Stem Cell Gene Therapy Appears Safe, May Protect Cells against HIV Infection

A gene therapy technique that alters an HIV positive person's blood-producing stem cells to make them resistant to the virus appeared safe and led to stable populations of resistant cells in a small study described in the June 16, 2010 online edition of Science Translational Medicine, paving the way for further proof-of-concept studies of this approach.

Researchers have long hypothesized that removing all the susceptible immune system white blood cells from a person with HIV and replacing them with resistant cells might result in a cure, since the virus would no longer have targets to attack and would eventually burn itself out.

Removal and manipulation of immune cells is a potentially fatal procedure, however, and difficult to justify ethically, especially in an era when effective antiretroviral therapy can keep HIV positive people in relatively good health over the long term.

But replacement of hematopoietic progenitor cells, or blood-producing stem cells, after destruction of existing immune cells by chemotherapy is an accepted treatment for lymphoma and leukemia. The idea is to kill off the cancerous blood cells and introduce stem cells from bone marrow to reconstitute a new, cancer-free immune system.

In one real-life proof-of-concept case (described in the February 12, 2009 issue of the New England Journal Medicine), Gero Huetter and colleagues appear to have cured an HIV positive man with leukemia -- dubbed the "Berlin Patient" -- by replacing his immune cells with those from a donor with a naturally occurring but rare mutation known as CCR5-delta-32, which makes CD4 cells resistant to HIV infection. After 3 years, the man remains free of leukemia and HIV.

It is not practical for every person with HIV to receive a stem cell transplant from a naturally resistant donor, so researcher have explored another approach that involves removing an HIV positive person's own stem cells by a process called apheresis, using gene therapy to alter the cells, and returning them to the patient's body in the hopes that they will multiply and produce a new HIV-resistant immune system.

As described in the recent Science Translational Medicine report, David DiGiusto, John Zaia and colleagues at the City of Hope Medical Center near Los Angeles tried the experimental technique on 4 HIV positive patients undergoing hematopoietic stem cell transplants to treat lymphoma.

Usually some autologous (taken from and returned to the same individual) stem cells are removed from a patient and stored, the cancerous immune cells are destroyed, and the stem cells are then returned to reconstitute the immune system. In this study, in addition to replacing normal hematopoietic progenitor cells, the researchers also used gene therapy to alter a small subset of these cells to make them resistant to HIV in 3 different ways.

These changes were made using tiny pieces of RNA delivered by a lentivirus vector from the same broad family as HIV: a TAR decoy, a Tat/Rev short hairpin RNA, and a CCR5 ribozyme that alters one of the coreceptors HIV uses to enter cells. The modified cells, along with the normal stem cells, were then re-infused into the patients.

Results

• Laboratory analysis revealed that the gene-modified cells showed no difference in their hematopoietic potential, or ability to regenerate blood cells, compared with normal stem cells.
• In vitroanalysis showed that successful expression of the HIV-resistant stem cells initially reached as high as 22%, but declined to about 1% over 4 weeks.
• Gene-modified stem cells were successfully engrafted in all 4 patients by day 11.
• Expression of the vector and the altered anti-HIV genetic material was observed at low levels in multiple cell lineages for up to 24 months, although the number of modified cells was too small to have a therapeutic effect.
• There were no unexpected toxicities or side effects related to apheresis and infusion.

Thus, the study authors concluded, "[W]e 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."

In an accompanying commentary, Priya Shahand David Schaffer from the University of California at Berkeley wrote, "This study not only demonstrates the safety and long-term viability of this approach, but also highlights areas in which focused improvements in gene therapy strategies may provide the most impact in increasingly translating promise in the laboratory to efficacy in the clinic."

Investigator affiliations: Department of Hematology and Hematopoietic Cell Transplantation, Department of Molecular and Cellular Biology, Department of Virology, Clinical Immunobiology Correlative Studies Laboratory, General Clinical Research Center, and Center for Applied Technology Development, City of Hope, Duarte, CA; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Neurology, Washington University School of Medicine, St. Louis, MO.

6/22/10

Reference

DL DiGiusto, A Krishnan, L Lijing, J Zaia, and others. RNA-Based Gene Therapy for HIV with Lentiviral Vector–Modified CD34⁺ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma. Science Translational Medicine2(36): p36ra43. June 16, 2010.

PS Shah and DV Schaffer. Gene Therapy Takes a Cue from HAART: Combinatorial Antiviral Therapeutics Reach the Clinic (Perspective). Science Translational Medicine 2(36): p36ps30. June 16, 2010.

Other Source

Gene Therapy: The Frontier of HIV/AIDS Treatment. Science Translational Medicine Summaries for June 16, 2010.