A gene therapy approach for long-term normalization of blood pressure in hypertensive mice by ANP-secreting human skin grafts

Jean Philippe Therrien, Soo Mi Kim, Atsushi Terunuma, Yan Qin, Christine L. Tock, Wolfgang Pfützner, Manabu Ohyama, Jurgen Schnermann, Jonathan C. Vogel

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 selectablemarker 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.

Original languageEnglish
Pages (from-to)1178-1183
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number3
DOIs
Publication statusPublished - 2010 Jan 19

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Keywords

  • Human engineered skin
  • Hypertension
  • Keratinocytes
  • Multi-drug resistance gene
  • Retroviral vectors

ASJC Scopus subject areas

  • General

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