency having a single enzyme defect. This non-viral delivery method allows multi-dose, systemic administration for treatment of inherited metabolic diseases.</description><subject>Ammonia</subject><subject>Animal models</subject><subject>Animals</subject><subject>Deoxyribonucleic acid</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>Enzymes</subject><subject>Genetic Therapy - methods</subject><subject>Hepatocytes</subject><subject>Histopathology</subject><subject>hybrid mRNA technology delivery system</subject><subject>i-ERT</subject><subject>inherited metabolic disorder</subject><subject>intracellular enzyme replacement therapy</subject><subject>lipid nanoparticle</subject><subject>Lipids</subject><subject>Liver</subject><subject>LNP</subject><subject>Male</subject><subject>Metabolic Networks and Pathways</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Micelles</subject><subject>mRNA</subject><subject>mRNA delivery</subject><subject>Nanoparticles</subject><subject>Nanotechnology</subject><subject>Nuclease</subject><subject>Original</subject><subject>Ornithine</subject><subject>Ornithine Carbamoyltransferase - genetics</subject><subject>Ornithine Carbamoyltransferase - metabolism</subject><subject>Ornithine Carbamoyltransferase Deficiency Disease - genetics</subject><subject>Ornithine Carbamoyltransferase Deficiency Disease - metabolism</subject><subject>Ornithine Carbamoyltransferase Deficiency Disease - therapy</subject><subject>ornithine transcarbamylase deficiency</subject><subject>Orotic acid</subject><subject>OTCD</subject><subject>Otcspf -ash mice</subject><subject>Particle size</subject><subject>Polyethylene glycol</subject><subject>Polymer solubility</subject><subject>Polymers</subject><subject>Protein biosynthesis</subject><subject>Proteins</subject><subject>RNA, Messenger - administration & dosage</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>Software</subject><subject>Studies</subject><subject>Urea - metabolism</subject><subject>Vectors (Biology)</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN1LwzAUxYMoTqd_gSAFn1dz26ZtHlTG_IThQOZzyJLbLWNtZ9IN-t-bfTj0xad74J577uFHyBXQECikt_OwLZsZhhGFLIQopFFyRM6ARaxHvT4-aEg75Ny5uVfAeHpKOhFP4pjH_Iw8jKWdYoM6KD_e-8F4hlYu26CobTCylWlmpsJgbGXllLQTWbYL6TB4xMIog5VqL8hJIRcOL_ezSz6fn8aD195w9PI26A97KsmzpqcLVqRSc1XkSnGUOSso8pQxprOEA0-iGNQkw1gC0Eyjkt6eQa7TRMHEb7vkfpe7XE1K1AqrxsqFWFpTStuKWhrxd1OZmZjWa8E40DTlPuBmH2DrrxW6Rszrla18ZxEBzynleZx4V7xzKVs7Z7E4fAAqNtTFXGypiw11AZHwpP3V9e9yh5sfzN5wtzOgR7Q2aIXb4kNtLKpG6Nr8--AbGmaVmA</recordid><startdate>20180307</startdate><enddate>20180307</enddate><creator>Prieve, Mary G.</creator><creator>Harvie, Pierrot</creator><creator>Monahan, Sean D.</creator><creator>Roy, Debashish</creator><creator>Li, Allen G.</creator><creator>Blevins, Teri L.</creator><creator>Paschal, Amber E.</creator><creator>Waldheim, Matt</creator><creator>Bell, Eric C.</creator><creator>Galperin, Anna</creator><creator>Ella-Menye, Jean-Rene</creator><creator>Houston, Michael E.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>American Society of Gene & Cell Therapy</general><scope>6I.</scope><scope>AAFTH</scope><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>K9.</scope><scope>5PM</scope></search><sort><creationdate>20180307</creationdate><title>Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency</title><author>Prieve, Mary G. ; Harvie, Pierrot ; Monahan, Sean D. ; Roy, Debashish ; Li, Allen G. ; Blevins, Teri L. ; Paschal, Amber E. ; Waldheim, Matt ; Bell, Eric C. ; Galperin, Anna ; Ella-Menye, Jean-Rene ; Houston, Michael E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-df5f6ad9cf8cc9ea85f0e96555d749194231cb7e3a1107decaf6a718d64c1b423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Ammonia</topic><topic>Animal models</topic><topic>Animals</topic><topic>Deoxyribonucleic acid</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>Enzymes</topic><topic>Genetic Therapy - methods</topic><topic>Hepatocytes</topic><topic>Histopathology</topic><topic>hybrid mRNA technology delivery system</topic><topic>i-ERT</topic><topic>inherited metabolic disorder</topic><topic>intracellular enzyme replacement therapy</topic><topic>lipid nanoparticle</topic><topic>Lipids</topic><topic>Liver</topic><topic>LNP</topic><topic>Male</topic><topic>Metabolic Networks and Pathways</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Micelles</topic><topic>mRNA</topic><topic>mRNA delivery</topic><topic>Nanoparticles</topic><topic>Nanotechnology</topic><topic>Nuclease</topic><topic>Original</topic><topic>Ornithine</topic><topic>Ornithine Carbamoyltransferase - genetics</topic><topic>Ornithine Carbamoyltransferase - metabolism</topic><topic>Ornithine Carbamoyltransferase Deficiency Disease - genetics</topic><topic>Ornithine Carbamoyltransferase Deficiency Disease - metabolism</topic><topic>Ornithine Carbamoyltransferase Deficiency Disease - therapy</topic><topic>ornithine transcarbamylase deficiency</topic><topic>Orotic acid</topic><topic>OTCD</topic><topic>Otcspf -ash mice</topic><topic>Particle size</topic><topic>Polyethylene glycol</topic><topic>Polymer solubility</topic><topic>Polymers</topic><topic>Protein biosynthesis</topic><topic>Proteins</topic><topic>RNA, Messenger - administration & dosage</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Small Interfering - genetics</topic><topic>Software</topic><topic>Studies</topic><topic>Urea - metabolism</topic><topic>Vectors (Biology)</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Prieve, Mary G.</creatorcontrib><creatorcontrib>Harvie, Pierrot</creatorcontrib><creatorcontrib>Monahan, Sean D.</creatorcontrib><creatorcontrib>Roy, Debashish</creatorcontrib><creatorcontrib>Li, Allen G.</creatorcontrib><creatorcontrib>Blevins, Teri L.</creatorcontrib><creatorcontrib>Paschal, Amber E.</creatorcontrib><creatorcontrib>Waldheim, Matt</creatorcontrib><creatorcontrib>Bell, Eric C.</creatorcontrib><creatorcontrib>Galperin, Anna</creatorcontrib><creatorcontrib>Ella-Menye, Jean-Rene</creatorcontrib><creatorcontrib>Houston, Michael E.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Prieve, Mary G.</au><au>Harvie, Pierrot</au><au>Monahan, Sean D.</au><au>Roy, Debashish</au><au>Li, Allen G.</au><au>Blevins, Teri L.</au><au>Paschal, Amber E.</au><au>Waldheim, Matt</au><au>Bell, Eric C.</au><au>Galperin, Anna</au><au>Ella-Menye, Jean-Rene</au><au>Houston, Michael E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2018-03-07</date><risdate>2018</risdate><volume>26</volume><issue>3</issue><spage>801</spage><epage>813</epage><pages>801-813</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.
In this issue of Molecular Therapy, Prieve et al. describe a novel, targeted mRNA delivery system that corrects a rare liver disease in a murine model of ornithine transcarbamylase deficiency having a single enzyme defect. This non-viral delivery method allows multi-dose, systemic administration for treatment of inherited metabolic diseases.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>29433939</pmid><doi>10.1016/j.ymthe.2017.12.024</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular therapy, 2018-03, Vol.26 (3), p.801-813 |
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| subjects | Ammonia Animal models Animals Deoxyribonucleic acid Disease Disease Models, Animal DNA Enzymes Genetic Therapy - methods Hepatocytes Histopathology hybrid mRNA technology delivery system i-ERT inherited metabolic disorder intracellular enzyme replacement therapy lipid nanoparticle Lipids Liver LNP Male Metabolic Networks and Pathways Mice Mice, Knockout Micelles mRNA mRNA delivery Nanoparticles Nanotechnology Nuclease Original Ornithine Ornithine Carbamoyltransferase - genetics Ornithine Carbamoyltransferase - metabolism Ornithine Carbamoyltransferase Deficiency Disease - genetics Ornithine Carbamoyltransferase Deficiency Disease - metabolism Ornithine Carbamoyltransferase Deficiency Disease - therapy ornithine transcarbamylase deficiency Orotic acid OTCD Otcspf -ash mice Particle size Polyethylene glycol Polymer solubility Polymers Protein biosynthesis Proteins RNA, Messenger - administration & dosage RNA, Messenger - genetics RNA, Small Interfering - genetics Software Studies Urea - metabolism Vectors (Biology) |
| title | Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency |
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