title: Human erythropoietin gene therapy for patients with chronic renal failure.
abstract: 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 cytomegalovirus (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 after 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. Antierythropoietin 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, nonimmunogenic delivery system should be tested as gene vehicles.
authors.affiliation: Department of Plastic Surgery, Rambam Medical Center, Haifa, Israel.
authors.forename: Yitzhak
authors.initials: Y
authors.lastname: Lippin
authors.forename: Michal
authors.initials: M
authors.lastname: Dranitzki-Elhalel
authors.forename: Einat
authors.initials: E
authors.lastname: Brill-Almon
authors.forename: Chava
authors.initials: C
authors.lastname: Mei-Zahav
authors.forename: Sarah
authors.initials: S
authors.lastname: Mizrachi
authors.forename: Yael
authors.initials: Y
authors.lastname: Liberman
authors.forename: Adrian
authors.initials: A
authors.lastname: Iaina
authors.forename: Eli
authors.initials: E
authors.lastname: Kaplan
authors.forename: Eduardo
authors.initials: E
authors.lastname: Podjarny
authors.forename: Evelyne
authors.initials: E
authors.lastname: Zeira
authors.forename: Menahem
authors.initials: M
authors.lastname: Harati
authors.forename: Nicole
authors.initials: N
authors.lastname: Casadevall
authors.forename: Noam
authors.initials: N
authors.lastname: Shani
authors.forename: Eithan
authors.initials: E
authors.lastname: Galun
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000740:Anemia / Q000628:therapy; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D003587:Cytomegalovirus / Q000235:genetics; D004921:Erythropoietin / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000628:therapy*; D008875:Middle Aged; D011994:Recombinant Proteins; D012156:Reticulocytes / Q000166:cytology / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
chemical_list: D011994:Recombinant Proteins; D004921:Erythropoietin