| A gene therapy approach for long-term normalization of blood pressure in hypertensive mice by ANP-secreting human skin grafts. | |
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MedLine Citation:
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PMID: 20080656 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The use of bioengineered human skin as a bioreactor to deliver therapeutic factors has a number of advantages including accessibility that allows manipulation and monitoring of genetically modified cells. We demonstrate a skin gene therapy approach that can regulate blood pressure and treat systemic hypertension by expressing atrial natriuretic peptide (ANP), a hormone able to decrease blood pressure, in bioengineered human skin equivalents (HSE). Additionally, the expression of a selectable marker gene, multidrug resistance (MDR) type 1, is linked to ANP expression on a bicistronic vector and was coexpressed in the human keratinocytes and fibroblasts of the HSE that were grafted onto immunocompromised mice. Topical treatments of grafted HSE with the antimitotic agent colchicine select for keratinocyte progenitors that express both MDR and ANP. Significant plasma levels of human ANP were detected in mice grafted with HSE expressing ANP from either keratinocytes or fibroblasts, and topical selection of grafted HSE resulted in persistent high levels of ANP expression in vivo. Mice with elevated plasma levels of human ANP showed lower renin levels and, correspondingly, had lower systemic blood pressure than controls. Furthermore, mice with HSE grafts expressing human ANP did not develop elevated blood pressure when fed a high-salt diet. These findings illustrate the potential of this human skin gene therapy approach to deliver therapeutic molecules systemically for long-term treatment of diverse diseases. |
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Authors:
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Jean-Philippe Therrien; Soo Mi Kim; Atsushi Terunuma; Yan Qin; Christine L Tock; Wolfgang Pfützner; Manabu Ohyama; Jurgen Schnermann; Jonathan C Vogel |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-01-11 |
Journal Detail:
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Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 107 ISSN: 1091-6490 ISO Abbreviation: Proc. Natl. Acad. Sci. U.S.A. Publication Date: 2010 Jan |
Date Detail:
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Created Date: 2010-02-05 Completed Date: 2010-03-26 Revised Date: 2010-09-28 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 1178-83 Citation Subset: IM |
Affiliation:
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Dermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1908, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Atrial Natriuretic Factor / secretion* Blood Pressure* Cells, Cultured Flow Cytometry Gene Therapy* Humans Hypertension / physiopathology, therapy* Male Mice Skin Transplantation* |
| Grant Support | |
ID/Acronym/Agency:
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//Canadian Institutes of Health Research |
| Chemical | |
Reg. No./Substance:
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85637-73-6/Atrial Natriuretic Factor |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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