O-26: Somatic gene therapy for hypertension with adeno-associated delivery of antisense to angiotensin type 1 receptor mRNA
Introduction: The goal of gene therapy for hypertension is to produce safe, prolonged reductions of high blood pressure with a single administration of a transgene. We have develeloped gene therapy using adeno-associated virus (AAV) antisense (AS) as a vector because it is safe, stable and effective...
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| Veröffentlicht in: | American journal of hypertension 2001-04, Vol.14 (S1), p.12A-12A |
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| container_title | American journal of hypertension |
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| creator | Phillips, M. I. Kimura, B. Zhang, Y. C. Gelband, C. H. Mohuczy, D. |
| description | Introduction: The goal of gene therapy for hypertension is to produce safe, prolonged reductions of high blood pressure with a single administration of a transgene. We have develeloped gene therapy using adeno-associated virus (AAV) antisense (AS) as a vector because it is safe, stable and effective. To test systemic injection in an adult hypertensive model, this study uses double transgenic (dt) mice, with human renin (hR) and human transgenes. In these mice, plasma Ang II levels are elevated and blood pressure increased (~140-160 mmHg), compared to controls (~100 mmHg). Methods: Therefore, dt mice with established baseline BP of >140-160 mmHg (n=5) were systemically injected (100 μl) with a single dose of 4x1010 infectious particles of rAAV-AT1R-AS. The rAAV contained a CMV promoter and neo1 reporter gene. Control (n=5) received the rAAV vector without AS. Blood pressure recordings by the tailcuff method were made once per week for up to 6 months. Results: One week after injection, BP decreased by 35-50 mmHg (p |
| doi_str_mv | 10.1016/S0895-7061(01)01343-7 |
| format | Article |
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I. ; Kimura, B. ; Zhang, Y. C. ; Gelband, C. H. ; Mohuczy, D.</creator><creatorcontrib>Phillips, M. I. ; Kimura, B. ; Zhang, Y. C. ; Gelband, C. H. ; Mohuczy, D.</creatorcontrib><description>Introduction: The goal of gene therapy for hypertension is to produce safe, prolonged reductions of high blood pressure with a single administration of a transgene. We have develeloped gene therapy using adeno-associated virus (AAV) antisense (AS) as a vector because it is safe, stable and effective. To test systemic injection in an adult hypertensive model, this study uses double transgenic (dt) mice, with human renin (hR) and human transgenes. In these mice, plasma Ang II levels are elevated and blood pressure increased (~140-160 mmHg), compared to controls (~100 mmHg). Methods: Therefore, dt mice with established baseline BP of >140-160 mmHg (n=5) were systemically injected (100 μl) with a single dose of 4x1010 infectious particles of rAAV-AT1R-AS. The rAAV contained a CMV promoter and neo1 reporter gene. Control (n=5) received the rAAV vector without AS. Blood pressure recordings by the tailcuff method were made once per week for up to 6 months. Results: One week after injection, BP decreased by 35-50 mmHg (p<0.001, compared to baseline). The normalized blood pressure persisted for the full length of the study. Individual mice were sacrificed at 14-28 weeks and tissues taken for detection of rAAV-AT1-R-AS. At both time periods, the AS-AT1R transgene was present in lung, kidney, liver, heart, adrenal gland and fat. The rAAV was not detected in the brain. Renal arterioles (n=6) showed a reduction (50%) contractile response to increasing log doses of Ang II, compared to controls (n=6) (p<0.01). Autoradiography of AT1-R showed a reduction in receptors in the rAAT-AT1R-AS treated group only. Conclusion: The results demonstrated that a single systemic delivery of rAAV-AT1R-AS in adult, hypertensive mice produces a profound decrease in blood pressure for at least 6 months. The prolonged effect is due to the continuous expression of the AT1R AS transgene inhibiting AT1 receptors. The results encourage further development of the rAAV with engineering to make AS transgene expression tissue-specific and switchable on or off for safety.</description><identifier>ISSN: 0895-7061</identifier><identifier>EISSN: 1941-7225</identifier><identifier>EISSN: 1879-1905</identifier><identifier>DOI: 10.1016/S0895-7061(01)01343-7</identifier><identifier>CODEN: AJHYE6</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>AAV (Adeno associated virus) ; Antisense ; AT1 receptor</subject><ispartof>American journal of hypertension, 2001-04, Vol.14 (S1), p.12A-12A</ispartof><rights>Copyright Nature Publishing Group Apr 2001</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Phillips, M. I.</creatorcontrib><creatorcontrib>Kimura, B.</creatorcontrib><creatorcontrib>Zhang, Y. C.</creatorcontrib><creatorcontrib>Gelband, C. H.</creatorcontrib><creatorcontrib>Mohuczy, D.</creatorcontrib><title>O-26: Somatic gene therapy for hypertension with adeno-associated delivery of antisense to angiotensin type 1 receptor mRNA</title><title>American journal of hypertension</title><addtitle>AJH</addtitle><description>Introduction: The goal of gene therapy for hypertension is to produce safe, prolonged reductions of high blood pressure with a single administration of a transgene. We have develeloped gene therapy using adeno-associated virus (AAV) antisense (AS) as a vector because it is safe, stable and effective. To test systemic injection in an adult hypertensive model, this study uses double transgenic (dt) mice, with human renin (hR) and human transgenes. In these mice, plasma Ang II levels are elevated and blood pressure increased (~140-160 mmHg), compared to controls (~100 mmHg). Methods: Therefore, dt mice with established baseline BP of >140-160 mmHg (n=5) were systemically injected (100 μl) with a single dose of 4x1010 infectious particles of rAAV-AT1R-AS. The rAAV contained a CMV promoter and neo1 reporter gene. Control (n=5) received the rAAV vector without AS. Blood pressure recordings by the tailcuff method were made once per week for up to 6 months. Results: One week after injection, BP decreased by 35-50 mmHg (p<0.001, compared to baseline). The normalized blood pressure persisted for the full length of the study. Individual mice were sacrificed at 14-28 weeks and tissues taken for detection of rAAV-AT1-R-AS. At both time periods, the AS-AT1R transgene was present in lung, kidney, liver, heart, adrenal gland and fat. The rAAV was not detected in the brain. Renal arterioles (n=6) showed a reduction (50%) contractile response to increasing log doses of Ang II, compared to controls (n=6) (p<0.01). Autoradiography of AT1-R showed a reduction in receptors in the rAAT-AT1R-AS treated group only. Conclusion: The results demonstrated that a single systemic delivery of rAAV-AT1R-AS in adult, hypertensive mice produces a profound decrease in blood pressure for at least 6 months. The prolonged effect is due to the continuous expression of the AT1R AS transgene inhibiting AT1 receptors. The results encourage further development of the rAAV with engineering to make AS transgene expression tissue-specific and switchable on or off for safety.</description><subject>AAV (Adeno associated virus)</subject><subject>Antisense</subject><subject>AT1 receptor</subject><issn>0895-7061</issn><issn>1941-7225</issn><issn>1879-1905</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpFzU1LAzEQBuAgCtaPnyAEvOghOtlssq03KdYPihUVkV6WdDPbptrNmqRq8c8brOhlhoFn3peQAw4nHLg6fYBuT7ICFD8Cfgxc5IIVG6TDezlnRZbJTdL5I9tkJ4Q5AORK8Q75GrFMndEHt9DRVnSKDdI4Q6_bFa2dp7NViz5iE6xr6IeNM6oNNo7pEFxldURDDb7ad_Qr6mqqm2hD0inEpWNq3c9vQ2PKoZx6rLCNKXdxf3u-R7Zq_Rpw_3fvksfBxWP_ig1Hl9f98yGzPQ5sgqJraqlFV8nMoMnzCYIWvNYGtEwzn0BWFTVUpkCNE1mpClJNXkClegbFLjlcx7bevS0xxHLulr5JjSWHTCkhRQ5J0bVqdFx6LFtvF9qvSj2fZQA8kyoRtiY2RPz8F_6lVIUoZHn1PC7F3Y0QT4Nx2Rff8Q182w</recordid><startdate>200104</startdate><enddate>200104</enddate><creator>Phillips, M. 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H. ; Mohuczy, D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-i910-be38df5a38652ded44be0a31fad0a5fad4b02c7f0cd7eaeb5c6c0ece470c69de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>AAV (Adeno associated virus)</topic><topic>Antisense</topic><topic>AT1 receptor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Phillips, M. I.</creatorcontrib><creatorcontrib>Kimura, B.</creatorcontrib><creatorcontrib>Zhang, Y. C.</creatorcontrib><creatorcontrib>Gelband, C. H.</creatorcontrib><creatorcontrib>Mohuczy, D.</creatorcontrib><collection>Istex</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>American journal of hypertension</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Phillips, M. I.</au><au>Kimura, B.</au><au>Zhang, Y. C.</au><au>Gelband, C. H.</au><au>Mohuczy, D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>O-26: Somatic gene therapy for hypertension with adeno-associated delivery of antisense to angiotensin type 1 receptor mRNA</atitle><jtitle>American journal of hypertension</jtitle><addtitle>AJH</addtitle><date>2001-04</date><risdate>2001</risdate><volume>14</volume><issue>S1</issue><spage>12A</spage><epage>12A</epage><pages>12A-12A</pages><issn>0895-7061</issn><eissn>1941-7225</eissn><eissn>1879-1905</eissn><coden>AJHYE6</coden><abstract>Introduction: The goal of gene therapy for hypertension is to produce safe, prolonged reductions of high blood pressure with a single administration of a transgene. We have develeloped gene therapy using adeno-associated virus (AAV) antisense (AS) as a vector because it is safe, stable and effective. To test systemic injection in an adult hypertensive model, this study uses double transgenic (dt) mice, with human renin (hR) and human transgenes. In these mice, plasma Ang II levels are elevated and blood pressure increased (~140-160 mmHg), compared to controls (~100 mmHg). Methods: Therefore, dt mice with established baseline BP of >140-160 mmHg (n=5) were systemically injected (100 μl) with a single dose of 4x1010 infectious particles of rAAV-AT1R-AS. The rAAV contained a CMV promoter and neo1 reporter gene. Control (n=5) received the rAAV vector without AS. Blood pressure recordings by the tailcuff method were made once per week for up to 6 months. Results: One week after injection, BP decreased by 35-50 mmHg (p<0.001, compared to baseline). The normalized blood pressure persisted for the full length of the study. Individual mice were sacrificed at 14-28 weeks and tissues taken for detection of rAAV-AT1-R-AS. At both time periods, the AS-AT1R transgene was present in lung, kidney, liver, heart, adrenal gland and fat. The rAAV was not detected in the brain. Renal arterioles (n=6) showed a reduction (50%) contractile response to increasing log doses of Ang II, compared to controls (n=6) (p<0.01). Autoradiography of AT1-R showed a reduction in receptors in the rAAT-AT1R-AS treated group only. Conclusion: The results demonstrated that a single systemic delivery of rAAV-AT1R-AS in adult, hypertensive mice produces a profound decrease in blood pressure for at least 6 months. The prolonged effect is due to the continuous expression of the AT1R AS transgene inhibiting AT1 receptors. The results encourage further development of the rAAV with engineering to make AS transgene expression tissue-specific and switchable on or off for safety.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><doi>10.1016/S0895-7061(01)01343-7</doi></addata></record> |
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| ispartof | American journal of hypertension, 2001-04, Vol.14 (S1), p.12A-12A |
| issn | 0895-7061 1941-7225 1879-1905 |
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| source | Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | AAV (Adeno associated virus) Antisense AT1 receptor |
| title | O-26: Somatic gene therapy for hypertension with adeno-associated delivery of antisense to angiotensin type 1 receptor mRNA |
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