Treatment News : Virus-Free Gene Therapy for HIV Shows Promise - by Tim Horn

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July 5, 2012

Virus-Free Gene Therapy for HIV Shows Promise

by Tim Horn

An experimental gene therapy for HIV may actually be easier—and even safer—than experts originally hoped. Experimenting with zinc finger nucleases (ZFNs), researchers at the Scripps Research Institute in La Jolla, California, have discovered it’s possible to cut out an undesirable “middle man”—a virus (not HIV) that carries the gene-altering payload to cells in the body. Until now, such viral vectors were considered a necessary element of gene therapy.   

The new ZFN technique, tested by Carlos Barbas, PhD, of Scripps and his colleagues, is reviewed in the July issue of the journal Nature Methods.

“We showed that we can modify the genomes of cells without the troubles that have long been linked to traditional gene therapy techniques,” said Barbas in an accompanying news announcement.

ZFNs—including SB-278, being developed by Sangamo BioSciences—are of particular interest to HIV researchers and have garnered a lot of attention by AIDS treatment activists and the community press.

How do ZFNs work? First, some background: After HIV binds to the CD4 protein on CD4 cells, the virus must then latch onto another receptor on the cell’s surface—either CCR5 or CXCR4. Usually, when people contract HIV, their virus starts off using the CCR5 receptor. Later on, as HIV disease progresses, the virus can switch to the CXCR4 receptor—this occurs in about 50 percent of treatment-experienced patients.

Selzentry (maraviroc), an antiretroviral approved by the U.S. Food and Drug Administration, works by blocking the interaction between CCR5 and HIV, ultimately retarding the virus’s ability to infect CD4 cells. ZFNs like SB-728 can go one step further—they can block the gene responsible for making CCR5, mimicking a naturally occurring human mutation that renders individuals largely resistant to the virus.

This mutation, dubbed CCR5 delta-32, appears to have no harmful effect in the human body. There’s also the case of Timothy Brown, a.k.a. the Berlin Patient, an HIV-positive leukemia patient who was cured of both diseases when he received a bone marrow transplant from a “matched” donor who had inherited this delta-32 CCR5 mutation from both parents. (When the mutation is inherited from one parent, CCR5 is produced, but it’s at low quantities and is associated with slower HIV disease progression. When the mutation is inherited from both parents, which is very rare, little or no CCR5 is expressed on CD4 cells, rendering the cells impervious to forms of HIV that use the CCR5 receptor to enter cells.)

ZFNs have both therapeutic and curative potential. At present, the most widely known research involves Sangamo’s therapeutic-focused CCR5-knockout ZFN, which is dubbed SB-728-T. Therapy involves removing CD4 cells from patients’ blood, treating the cells with SB-728-T to knock out the CCR5 gene, multiplying the cells in the lab, then transplanting the HIV-resistant genetically modified cells back into the body.  

The latest breakthrough involves the actual cell treatment process. Scientists had assumed that ZFN proteins cannot cross cell membranes, so the standard ZFN delivery method has been a gene-therapy technique in which a relatively harmless virus is used to carry a designer ZFN gene into cells. Once inside, the ZFN gene starts producing ZFN proteins, which seek and destroy their target gene within the cellular DNA.

One potential risk of this approach is that viral DNA—even if the virus is not a retrovirus—may end up being incorporated randomly into cellular DNA, disrupting a valuable gene such as a tumor-suppressor gene. Another risk with this delivery method is that ZFN genes will end up producing too many ZFN proteins, resulting in a high number of “off-target” DNA cuts.

Finally, gene therapies that employ viral DNA may not be effective—or may need to be delayed—in people with antibodies to the virus being used. For example, if a common cold virus is used to deliver the gene therapy to cells, possible candidates may be excluded from clinical trials because they have high levels of virus-specific antibodies that may attack the ZFNs.   

Barbas and his colleagues set out to find a safer ZFN delivery method that didn’t introduce viruses or other genetic material into cells. They experimented initially with ZFN proteins that carry extra protein segments to help them penetrate cell membranes, but these modified ZFNs turned out to be hard to produce in useful quantities. Eventually, the scientists recognized that the zinc-finger segments of ordinary ZFNs have properties that might enable the proteins to get through cell membranes on their own.

“We tried working with unmodified ZFNs, and lo and behold, they were easy to produce and entered cells quite efficiently,” Barbas said.

Next, the team showed how the new technique could be used in a ZFN-based strategy against HIV infection.

Using Sangamo’s SB-728-T results as a comparison, Barbas and his team showed that they could achieve the same effect with their simpler ZFN-delivery method. They added ZFN proteins directly to human CD4 cells in a culture dish and found that within hours, a significant fraction of the ZFN-treated cells showed sharp reductions in CCR5 gene activity.

After several applications of ZFNs, aided by a special cooling method that improves the ability of the proteins to get across cell membranes, the scientists were able to inactivate CCR5 genes with an efficiency similar to that of the gene therapy-based approach, Barbas said.

The new approach also appeared to be safer. A DNA-based method the team used for comparison and the viral-based methods reported in the literature by others ended up producing ZFNs for up to several days, causing a significant amount of off-target DNA damage. But the directly delivered ZFN proteins remained intact within cells for only a few hours, causing minimal off-target damage.

“At some off-target locations where the gene therapy approach frequently causes damage, we saw no damage at all from this new technique,” Barbas said.

Barbas and his colleagues are currently experimenting with a variety of other cell types, including hematopoietic stem cells. Similar to what Sangamo is attempting with its lead candidate SB-728, Barbas hopes to explore his team’s viral DNA-free ZFN approach to turn stem cells into “tiny factories” for producing HIV-resistant CD4 cells, potentially facilitating the cure for people living with the virus.

Search: hiv, zinc finger nuclease, zfn, sangamo, scripps, vector, virus, lentivirus

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  comments 1 - 15 (of 22 total)     next > >>

mborovets, , 2013-05-30 13:31:06
this means immune system impossible to change with one infusion. but if scientists made the procedure cheep and automatic it could be used monthly/yearly instead of toxic HAART

mborovets, , 2013-05-29 19:04:31
similar trial showed infused stem cells don't live long enough in human body. google "hiv OZ1". they dissapear after one year. the main producer of blood cells is still morrow bone with larger quantity of stem cells than could be infused. that is why the Berlin patient experience is not repeatable with infusion of stem cells.

good work

Leon, , 2012-12-31 07:03:05
The HIV cure industry is a scam that goes something like this. Set up a pharama company to develop "HIV cure", government gives massive grant, trial commences and then company disappears. The only reason they set up these trials is to get the grant money. If you want to donate your body to trials then only enter NON government funded trials, i.e. non hiv.

Phil-Philippines, Davao City, 2012-12-15 22:49:50
I am diagnosed for more than a year now. A year ago, I took care of my partner who is only 21 years old and I am only 22 years old. I saved his life by being his primary health care, given the fact that I am a nurse by profession. He also saved my life because without him manifesting AIDS infections I would not decide to get my self tested. I am now switching a profession from Health Care professional to a High School educator. Gene Therapy is our topic this week.This gives us all a HOPE to LIFE

Brian, Boston, MA, 2012-11-24 08:57:39
Best work being done with private funds IMHO-now if the Delaney projects at NIH can get people to think this way maybe Martin's dream will be achieved of an actual cure-dark forces seem to be working against us but white hats are always out there. There is a cure for Hep C out there but the companies will not work together and it is delaying treatment for patients in the thousands who may die for profits-sign petition at or

Chris, Cape town, 2012-10-26 14:47:32
I was diagnosed in February this year, and would like to know how one takes part in these clinical trials. It's just funny that the information about clinical trials is not easily accessible. I really wouldn't mind dying from undergoing a trial just as long as I know that it will help other people. I wish that this information was more easily accessible. Must thank all those doctors and researchers who've made it their lives mission to try and find a cure.

Johnny, London, 2012-10-26 14:35:34
This sounds very good and promising. My main question is what is the projected cost for this kind of treatment? I'm clueless as to the costs for stem cell transplants. I would assume that this would be extremely expensive. Another question, is what if you have the money and would like to undergo the treatment who or how do you get in touch with the right kind of people. I just believe that people should have the option to try it out even though it's not FDA approved.

Trece, Chicago, 2012-08-03 14:42:26
I really hope that this new clinical trial is something to actually believe in, I'm ready to live a more active healthy life without taking medz! Please, Please, PLEASE keep up the good work! If this study is really what they say then I'm willing to become a part of the study by any means necessary!

Keith, Dublin, 2012-07-15 17:20:53
They have yet to prove if ZFN works in the first place never mind trying to find different ways to deliver it, sometimes I feel these people are just talking to themselves. Personally I have great hopes for this cord blood idea currently been done and if that works (and we will know soon not in 10 yrs) then AIDS is cured. Failing that what they need to work on is getting rid of HAART or creating non toxic treatment even if you do have to take it daily

Alex, Toronto, 2012-07-14 09:37:20
This is very hopeful and I know that someday sooner then we have anticipated, this will be available to all people in my life time while I still got my dark hair and still look youthful

Alex, Toronto, 2012-07-14 09:01:19
I hope and pray that someday very soon this treatment with zero side effects to be available for every person who is affected by viral infections, including HIV and other sexually transmuted deceases.

Brian, Vancouver, Wa, 2012-07-11 15:31:02
I am in agreement with Michael from Berlin. My CD4 hasn't risen above 170 in the past 3 years and I've played the "adherence" game almost perfectly. At this point I'm willing to try anything. This is a long and agonizing condition. I'd rather have cancer - it's either something they can fix or they can't. Being strung out on expensive medication seems like we are just putting our money into big pharma. It's sad to think that all I need to do is stop taking meds and it will all be over with

Mico, Somewhere, Maryland, 2012-07-11 10:06:27
I want to join the study. Disappointed to hear, it currently is restricted to those infected 5 years or less. But, hopeful, that the study will be expanded. Plus, I'm just under the 500 cd4 mark. But, I'm willing. Go figure. I have younger friends, afraid to try, those who would currently qualify for the study. Yet, I'm not afraid. Such is life. Go fearless into the night and perhaps, one will catch a new dawn! Keep hopeful. I know I will.

Ulysses, Detroit MI, 2012-07-11 01:19:55
Having been diagnosed in July 1985, I have lived with HIV-AIDS for 27 years,as of this month. It has been my prayer that a cure for HIV-AIDS would be found before I die. This new research results is very promising and I would be willing to participate in clinical trials once they have found a way to make their results more stable and less threatening to the health of the receipient. After the "cure" is found, I am concerned about those who may become careless, and breed new disease threat.

comments 1 - 15 (of 22 total)     next > >>

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