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Blood, 1 October 2005, Vol. 106, No. 7, pp. 2280-2286.
Prepublished online as a Blood First Edition Paper on March 29, 2005; DOI 10.1182/blood-2004-11-4174.
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Submitted November 2, 2004
Accepted March 9, 2005
Human erythropoietin gene therapy for patients with chronic renal failure
Yitzhak Lippin, Michal Dranitzki-Elhalel, Einat Brill-Almon, Chava Mei-Zahav, Sarah Mizrachi, Yael Liberman, Adrian Iaina, Eli Kaplan, Eduardo Podjarny, Evelyne Zeira, Menahem Harati, Nicole Casadevall, Noam Shani, and Eithan Galun*
Department of Plastic Surgery, Rambam Medical Center, Haifa, Israel
Department of Medicine, Hadassah - Hebrew University Hospital, Jerusalem, Israel
Medgenics Inc., Biogenics Ltd,, Misgav, Israel
Goldyne Savad Institute of Gene Therapy, Hadassah - Hebrew University Hospital, Jerusalem, Israel
Department of Nephrology, Sourasky Medical Center, Tel-Aviv, Israel
Nephrologist, Herzliah, Israel
Laboratoire d'Hematologie, Hotel Dieu and INSERM 362, Paris, France
* Corresponding author; email: galun{at}md2.huji.ac.il.
Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical condition is anemia. Patients with anemia of chronic renal failure are treated with Erythropoietin. The objective of this study was to develop a therapeutic platform for serum secreted proteins like erythropoietin.
We developed a tissue protein factory based on dermal cores (Biopump) harvested and implanted autologously. In this study, an adenovector was designed to express the human Erythropoietin under the control of the CMV promoter. This vector transduced the harvested dermal cores ex vivo. The transduced cores were implanted and Erythropoietin and reticulocyte counts were measured.
Dermal cores were harvested from 13 patients with chronic renal failure, and implantation was performed in 10. There were no significant drug related side- effects to this procedure. Erythropoietin serum levels increased significantly to therapeutic levels from day 1 post implantation reaching a peak during the first week of follow-up. The expression period was transient for up to 14 days. The rise of Erythropoietin was followed by a transient significant increase in reticulocyte counts. The decrease of Erythropoietin expression coincided with a significant dermal infiltrate of CD8 cytotoxic T cells. Anti Erythropoietin antibodies were not detected until day 90 following implantation.
Implantation of dermal cores ex vivo transduced with human genes could eventually be used in the clinical setting to express therapeutic serum proteins. However, non-immunogenic delivery system should be tested as gene vehicles.
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