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Sci Transl Med 16 June 2010:
Vol. 2, Issue 36, p. 36ra43
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3000931
  • Research Article
Gene Therapy

RNA-Based Gene Therapy for HIV with Lentiviral Vector–Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma

  1. David L. DiGiusto1,*,
  2. Amrita Krishnan1,*,
  3. Lijing Li1,
  4. Haitang Li2,
  5. Shirley Li3,
  6. Anitha Rao1,
  7. Shu Mi4,
  8. Priscilla Yam3,
  9. Sherri Stinson5,
  10. Michael Kalos6,
  11. Joseph Alvarnas1,
  12. Simon F. Lacey4,
  13. Jiing-Kuan Yee3,
  14. Mingjie Li7,
  15. Larry Couture3,8,
  16. David Hsu8,
  17. Stephen J. Forman1,
  18. John J. Rossi2,† and
  19. John A. Zaia3
  1. 1Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.
  2. 2Department of Molecular and Cellular Biology, City of Hope, Duarte, CA 91010, USA.
  3. 3Department of Virology, City of Hope, Duarte, CA 91010, USA.
  4. 4Clinical Immunobiology Correlative Studies Laboratory, City of Hope, Duarte, CA 91010, USA.
  5. 5General Clinical Research Center, City of Hope, Duarte, CA 91010, USA.
  6. 6Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  7. 7Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  8. 8Center for Applied Technology Development, City of Hope, Duarte, CA 91010, USA.
  1. †To whom correspondence should be addressed. E-mail: jrossi{at}coh.org

Abstract

AIDS patients who develop lymphoma are often treated with transplanted hematopoietic progenitor cells. As a first step in developing a hematopoietic cell–based gene therapy treatment, four patients undergoing treatment with these transplanted cells were also given gene-modified peripheral blood–derived (CD34+) hematopoietic progenitor cells expressing three RNA-based anti-HIV moieties (tat/rev short hairpin RNA, TAR decoy, and CCR5 ribozyme). In vitro analysis of these gene-modified cells showed no differences in their hematopoietic potential compared with nontransduced cells. In vitro estimates of successful expression of the anti-HIV moieties were initially as high as 22% but declined to ~1% over 4 weeks of culture. Ethical study design required that patients be transplanted with both gene-modified and unmanipulated hematopoietic progenitor cells obtained from the patient by apheresis. Transfected cells were successfully engrafted in all four infused patients by day 11, and there were no unexpected infusion-related toxicities. Persistent vector expression in multiple cell lineages was observed at low levels for up to 24 months, as was expression of the introduced small interfering RNA and ribozyme. Therefore, we have demonstrated stable vector expression in human blood cells after transplantation of autologous gene-modified hematopoietic progenitor cells. These results support the development of an RNA-based cell therapy platform for HIV.

Footnotes

  • ↵* These authors contributed equally to this work.

  • Citation: D. L. DiGiusto, A. Krishnan, L. Li, H. Li, S. Li, A. Rao, S. Mi, P. Yam, S. Stinson, M. Kalos, J. Alvarnas, S. F. Lacey, J.-K. Yee, M. Li, L. Couture, D. Hsu, S. J. Forman, J. J. Rossi, J. A. Zaia, RNA-Based Gene Therapy for HIV with Lentiviral Vector–Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma. Sci. Transl. Med. 2, 36ra43 (2010).

Citation: D. L. DiGiusto, A. Krishnan, L. Li, H. Li, S. Li, A. Rao, S. Mi, P. Yam, S. Stinson, M. Kalos, J. Alvarnas, S. F. Lacey, J.-K. Yee, M. Li, L. Couture, D. Hsu, S. J. Forman, J. J. Rossi, J. A. Zaia, RNA-Based Gene Therapy for HIV with Lentiviral Vector–Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma. Sci. Transl. Med. 2, 36ra43 (2010).
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