Advertisement covers The 18th Conference on Retroviruses and Opportunistic Infections (CROI 2011)

Gene Therapy Makes Small but Promising Early Steps Forward as Potential Form of HIV Treatment

March 1, 2011

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The following is our transcript of a press conference that took place on Feb. 28, the first full day of CROI 2011. In it, three researchers -- Jay Lalezari, M.D., Craig Wilen and Paula Cannon, Ph.D. -- summarized the findings of studies they were presenting at the conference related to developments in gene therapies for the treatment of HIV infection. Lalezari begins by referring to an experimental gene therapy approach under development by Sangamo BioSciences, Inc., which essentially seeks to remove the CCR5 gene from a patient's T cells.

Jay Lalezari: What Sangamo has brought forward is a gene modification strategy that for the first time allows us to precisely and permanently disrupt the CCR5 gene. Why that's important is that when you disrupt the gene, you also permanently disrupt receptor expression. And as we know CCR5 is the major co-receptor that HIV uses to gain cell entry. We have the natural experiment from the delta-32 mutation showing that in the homozygote they're protected from infection. The heterozygote has delayed disease progression. And even the Berlin patient further validates that CCR5 is an appropriate target for HIV, although the experience of that individual is less relevant.

What the gene therapy with Sangamo can do is specifically disable the CCR5 gene. Whether we're using peripheral cells or stem cells, the idea is to then give patients back cells which are themselves immune to HIV. I think the potential benefit of that remains to be determined in the coming studies.

What we did in our study is send patients to an outpatient infusion center where they had their blood harvested over a three-hour filtration process. Blood was sent to a manufacturing center. The cells were transduced using the Sangamo vector. The cells were then frozen and shipped back to our site, where we then infused them back into the patients with just a little bit of Tylenol.


The six take-home messages of the study are that, number one, the infusions were well tolerated. Don't appear to be any safety issues.

Number two, we saw a clinically significant increase in CD4 counts: Five of the six patients had T cells that were over 500 that were sustained throughout the observation period.

The third thing was that not only do we see increases in CD4 counts, but we saw a reversion of the CD4-CD8 ratio back to normal in three of five subjects. One of the subjects started with the normal ratio. And that reversion back to normal -- most HIV-negative individuals have a ratio greater than 1. The [inaudible] of HIV is a reversion, or inversion, of that ratio to less than 1. So we normalize that ratio in three of five patients, and that observation continued throughout the study period.

Number four is that in concert with these CD4 counts in normal ratios, we saw engraftment and apparent expansion of these modified cells. So the cells took in all six patients.

One patient had diminished responses because of an antiviral antibody issue. But five of the six showed significant engraftment and expansion of those cells, sort of a threefold increase above what would have been predicted based on the input of cells at the infusion. Engraftment, infusion; the nature of that expansion is open for debate. It's unlikely to be a distribution issue, because we did see the cells traffic normally to the gut mucosa. And whether that expansion is an artifact of the manufacturing process, which does involve T-cell activation, or whether it's real T-cell proliferation, which would be a very good thing, remains to be determined.

Along with the expansion, we saw persistence of these cells in the blood. At day 90, using a PCR assay, we were able to show a total of between 6% and 7% of the cells in the peripheral blood remained modified at three months. And there's a sense that that set point at day 90 predicts what comes later.

Finally, similar to the levels in peripheral blood, we did rectal biopsy and were able to see persistence of the virus in that tissue as well, at levels that were similar.

So: The procedure was safe. We had increases in CD4 counts. We normalized the ratios. We had engraftment of the cells. We had expansions of the cells. There was persistence, and there was good homing and trafficking to the gut.

The only thing I want to say is, though: These results were probably as good as we could have hoped for in this population. What I have been getting a lot of phone calls from people saying, "I want to do an interview with you about the cure research." And I just want to say that that is way overstated, it is an overreach of the data. I would just ask all of you to show a little bit of restraint in reporting these results. Remember, we have to careful when we throw around the C word. There are a lot of folks out there with hopes and dreams attached to that word. I just want to be cautious about that. Thanks.

Scott Hammer: Thank you, Jay. Craig?

Craig Wilen: As alluded to, our long-term goal to this project is to really recapitulate the success of the Berlin patient. While a cure is not near, that is our long-term and ultimate goal.

While the vast majority of viruses utilize the CCR5 pathway, a lot of individuals, particularly those who are treatment-experienced and late-stage, have viruses that can access another pathway called CXCR4. Viruses that utilize CXCR4 are more pathogenic in vitro. And the emergence of viruses that can use CXCR4 heralds progression to AIDS and a poor disease prognosis. So it's possible that disrupting CCR5 may not be sufficient for at least all patients.

Sangamo has developed ZFNs [zinc finger nucleases] specific to the CXCR4 gene, and this has enabled us to genetically disrupt CXCR4 in human T cells. And this disruption is efficient. It's stable. It confers robust survival advantage in the presence of diverse HIV strains in vitro. This is all preclinical development work.

We then performed humanized mouse studies, where we put CXCR4-disrupted human cells into mice and challenged them with HIV. This conferred protection to X4 virus and has given very promising preclinical results.

One thing that did emerge from the mouse study is that virus that utilized the CCR5 pathway actually emerged. What this does is it suggests that we need to, for maximum therapeutic effect, target both CCR5 and CXCR4 in the patients' own cells simultaneously. Future work is going to be addressing optimal ways to disrupt both HIV co-receptors at the same time.

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This article was provided by TheBodyPRO. It is a part of the publication The 18th Conference on Retroviruses and Opportunistic Infections.

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