Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector
Background Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently, there is no effective cure. Methods With the aim of developing a gene...
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| Veröffentlicht in: | The journal of gene medicine 2017-11, Vol.19 (11), p.376-386 |
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| creator | Ventosa, Maria Wu, Zetang Lim, Filip |
| description | Background
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently, there is no effective cure.
Methods
With the aim of developing a gene therapy for FA neuropathology, we describe the construction and preliminary characterization of a high‐capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B‐FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5‐kb promoter and the FXN cDNA with the inclusion of intron 1.
Results
We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglia neurons with the H24B‐FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B‐FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.
Conclusions
The results of the present study support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy. |
| doi_str_mv | 10.1002/jgm.2993 |
| format | Article |
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Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently, there is no effective cure.
Methods
With the aim of developing a gene therapy for FA neuropathology, we describe the construction and preliminary characterization of a high‐capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B‐FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5‐kb promoter and the FXN cDNA with the inclusion of intron 1.
Results
We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglia neurons with the H24B‐FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B‐FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.
Conclusions
The results of the present study support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.</description><identifier>ISSN: 1099-498X</identifier><identifier>EISSN: 1521-2254</identifier><identifier>DOI: 10.1002/jgm.2993</identifier><identifier>PMID: 29044877</identifier><language>eng</language><publisher>England: Wiley Periodicals Inc</publisher><subject>Animals ; Ataxia ; Cell Line, Tumor ; Cells, Cultured ; Chlorocebus aethiops ; Dorsal root ganglia ; dorsal root ganglion transduction ; Feasibility studies ; Fetuses ; Frataxin ; Friedreich Ataxia - genetics ; Friedreich Ataxia - metabolism ; Friedreich Ataxia - therapy ; Friedreich's ataxia ; Ganglia, Spinal - cytology ; Ganglia, Spinal - metabolism ; gene delivery ; Gene Expression Regulation ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors - genetics ; HEK293 Cells ; Herpes simplex ; Herpesvirus 1, Human - genetics ; high‐capacity viral vectors ; Humans ; Inoculation ; Iron-Binding Proteins - genetics ; Iron-Binding Proteins - metabolism ; Mitochondria ; Rats, Sprague-Dawley ; Rodents ; Time Factors ; Transgenes - genetics ; Vero Cells ; Viruses</subject><ispartof>The journal of gene medicine, 2017-11, Vol.19 (11), p.376-386</ispartof><rights>Copyright © 2017 John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3493-df2183e647d86814a78d3365b2289cd79843eafefb9aac988e3be1e577e870573</citedby><cites>FETCH-LOGICAL-c3493-df2183e647d86814a78d3365b2289cd79843eafefb9aac988e3be1e577e870573</cites><orcidid>0000-0001-6570-1017</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjgm.2993$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjgm.2993$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27928,27929,45578,45579</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29044877$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ventosa, Maria</creatorcontrib><creatorcontrib>Wu, Zetang</creatorcontrib><creatorcontrib>Lim, Filip</creatorcontrib><title>Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector</title><title>The journal of gene medicine</title><addtitle>J Gene Med</addtitle><description>Background
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently, there is no effective cure.
Methods
With the aim of developing a gene therapy for FA neuropathology, we describe the construction and preliminary characterization of a high‐capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B‐FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5‐kb promoter and the FXN cDNA with the inclusion of intron 1.
Results
We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglia neurons with the H24B‐FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B‐FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.
Conclusions
The results of the present study support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.</description><subject>Animals</subject><subject>Ataxia</subject><subject>Cell Line, Tumor</subject><subject>Cells, Cultured</subject><subject>Chlorocebus aethiops</subject><subject>Dorsal root ganglia</subject><subject>dorsal root ganglion transduction</subject><subject>Feasibility studies</subject><subject>Fetuses</subject><subject>Frataxin</subject><subject>Friedreich Ataxia - genetics</subject><subject>Friedreich Ataxia - metabolism</subject><subject>Friedreich Ataxia - therapy</subject><subject>Friedreich's ataxia</subject><subject>Ganglia, Spinal - cytology</subject><subject>Ganglia, Spinal - metabolism</subject><subject>gene delivery</subject><subject>Gene Expression Regulation</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - genetics</subject><subject>HEK293 Cells</subject><subject>Herpes simplex</subject><subject>Herpesvirus 1, Human - genetics</subject><subject>high‐capacity viral vectors</subject><subject>Humans</subject><subject>Inoculation</subject><subject>Iron-Binding Proteins - genetics</subject><subject>Iron-Binding Proteins - metabolism</subject><subject>Mitochondria</subject><subject>Rats, Sprague-Dawley</subject><subject>Rodents</subject><subject>Time Factors</subject><subject>Transgenes - genetics</subject><subject>Vero Cells</subject><subject>Viruses</subject><issn>1099-498X</issn><issn>1521-2254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtKxDAUhoMoOl7AJ5CAGzcdc-skWYp4ZdTFqLgQSqY9HTK0yZi0XnY-gs_ok1idUUFwdc7i4-PnQ2ibkj4lhO1PJ3Wfac2XUI-mjCaMpWK5-4nWidDqbg2txzglhEql9CpaY5oIoaTsoftRGxtjHRT4-O4Sw_MsQIzWO2wdLnyIpsLB-wZPjJtU1uAy-Bob7LwLMKtsbhr7CHgCztc2x6ej2_fXN4ofIW982EQrpakibC3uBro5Pro-PE2GVydnhwfDJOdC86QoGVUcBkIWaqCoMFIVnA_SMWNK54XUSnAwJZRjbUyulQI-BgqplKAkSSXfQHtz7yz4hxZik9U25lBVxoFvY0Z1ylKmGRUduvsHnfo2uG5dRw2UTrtC4leYBx9jgDKbBVub8JJRkn0Wz7ri2WfxDt1ZCNtxDcUP-J24A5I58GQrePlXlJ2fXHwJPwAgSYoj</recordid><startdate>201711</startdate><enddate>201711</enddate><creator>Ventosa, Maria</creator><creator>Wu, Zetang</creator><creator>Lim, Filip</creator><general>Wiley Periodicals 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>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6570-1017</orcidid></search><sort><creationdate>201711</creationdate><title>Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector</title><author>Ventosa, Maria ; Wu, Zetang ; Lim, Filip</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3493-df2183e647d86814a78d3365b2289cd79843eafefb9aac988e3be1e577e870573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Ataxia</topic><topic>Cell Line, Tumor</topic><topic>Cells, Cultured</topic><topic>Chlorocebus aethiops</topic><topic>Dorsal root ganglia</topic><topic>dorsal root ganglion transduction</topic><topic>Feasibility studies</topic><topic>Fetuses</topic><topic>Frataxin</topic><topic>Friedreich Ataxia - genetics</topic><topic>Friedreich Ataxia - metabolism</topic><topic>Friedreich Ataxia - therapy</topic><topic>Friedreich's ataxia</topic><topic>Ganglia, Spinal - cytology</topic><topic>Ganglia, Spinal - metabolism</topic><topic>gene delivery</topic><topic>Gene Expression Regulation</topic><topic>Gene therapy</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - genetics</topic><topic>HEK293 Cells</topic><topic>Herpes simplex</topic><topic>Herpesvirus 1, Human - genetics</topic><topic>high‐capacity viral vectors</topic><topic>Humans</topic><topic>Inoculation</topic><topic>Iron-Binding Proteins - genetics</topic><topic>Iron-Binding Proteins - metabolism</topic><topic>Mitochondria</topic><topic>Rats, Sprague-Dawley</topic><topic>Rodents</topic><topic>Time Factors</topic><topic>Transgenes - genetics</topic><topic>Vero Cells</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ventosa, Maria</creatorcontrib><creatorcontrib>Wu, Zetang</creatorcontrib><creatorcontrib>Lim, Filip</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The journal of gene medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ventosa, Maria</au><au>Wu, Zetang</au><au>Lim, Filip</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector</atitle><jtitle>The journal of gene medicine</jtitle><addtitle>J Gene Med</addtitle><date>2017-11</date><risdate>2017</risdate><volume>19</volume><issue>11</issue><spage>376</spage><epage>386</epage><pages>376-386</pages><issn>1099-498X</issn><eissn>1521-2254</eissn><abstract>Background
Friedreich's ataxia (FA) is an autosomal recessive neurodegenerative disease caused by mutations in the frataxin gene (FXN), which lead to reduced levels of the essential mitochondrial protein frataxin. Currently, there is no effective cure.
Methods
With the aim of developing a gene therapy for FA neuropathology, we describe the construction and preliminary characterization of a high‐capacity nonreplicative genomic herpes simplex virus type 1 vector (H24B‐FXNlac vector) carrying a reduced version of the human FXN genomic locus, comprising the 5‐kb promoter and the FXN cDNA with the inclusion of intron 1.
Results
We show that the transgene cassette contains the elements necessary to preserve physiological neuronal regulation of human FXN expression. Transduction of cultured fetal rat dorsal root ganglia neurons with the H24B‐FXNlac vector results in sustained expression of human FXN transcripts and frataxin protein. Rat footpad inoculation with the H24B‐FXNlac vector results in human FXN transgene delivery to the dorsal root ganglia, with expression persisting for at least 1 month.
Conclusions
The results of the present study support the feasibility of using this vector for sustained neuronal expression of human frataxin for FA gene therapy.</abstract><cop>England</cop><pub>Wiley Periodicals Inc</pub><pmid>29044877</pmid><doi>10.1002/jgm.2993</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6570-1017</orcidid></addata></record> |
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| subjects | Animals Ataxia Cell Line, Tumor Cells, Cultured Chlorocebus aethiops Dorsal root ganglia dorsal root ganglion transduction Feasibility studies Fetuses Frataxin Friedreich Ataxia - genetics Friedreich Ataxia - metabolism Friedreich Ataxia - therapy Friedreich's ataxia Ganglia, Spinal - cytology Ganglia, Spinal - metabolism gene delivery Gene Expression Regulation Gene therapy Genetic Therapy - methods Genetic Vectors - genetics HEK293 Cells Herpes simplex Herpesvirus 1, Human - genetics high‐capacity viral vectors Humans Inoculation Iron-Binding Proteins - genetics Iron-Binding Proteins - metabolism Mitochondria Rats, Sprague-Dawley Rodents Time Factors Transgenes - genetics Vero Cells Viruses |
| title | Sustained FXN expression in dorsal root ganglia from a nonreplicative genomic HSV‐1 vector |
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