Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase

A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Human gene therapy. Clinical development 2013-09, Vol.24 (3), p.127-133
Hauptverfasser: Conlon, Thomas J, Erger, Kirsten, Porvasnik, Stacy, Cossette, Travis, Roberts, Cheryl, Combee, Lynn, Islam, Saleem, Kelley, Jeffry, Cloutier, Denise, Clément, Nathalie, Abernathy, Corinne R, Byrne, Barry J
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 133
container_issue 3
container_start_page 127
container_title Human gene therapy. Clinical development
container_volume 24
creator Conlon, Thomas J
Erger, Kirsten
Porvasnik, Stacy
Cossette, Travis
Roberts, Cheryl
Combee, Lynn
Islam, Saleem
Kelley, Jeffry
Cloutier, Denise
Clément, Nathalie
Abernathy, Corinne R
Byrne, Barry J
description A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid α-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/μg genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/μg gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0×10(6) vg/μg gDNA, followed by a decrease to 1.0×10(3) vg/μg gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.
doi_str_mv 10.1089/humc.2013.147
format Article
fullrecord <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4003472</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>24021025</sourcerecordid><originalsourceid>FETCH-LOGICAL-c387t-98860cf0a6a48d30e755f59c90288ca5deaac7721bfef7407e2c6acb71c13b3e3</originalsourceid><addsrcrecordid>eNpVkc1KBDEMx4soKrpHr9IXmLVfs-1eBBG_YEEPei6ZtLNWZluZdkQfyxfxmZxlddFcEsg__4T8CDnhbMqZmZ89DyucCsbllCu9Qw6FFKoyM1XvbmupD8gk5xc2hjGKC71PDoRigjNRH5Ly0HvsQgwIHS3pPWDq0vKDQnS0CcmFXPrQDCWkSHMZXPCZppaOQ2nVhAixUHA-pgpyThigeEffQj9kyul4HUQKGBz9-qyW3YApBwfZH5O9FrrsJz_5iDxdXz1e3laL-5u7y4tFhdLoUs2NmTFsGcxAGSeZ13Xd1nOcM2EMQu08AGoteNP6ViumvcAZYKM5ctlIL4_I-cb3dWhW3qGPpYfOvvZhBf2HTRDs_04Mz3aZ3qxiTCotRoNqY4B9yrn37XaWM7smYNcE7JqAHQmM-tO_C7fq33_Lb8duh1I</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Conlon, Thomas J ; Erger, Kirsten ; Porvasnik, Stacy ; Cossette, Travis ; Roberts, Cheryl ; Combee, Lynn ; Islam, Saleem ; Kelley, Jeffry ; Cloutier, Denise ; Clément, Nathalie ; Abernathy, Corinne R ; Byrne, Barry J</creator><creatorcontrib>Conlon, Thomas J ; Erger, Kirsten ; Porvasnik, Stacy ; Cossette, Travis ; Roberts, Cheryl ; Combee, Lynn ; Islam, Saleem ; Kelley, Jeffry ; Cloutier, Denise ; Clément, Nathalie ; Abernathy, Corinne R ; Byrne, Barry J</creatorcontrib><description>A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid α-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/μg genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/μg gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0×10(6) vg/μg gDNA, followed by a decrease to 1.0×10(3) vg/μg gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.</description><identifier>ISSN: 2324-8637</identifier><identifier>EISSN: 2324-8645</identifier><identifier>DOI: 10.1089/humc.2013.147</identifier><identifier>PMID: 24021025</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>alpha-Glucosidases - genetics ; alpha-Glucosidases - metabolism ; Animals ; Dependovirus - genetics ; Dependovirus - metabolism ; Female ; Genetic Therapy ; Genetic Vectors - administration &amp; dosage ; Genetic Vectors - adverse effects ; Genetic Vectors - pharmacokinetics ; Glycogen Storage Disease Type II - therapy ; Humans ; Male ; Rabbits ; Recombinant Proteins - administration &amp; dosage ; Recombinant Proteins - adverse effects ; Recombinant Proteins - pharmacokinetics</subject><ispartof>Human gene therapy. Clinical development, 2013-09, Vol.24 (3), p.127-133</ispartof><rights>Copyright 2013, Mary Ann Liebert, Inc. 2013</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-98860cf0a6a48d30e755f59c90288ca5deaac7721bfef7407e2c6acb71c13b3e3</citedby><cites>FETCH-LOGICAL-c387t-98860cf0a6a48d30e755f59c90288ca5deaac7721bfef7407e2c6acb71c13b3e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24021025$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Conlon, Thomas J</creatorcontrib><creatorcontrib>Erger, Kirsten</creatorcontrib><creatorcontrib>Porvasnik, Stacy</creatorcontrib><creatorcontrib>Cossette, Travis</creatorcontrib><creatorcontrib>Roberts, Cheryl</creatorcontrib><creatorcontrib>Combee, Lynn</creatorcontrib><creatorcontrib>Islam, Saleem</creatorcontrib><creatorcontrib>Kelley, Jeffry</creatorcontrib><creatorcontrib>Cloutier, Denise</creatorcontrib><creatorcontrib>Clément, Nathalie</creatorcontrib><creatorcontrib>Abernathy, Corinne R</creatorcontrib><creatorcontrib>Byrne, Barry J</creatorcontrib><title>Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase</title><title>Human gene therapy. Clinical development</title><addtitle>Hum Gene Ther Clin Dev</addtitle><description>A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid α-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/μg genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/μg gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0×10(6) vg/μg gDNA, followed by a decrease to 1.0×10(3) vg/μg gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.</description><subject>alpha-Glucosidases - genetics</subject><subject>alpha-Glucosidases - metabolism</subject><subject>Animals</subject><subject>Dependovirus - genetics</subject><subject>Dependovirus - metabolism</subject><subject>Female</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors - administration &amp; dosage</subject><subject>Genetic Vectors - adverse effects</subject><subject>Genetic Vectors - pharmacokinetics</subject><subject>Glycogen Storage Disease Type II - therapy</subject><subject>Humans</subject><subject>Male</subject><subject>Rabbits</subject><subject>Recombinant Proteins - administration &amp; dosage</subject><subject>Recombinant Proteins - adverse effects</subject><subject>Recombinant Proteins - pharmacokinetics</subject><issn>2324-8637</issn><issn>2324-8645</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1KBDEMx4soKrpHr9IXmLVfs-1eBBG_YEEPei6ZtLNWZluZdkQfyxfxmZxlddFcEsg__4T8CDnhbMqZmZ89DyucCsbllCu9Qw6FFKoyM1XvbmupD8gk5xc2hjGKC71PDoRigjNRH5Ly0HvsQgwIHS3pPWDq0vKDQnS0CcmFXPrQDCWkSHMZXPCZppaOQ2nVhAixUHA-pgpyThigeEffQj9kyul4HUQKGBz9-qyW3YApBwfZH5O9FrrsJz_5iDxdXz1e3laL-5u7y4tFhdLoUs2NmTFsGcxAGSeZ13Xd1nOcM2EMQu08AGoteNP6ViumvcAZYKM5ctlIL4_I-cb3dWhW3qGPpYfOvvZhBf2HTRDs_04Mz3aZ3qxiTCotRoNqY4B9yrn37XaWM7smYNcE7JqAHQmM-tO_C7fq33_Lb8duh1I</recordid><startdate>201309</startdate><enddate>201309</enddate><creator>Conlon, Thomas J</creator><creator>Erger, Kirsten</creator><creator>Porvasnik, Stacy</creator><creator>Cossette, Travis</creator><creator>Roberts, Cheryl</creator><creator>Combee, Lynn</creator><creator>Islam, Saleem</creator><creator>Kelley, Jeffry</creator><creator>Cloutier, Denise</creator><creator>Clément, Nathalie</creator><creator>Abernathy, Corinne R</creator><creator>Byrne, Barry J</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>5PM</scope></search><sort><creationdate>201309</creationdate><title>Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase</title><author>Conlon, Thomas J ; Erger, Kirsten ; Porvasnik, Stacy ; Cossette, Travis ; Roberts, Cheryl ; Combee, Lynn ; Islam, Saleem ; Kelley, Jeffry ; Cloutier, Denise ; Clément, Nathalie ; Abernathy, Corinne R ; Byrne, Barry J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-98860cf0a6a48d30e755f59c90288ca5deaac7721bfef7407e2c6acb71c13b3e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>alpha-Glucosidases - genetics</topic><topic>alpha-Glucosidases - metabolism</topic><topic>Animals</topic><topic>Dependovirus - genetics</topic><topic>Dependovirus - metabolism</topic><topic>Female</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors - administration &amp; dosage</topic><topic>Genetic Vectors - adverse effects</topic><topic>Genetic Vectors - pharmacokinetics</topic><topic>Glycogen Storage Disease Type II - therapy</topic><topic>Humans</topic><topic>Male</topic><topic>Rabbits</topic><topic>Recombinant Proteins - administration &amp; dosage</topic><topic>Recombinant Proteins - adverse effects</topic><topic>Recombinant Proteins - pharmacokinetics</topic><toplevel>online_resources</toplevel><creatorcontrib>Conlon, Thomas J</creatorcontrib><creatorcontrib>Erger, Kirsten</creatorcontrib><creatorcontrib>Porvasnik, Stacy</creatorcontrib><creatorcontrib>Cossette, Travis</creatorcontrib><creatorcontrib>Roberts, Cheryl</creatorcontrib><creatorcontrib>Combee, Lynn</creatorcontrib><creatorcontrib>Islam, Saleem</creatorcontrib><creatorcontrib>Kelley, Jeffry</creatorcontrib><creatorcontrib>Cloutier, Denise</creatorcontrib><creatorcontrib>Clément, Nathalie</creatorcontrib><creatorcontrib>Abernathy, Corinne R</creatorcontrib><creatorcontrib>Byrne, Barry J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human gene therapy. Clinical development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Conlon, Thomas J</au><au>Erger, Kirsten</au><au>Porvasnik, Stacy</au><au>Cossette, Travis</au><au>Roberts, Cheryl</au><au>Combee, Lynn</au><au>Islam, Saleem</au><au>Kelley, Jeffry</au><au>Cloutier, Denise</au><au>Clément, Nathalie</au><au>Abernathy, Corinne R</au><au>Byrne, Barry J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase</atitle><jtitle>Human gene therapy. Clinical development</jtitle><addtitle>Hum Gene Ther Clin Dev</addtitle><date>2013-09</date><risdate>2013</risdate><volume>24</volume><issue>3</issue><spage>127</spage><epage>133</epage><pages>127-133</pages><issn>2324-8637</issn><eissn>2324-8645</eissn><abstract>A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid α-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/μg genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/μg gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0×10(6) vg/μg gDNA, followed by a decrease to 1.0×10(3) vg/μg gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>24021025</pmid><doi>10.1089/humc.2013.147</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 2324-8637
ispartof Human gene therapy. Clinical development, 2013-09, Vol.24 (3), p.127-133
issn 2324-8637
2324-8645
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4003472
source MEDLINE; Alma/SFX Local Collection
subjects alpha-Glucosidases - genetics
alpha-Glucosidases - metabolism
Animals
Dependovirus - genetics
Dependovirus - metabolism
Female
Genetic Therapy
Genetic Vectors - administration & dosage
Genetic Vectors - adverse effects
Genetic Vectors - pharmacokinetics
Glycogen Storage Disease Type II - therapy
Humans
Male
Rabbits
Recombinant Proteins - administration & dosage
Recombinant Proteins - adverse effects
Recombinant Proteins - pharmacokinetics
title Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-30T07%3A27%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Preclinical%20toxicology%20and%20biodistribution%20studies%20of%20recombinant%20adeno-associated%20virus%201%20human%20acid%20%CE%B1-glucosidase&rft.jtitle=Human%20gene%20therapy.%20Clinical%20development&rft.au=Conlon,%20Thomas%20J&rft.date=2013-09&rft.volume=24&rft.issue=3&rft.spage=127&rft.epage=133&rft.pages=127-133&rft.issn=2324-8637&rft.eissn=2324-8645&rft_id=info:doi/10.1089/humc.2013.147&rft_dat=%3Cpubmed_cross%3E24021025%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/24021025&rfr_iscdi=true