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No More Science Fiction -- HIV Gene Therapy Delivers


A gene therapy technique using a zinc finger nuclease to disable expression of CCR5 co-receptors on CD4 cells led to robust T-cell increases in a small study reported at the 18th Conference on Retroviruses and Opportunistic Infection (CROI 2011) this week in Boston. A related study showed that a similar technique can knock out CXCR4 co-receptors. Trial participant Matt Sharp describes the study findings and his experience.

In what could be considered a scientific breakthrough in HIV research, gene therapy trials provided a buzz of excitement at an otherwise typical HIV/AIDS conference.

Jay Lalezari from Quest Clinical Research in San Francisco presented findings from a small Phase 1 clinical trial at a Monday session looking at "Innovative Therapeutic Approaches." A companion trial at the University of Pennsylvania was presented by Carl June at a closing session entitled "Obstacles to a Cure."

Participants in these studies are donating blood cells to be manipulated using zinc finger nucleases, which act like small molecular scissors, blocking expression of the CCR5 co-receptor on CD4 cells. This co-receptor is necessary for many strains of HIV to attach to and fuse into a CD4 cell, beginning its lifecycle of destruction. Other HIV strains use an alternate co-receptor called CXCR4.

Lalezari presented data on altered CD4 cells -- known as SB-728-T -- in 6 men who have been living with AIDS for over 20 years. Participants had continued low CD4 cell counts, ranging from 200 to 500 cells/mm3, despite having undetectable HIV viral load on antiretroviral therapy.

The study procedure involves removing blood from participants in an apheresis clinic. CD4 cells are extracted and processed with the zinc finger technology, disrupting the CCR5 gene. The altered cells are allowed to multiply and the new cells are then frozen and sent to the study clinic, where they are thawed and re-infused back into the participant in about 20 to 30 minutes.

Although the study was small, 5 of the 6 participants in the first 2 cohorts had an average increase of 200 CD4 cells during 1 year of follow-up after the infusion. The procedure was safe and well tolerated. One participant did not respond, most likely due to a lower baseline CD4 count.

About 25% of the donated cells had the CCR5 co-receptor removed, and when re-infused, 3%-6% of those cells remained present after 3 months. Showing that the treated cells can reach other areas of the body, rectal biopsies revealed that the cells migrated to the gut mucosa, which is an important HIV hiding place.

The motivation for this CCR5 deletion approach came from the successful treatment of Timothy Brown, also known as the "Berlin patient." [] Brown, living with AIDS and leukemia, received 2 bone marrow transplants from a donor with CD4 cells that were naturally deficient in CCR5 co-receptors due to an uncommon genetic mutation. Four years later, he is considered cured of AIDS and his leukemia is in remission. His case has spawned a new wave of HIV research that hopefully will lead to what is now characterized as a "functional cure."

There is a licensed antiretroviral drug that targets the CCR5 co-receptor -- maraviroc (Selzentry) -- but the gene therapy approach is an advance in improving the quality of life in people with HIV, who at this point need to take drugs the rest of their lives.

Sangamo, a small biotech company in Richmond, California, holds the patent for SB-728-T and is working with zinc finger nucleases in other disease areas. At CROI researchers from the University of Pennsylvania and Sangamo presented further work on manipulating the gene for CXCR4, the other important co-receptor for HIV. They hope to use both CCR5- and CXCR4-deleted cells in a combination approach.

This writer enrolled in the San Francisco trial, and I must admit it was thrilling to see my own data presented at CROI. I have been seeking a treatment that would boost my immune system, since I have not been able to increase my CD4 cells for over 20 years on antiretroviral therapy.

In October, when I received the first lab report, I was stunned to see the positive results. My T-cells had doubled and I experienced no side effects. Despite the unknowns of entering a Phase 1 gene modification trial, I recognize that much of the success of my HIV treatment history has happened because I chose to take risks along the way.

While it is important to understand that this research is far from being a cure for AIDS, the trial is a critical step in opening the minds of the cynics who refuse to believe a cure is attainable. Scientists and funders may also recognize that the ship has left the dock, and they may not want to miss a golden opportunity to help end the epidemic of our time.



J Lalezari, R Mitsuyasu, S Deeks, and others. Successful and Persistent Engraftment of ZFN-M-R5-D Autologous CD4 T Cells (SB-728-T) in Aviremic HIV-infected Subjects on HAART. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 46

C Wilen, J Wang, J Tilton, and others. Creating an HIV-resistant Immune System: Using CXCR4 ZFN to Edit the Human Genome. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 47.

P Tebas, B Levine, G Binder, and others. Disruption of CCR5 in Zinc Finger Nuclease-treated CD4 T Cells: Phase I Trials. 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011). Boston. February 27-March 2, 2011. Abstract 165.