Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency
During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T B NK severe combined immunodeficiency...
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| Veröffentlicht in: | Human gene therapy 2017-01, Vol.28 (1), p.112-124 |
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| creator | Punwani, Divya Kawahara, Misako Yu, Jason Sanford, Ukina Roy, Sushmita Patel, Kiran Carbonaro, Denise A Karlen, Andrea D Khan, Sara Cornetta, Kenneth Rothe, Michael Schambach, Axel Kohn, Donald B Malech, Harry L McIvor, R Scott Puck, Jennifer M Cowan, Morton J |
| description | During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T
B
NK
severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34
cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID. |
| doi_str_mv | 10.1089/hum.2016.064 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5278830</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1852656269</sourcerecordid><originalsourceid>FETCH-LOGICAL-c511t-c9d3684544171b1a1a352b62c562265dd631b0bf73c5b8fd65fc93c1d31cd5f3</originalsourceid><addsrcrecordid>eNqNkc9LwzAYhoMobk5vnqXgxYOd-ZImbS_CmL8GEw_uHtokdRlrM5N2sP_ejM2hnjwl8D28vN_3IHQJeAg4y-_mXT0kGPgQ8-QI9YGxNE4TQo7DHyc0xjQhPXTm_QJjoIynp6hHUg5AaN5Hs6luWrM2rvPRq1amaLWKxtY5LVtjm8hW0ci1ujY-ftCVkSbg0btea6cDVpemCfykrrvGqv1cbs7RSVUsvb7YvwM0e3qcjV_i6dvzZDyaxpIBtLHMFeVZwpIEUiihgIIyUnIiGSeEM6U4hRKXVUolK7NKcVbJnEpQFKRiFR2g-13sqitrrWSo5oqlWDlTF24jbGHE70lj5uLDrgUjaZZRHAJu9gHOfnbatyLsKfVyWTTadl5AxgOWYc7-gbJQmROeB_T6D7qwnWvCIQQJAiDlBPNA3e4o6az3TleH3oDFVqwIYsVWrAhiA371c9cD_G2SfgEbEp7v</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2135176206</pqid></control><display><type>article</type><title>Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Punwani, Divya ; Kawahara, Misako ; Yu, Jason ; Sanford, Ukina ; Roy, Sushmita ; Patel, Kiran ; Carbonaro, Denise A ; Karlen, Andrea D ; Khan, Sara ; Cornetta, Kenneth ; Rothe, Michael ; Schambach, Axel ; Kohn, Donald B ; Malech, Harry L ; McIvor, R Scott ; Puck, Jennifer M ; Cowan, Morton J</creator><creatorcontrib>Punwani, Divya ; Kawahara, Misako ; Yu, Jason ; Sanford, Ukina ; Roy, Sushmita ; Patel, Kiran ; Carbonaro, Denise A ; Karlen, Andrea D ; Khan, Sara ; Cornetta, Kenneth ; Rothe, Michael ; Schambach, Axel ; Kohn, Donald B ; Malech, Harry L ; McIvor, R Scott ; Puck, Jennifer M ; Cowan, Morton J</creatorcontrib><description>During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T
B
NK
severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34
cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.2016.064</identifier><identifier>PMID: 27611239</identifier><language>eng</language><publisher>United States: Mary Ann Liebert, Inc</publisher><subject>Alkylation ; Animals ; Aplasia ; Autografts ; B-Lymphocytes - cytology ; B-Lymphocytes - metabolism ; B-Lymphocytes - radiation effects ; CD34 antigen ; Cells, Cultured ; Chemotherapy ; Combined Modality Therapy ; Complications ; Deoxyribonucleic acid ; Disease Models, Animal ; DNA ; DNA damage ; DNA Repair - radiation effects ; Endocrine disorders ; Endonucleases - deficiency ; Endonucleases - genetics ; Exonuclease ; Fibroblasts ; Fibroblasts - cytology ; Fibroblasts - metabolism ; Fibroblasts - radiation effects ; Gamma Rays ; Gene regulation ; Genetic Therapy ; Genetic Vectors - administration & dosage ; Graft rejection ; Hematopoietic Stem Cell Transplantation ; Hematopoietic stem cells ; Hematopoietic Stem Cells - cytology ; Hematopoietic Stem Cells - metabolism ; Hematopoietic Stem Cells - radiation effects ; Humans ; Immortalization ; Ionizing radiation ; Lentivirus ; Lentivirus - genetics ; Lymphocytes ; Lymphocytes B ; Lymphocytes T ; Mice ; Mice, Knockout ; Mice, SCID ; Mutation ; Nuclear Proteins - deficiency ; Nuclear Proteins - genetics ; Patients ; Peripheral blood ; Preconditioning ; Radiation Tolerance - genetics ; Radiosensitivity ; Retroviridae ; Severe combined immunodeficiency ; Severe Combined Immunodeficiency - genetics ; Severe Combined Immunodeficiency - therapy ; Stem cell transplantation ; Stem cells ; T-Lymphocytes - cytology ; T-Lymphocytes - metabolism ; T-Lymphocytes - radiation effects ; Transcription ; Transplantation ; V(D)J recombination</subject><ispartof>Human gene therapy, 2017-01, Vol.28 (1), p.112-124</ispartof><rights>Copyright Mary Ann Liebert, Inc. Jan 2017</rights><rights>Copyright 2017, Mary Ann Liebert, Inc. 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c511t-c9d3684544171b1a1a352b62c562265dd631b0bf73c5b8fd65fc93c1d31cd5f3</citedby><cites>FETCH-LOGICAL-c511t-c9d3684544171b1a1a352b62c562265dd631b0bf73c5b8fd65fc93c1d31cd5f3</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/27611239$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Punwani, Divya</creatorcontrib><creatorcontrib>Kawahara, Misako</creatorcontrib><creatorcontrib>Yu, Jason</creatorcontrib><creatorcontrib>Sanford, Ukina</creatorcontrib><creatorcontrib>Roy, Sushmita</creatorcontrib><creatorcontrib>Patel, Kiran</creatorcontrib><creatorcontrib>Carbonaro, Denise A</creatorcontrib><creatorcontrib>Karlen, Andrea D</creatorcontrib><creatorcontrib>Khan, Sara</creatorcontrib><creatorcontrib>Cornetta, Kenneth</creatorcontrib><creatorcontrib>Rothe, Michael</creatorcontrib><creatorcontrib>Schambach, Axel</creatorcontrib><creatorcontrib>Kohn, Donald B</creatorcontrib><creatorcontrib>Malech, Harry L</creatorcontrib><creatorcontrib>McIvor, R Scott</creatorcontrib><creatorcontrib>Puck, Jennifer M</creatorcontrib><creatorcontrib>Cowan, Morton J</creatorcontrib><title>Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T
B
NK
severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34
cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID.</description><subject>Alkylation</subject><subject>Animals</subject><subject>Aplasia</subject><subject>Autografts</subject><subject>B-Lymphocytes - cytology</subject><subject>B-Lymphocytes - metabolism</subject><subject>B-Lymphocytes - radiation effects</subject><subject>CD34 antigen</subject><subject>Cells, Cultured</subject><subject>Chemotherapy</subject><subject>Combined Modality Therapy</subject><subject>Complications</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA Repair - radiation effects</subject><subject>Endocrine disorders</subject><subject>Endonucleases - deficiency</subject><subject>Endonucleases - genetics</subject><subject>Exonuclease</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - radiation effects</subject><subject>Gamma Rays</subject><subject>Gene regulation</subject><subject>Genetic Therapy</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Graft rejection</subject><subject>Hematopoietic Stem Cell Transplantation</subject><subject>Hematopoietic stem cells</subject><subject>Hematopoietic Stem Cells - cytology</subject><subject>Hematopoietic Stem Cells - metabolism</subject><subject>Hematopoietic Stem Cells - radiation effects</subject><subject>Humans</subject><subject>Immortalization</subject><subject>Ionizing radiation</subject><subject>Lentivirus</subject><subject>Lentivirus - genetics</subject><subject>Lymphocytes</subject><subject>Lymphocytes B</subject><subject>Lymphocytes T</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mice, SCID</subject><subject>Mutation</subject><subject>Nuclear Proteins - deficiency</subject><subject>Nuclear Proteins - genetics</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Preconditioning</subject><subject>Radiation Tolerance - genetics</subject><subject>Radiosensitivity</subject><subject>Retroviridae</subject><subject>Severe combined immunodeficiency</subject><subject>Severe Combined Immunodeficiency - genetics</subject><subject>Severe Combined Immunodeficiency - therapy</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>T-Lymphocytes - cytology</subject><subject>T-Lymphocytes - metabolism</subject><subject>T-Lymphocytes - radiation effects</subject><subject>Transcription</subject><subject>Transplantation</subject><subject>V(D)J recombination</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc9LwzAYhoMobk5vnqXgxYOd-ZImbS_CmL8GEw_uHtokdRlrM5N2sP_ejM2hnjwl8D28vN_3IHQJeAg4y-_mXT0kGPgQ8-QI9YGxNE4TQo7DHyc0xjQhPXTm_QJjoIynp6hHUg5AaN5Hs6luWrM2rvPRq1amaLWKxtY5LVtjm8hW0ci1ujY-ftCVkSbg0btea6cDVpemCfykrrvGqv1cbs7RSVUsvb7YvwM0e3qcjV_i6dvzZDyaxpIBtLHMFeVZwpIEUiihgIIyUnIiGSeEM6U4hRKXVUolK7NKcVbJnEpQFKRiFR2g-13sqitrrWSo5oqlWDlTF24jbGHE70lj5uLDrgUjaZZRHAJu9gHOfnbatyLsKfVyWTTadl5AxgOWYc7-gbJQmROeB_T6D7qwnWvCIQQJAiDlBPNA3e4o6az3TleH3oDFVqwIYsVWrAhiA371c9cD_G2SfgEbEp7v</recordid><startdate>201701</startdate><enddate>201701</enddate><creator>Punwani, Divya</creator><creator>Kawahara, Misako</creator><creator>Yu, Jason</creator><creator>Sanford, Ukina</creator><creator>Roy, Sushmita</creator><creator>Patel, Kiran</creator><creator>Carbonaro, Denise A</creator><creator>Karlen, Andrea D</creator><creator>Khan, Sara</creator><creator>Cornetta, Kenneth</creator><creator>Rothe, Michael</creator><creator>Schambach, Axel</creator><creator>Kohn, Donald B</creator><creator>Malech, Harry L</creator><creator>McIvor, R Scott</creator><creator>Puck, Jennifer M</creator><creator>Cowan, Morton 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>7QO</scope><scope>7QP</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201701</creationdate><title>Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency</title><author>Punwani, Divya ; Kawahara, Misako ; Yu, Jason ; Sanford, Ukina ; Roy, Sushmita ; Patel, Kiran ; Carbonaro, Denise A ; Karlen, Andrea D ; Khan, Sara ; Cornetta, Kenneth ; Rothe, Michael ; Schambach, Axel ; Kohn, Donald B ; Malech, Harry L ; McIvor, R Scott ; Puck, Jennifer M ; Cowan, Morton J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-c9d3684544171b1a1a352b62c562265dd631b0bf73c5b8fd65fc93c1d31cd5f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Alkylation</topic><topic>Animals</topic><topic>Aplasia</topic><topic>Autografts</topic><topic>B-Lymphocytes - cytology</topic><topic>B-Lymphocytes - metabolism</topic><topic>B-Lymphocytes - radiation effects</topic><topic>CD34 antigen</topic><topic>Cells, Cultured</topic><topic>Chemotherapy</topic><topic>Combined Modality Therapy</topic><topic>Complications</topic><topic>Deoxyribonucleic acid</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA Repair - radiation effects</topic><topic>Endocrine disorders</topic><topic>Endonucleases - deficiency</topic><topic>Endonucleases - genetics</topic><topic>Exonuclease</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - radiation effects</topic><topic>Gamma Rays</topic><topic>Gene regulation</topic><topic>Genetic Therapy</topic><topic>Genetic Vectors - administration & dosage</topic><topic>Graft rejection</topic><topic>Hematopoietic Stem Cell Transplantation</topic><topic>Hematopoietic stem cells</topic><topic>Hematopoietic Stem Cells - cytology</topic><topic>Hematopoietic Stem Cells - metabolism</topic><topic>Hematopoietic Stem Cells - radiation effects</topic><topic>Humans</topic><topic>Immortalization</topic><topic>Ionizing radiation</topic><topic>Lentivirus</topic><topic>Lentivirus - genetics</topic><topic>Lymphocytes</topic><topic>Lymphocytes B</topic><topic>Lymphocytes T</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mice, SCID</topic><topic>Mutation</topic><topic>Nuclear Proteins - deficiency</topic><topic>Nuclear Proteins - genetics</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Preconditioning</topic><topic>Radiation Tolerance - genetics</topic><topic>Radiosensitivity</topic><topic>Retroviridae</topic><topic>Severe combined immunodeficiency</topic><topic>Severe Combined Immunodeficiency - genetics</topic><topic>Severe Combined Immunodeficiency - therapy</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>T-Lymphocytes - cytology</topic><topic>T-Lymphocytes - metabolism</topic><topic>T-Lymphocytes - radiation effects</topic><topic>Transcription</topic><topic>Transplantation</topic><topic>V(D)J recombination</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Punwani, Divya</creatorcontrib><creatorcontrib>Kawahara, Misako</creatorcontrib><creatorcontrib>Yu, Jason</creatorcontrib><creatorcontrib>Sanford, Ukina</creatorcontrib><creatorcontrib>Roy, Sushmita</creatorcontrib><creatorcontrib>Patel, Kiran</creatorcontrib><creatorcontrib>Carbonaro, Denise A</creatorcontrib><creatorcontrib>Karlen, Andrea D</creatorcontrib><creatorcontrib>Khan, Sara</creatorcontrib><creatorcontrib>Cornetta, Kenneth</creatorcontrib><creatorcontrib>Rothe, Michael</creatorcontrib><creatorcontrib>Schambach, Axel</creatorcontrib><creatorcontrib>Kohn, Donald B</creatorcontrib><creatorcontrib>Malech, Harry L</creatorcontrib><creatorcontrib>McIvor, R Scott</creatorcontrib><creatorcontrib>Puck, Jennifer M</creatorcontrib><creatorcontrib>Cowan, Morton 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>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Punwani, Divya</au><au>Kawahara, Misako</au><au>Yu, Jason</au><au>Sanford, Ukina</au><au>Roy, Sushmita</au><au>Patel, Kiran</au><au>Carbonaro, Denise A</au><au>Karlen, Andrea D</au><au>Khan, Sara</au><au>Cornetta, Kenneth</au><au>Rothe, Michael</au><au>Schambach, Axel</au><au>Kohn, Donald B</au><au>Malech, Harry L</au><au>McIvor, R Scott</au><au>Puck, Jennifer M</au><au>Cowan, Morton J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>2017-01</date><risdate>2017</risdate><volume>28</volume><issue>1</issue><spage>112</spage><epage>124</epage><pages>112-124</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><abstract>During B and T lymphocyte maturation, V(D)J recombination is initiated by creation of DNA double-strand breaks. Artemis is an exonuclease essential for their subsequent repair by nonhomologous end-joining. Mutations in DCLRE1C, the gene encoding Artemis, cause T
B
NK
severe combined immunodeficiency (ART-SCID) and also confer heightened sensitivity to ionizing radiation and alkylating chemotherapy. Although allogeneic hematopoietic cell transplantation can treat ART-SCID, conditioning regimens are poorly tolerated, leading to early mortality and/or late complications, including short stature, endocrinopathies, and dental aplasia. However, without alkylating chemotherapy as preconditioning, patients usually have graft rejection or limited T cell and no B cell recovery. Thus, addition of normal DCLRE1C cDNA to autologous hematopoietic stem cells is an attractive strategy to treat ART-SCID. We designed a self-inactivating lentivirus vector containing human Artemis cDNA under transcriptional regulation of the human endogenous Artemis promoter (AProArt). Fibroblasts from ART-SCID patients transduced with AProArt lentivirus showed correction of radiosensitivity. Mobilized peripheral blood CD34
cells from an ART-SCID patient as well as hematopoietic stem cells from Artemis-deficient mice demonstrated restored T and B cell development following AProArt transduction. Murine hematopoietic cells transduced with AProArt exhibited no increase in replating potential in an in vitro immortalization assay, and analysis of AProArt lentivirus insertions showed no predilection for sites that could activate oncogenes. These efficacy and safety findings support institution of a clinical trial of gene addition therapy for ART-SCID.</abstract><cop>United States</cop><pub>Mary Ann Liebert, Inc</pub><pmid>27611239</pmid><doi>10.1089/hum.2016.064</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Human gene therapy, 2017-01, Vol.28 (1), p.112-124 |
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| language | eng |
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| source | MEDLINE; Alma/SFX Local Collection |
| subjects | Alkylation Animals Aplasia Autografts B-Lymphocytes - cytology B-Lymphocytes - metabolism B-Lymphocytes - radiation effects CD34 antigen Cells, Cultured Chemotherapy Combined Modality Therapy Complications Deoxyribonucleic acid Disease Models, Animal DNA DNA damage DNA Repair - radiation effects Endocrine disorders Endonucleases - deficiency Endonucleases - genetics Exonuclease Fibroblasts Fibroblasts - cytology Fibroblasts - metabolism Fibroblasts - radiation effects Gamma Rays Gene regulation Genetic Therapy Genetic Vectors - administration & dosage Graft rejection Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - metabolism Hematopoietic Stem Cells - radiation effects Humans Immortalization Ionizing radiation Lentivirus Lentivirus - genetics Lymphocytes Lymphocytes B Lymphocytes T Mice Mice, Knockout Mice, SCID Mutation Nuclear Proteins - deficiency Nuclear Proteins - genetics Patients Peripheral blood Preconditioning Radiation Tolerance - genetics Radiosensitivity Retroviridae Severe combined immunodeficiency Severe Combined Immunodeficiency - genetics Severe Combined Immunodeficiency - therapy Stem cell transplantation Stem cells T-Lymphocytes - cytology T-Lymphocytes - metabolism T-Lymphocytes - radiation effects Transcription Transplantation V(D)J recombination |
| title | Lentivirus Mediated Correction of Artemis-Deficient Severe Combined Immunodeficiency |
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