December 7, 2008

December 7, 2008
Path to a Cure?


Thanks for stopping by to check out another day in my life. I hope you are having a great and safe weekend so far. It has been a great one for me.

As many of you know, I am currently traveling around to several cities in the United States doing our event for children affected and effected by HIV and AIDS called the Teddy Bear Touchdown. We take the generous gifts from our donors and do a holiday party for the children and have a local singing group in each city come and sing holiday music during the event. Every child receives a teddy bear and at least one or two other gifts in the bag. There is nothing as rewarding as the smiles and happy tears of these kids as they open their gifts. Most of these children come from financially challenged families and without our great donors would not have received a gift this holiday season.

But on to my topic of the day which is there a path to a cure for HIV and AIDS?

Recent news about a possible cure for HIV in a stem cell transplant patient could jump start the related field of gene therapy. Stem cell expert Dr. David Scadden talks about the risks and the hopes that are moving researchers forward.

Major worldwide media recently covered the story of an HIV positive leukemia patient in Berlin who has possibly been “cured” of his HIV after a stem cell transplant to treat his cancer. The transplant specialist, Gero Hütter, MD, from the Berlin Charité Hospital, used stem cells from a donor with a rare genetic mutation that prevented his CD4 cells from producing CCR5 receptors and, thus, rendered him virtually immune to HIV.

Since the transplant nearly two years ago, the leukemia patient, now in remission, has been able to stay off antiretroviral therapy. Dr. Hütter has so far been unable to locate HIV in his body and some news sources have called this a possible cure. Before making a similar declaration, many researchers and activists are cautiously waiting for independent verification of the patient’s blood and tissue samples.

Even if the patient turns out to have beat back HIV permanently, it is unlikely that stem cell transplants are going to become a routine treatment. Not only do they often cost at least a quarter of a million dollars, but patients also typically receive whole body radiation or high dose chemotherapy to make space for the transplanted cells a process called preconditioning and both treatments come with a high risk of serious side effects and death.

Instead of debating the merits of moving forward with stem cell transplants for everyone, AIDSmeds decided to ask stem cell specialist David Scadden, MD, from Harvard Medical School in Boston, how Hütter’s experiment may influence the development of gene therapy and other similar approaches to treat and perhaps one day cure HIV.

Can you tell us how the Berlin stem cell transplant case may inform or influence gene therapy?

This concept that you might be able to provide an immune system that is resistant to HIV is certainly one that has been around for a long time and certainly still has a lot of intellectual validity, and it is wonderful that there might be some experimental validation of it.

Two things about it: First, does it really require the sort of severe [destruction] of existing cells that might serve as [HIV] reservoirs that this patient went through? Second, is it possible to modify an immune system [without first having to wipe it out], enabling it to become effective at seeking and destroying those reservoirs and getting rid of them?

I do not think we can tell from this experiment, but I think that the latter possibility does not sound theoretically impossible. It is one that the field certainly remains interested in trying to discover.

Is anyone looking at the possibility of genetically reprogramming a person’s own stem cells so that the new cells they produce can not make CCR5?

Yes, but one of the problems with previous gene therapy approaches was that the means of [transplanting] the cells was very poor. We did not know much about how to keep these new genes that were in the cells turned on. It is one of the reasons why I got more involved in the basic research of stem cells, with the hope that by ultimately learning more we will be able to actually do this.

In the meantime, there is been a process that is called zinc finger exonuclease, which is an effort to try to delete genes in cells, and this is one [method] with particular appeal. There is a company that has been formed around developing this molecular tool for gene therapy.

Do you think we may be more likely to try these kind of experiments first in people who have run out of other treatment options, the way we often do with antiretrovirals, or would anyone be eligible for these early gene therapy trials?

Well, you know one of the issues is that if you want to do it just in mature lymphocytes [T cells circulating in the body], then you can infuse those and the person does not need preconditioning. But if you would like to have this be in a stem cell, so that all of the immune cells have the capacity to be resistant to the virus, then the problem with stem cell transplants is that [the new] stem cells are in competition for a limited space, and you have to move out the existing stem cells. So you usually do that with something that is fairly toxic. And so a person would have to be able to tolerate the rigors of preconditioning and a transplant.

That sometimes is done in a very short order. We do that now for lymphoma patients. Some places even do it as an outpatient procedure. We still do it inpatient [in my clinic], but people can get very sick. They can feel really crummy, and so it has traditionally been something that we only do in patients with lymphoma.

When you are transplanting a person’s own stem cells, rather than from a matched donor, is there the need to do the same degree of immune destruction?

That is a great question, because you would imagine that you do not have to impair the immune system. But unfortunately you still have this issue of what is called niche occupancy which means you still need to have a vacancy for the new stem cells to set up shop. And because of that you still need to give something that is toxic to the existing stem cells. Recently there was a paper [on research that found] in a mouse you could use an antibody to do that, but in humans we are still forced to use things like chemotherapy and radiation.

Aside from the preconditioning, are there other safety concerns with things like the zinc finger approach or with gene therapy?

Yes. Any gene modification raises a lot of safety concerns, because you want to make sure that you are modifying only those areas [of the gene] that would be of benefit. One of the questions has been how specifically can you accomplish excising just one region of the genome and can you do it in both copies of the gene. And with any gene therapy of stem cells, you run the risk of some insertion site abnormality. So when the new gene finds its way into the chromosome to knock out the unwanted gene, the new gene disrupts other genes needed by the body.

This is what resulted in leukemia in the children transplanted with gene modified stem cells to fight severe combined immunodeficiency. So those are the caveats. That said, I think there is a better appreciation now for how to minimize those risks and if you are dealing with the setting where a person has very limited options and is looking at the ravages of HIV disease, I think those risks may end up making sense.

Since the majority of people who can not make CCR5 are Caucasian and usually of Nordic descent, would that impact the ability to find donors of African descent?

Yes, definitely. That has been one of the problems generally with bone marrow donation. There are ethnic and cultural differences in terms of the willingness of certain individuals to donate. Those that come from outside the Northern European descent group often have a difficult time finding a matched donor, even from these registries. These registries do not have a proportionate representation of our demographics.

To treat the growing proportion of HIV positive people in this country, and certainly worldwide, it sounds like we might need to find something similar to the CCR5 genetic defect in those populations before stem cell donations might be more widely possible?

Yes, or to find another method of CCR5 inhibition. The zinc finger concept is one method, but there are other technologies. There are interfering RNAs that may be able to reduce expression of genes, and they are also thought of as a potential future way to modify cells. There would also be a gene based approach, such as gene modification of a person’s own cells to overcome the risk of immunologic rejection or the transplanted cells attacking the person.

Basically, we are hoping to better understand how to reduce gene expression in a good way, to better isolate and put new genes in stem cells and to transplant those stem cells with fewer toxicities. Those are all areas of active investigation. We are hoping they are all going to get to a place where we are thinking about this on a much broader scale in the future, and I would like to say that I am hoping we are going to see that soon. It has been a long time.

So stayed tuned for these and other developments. But I always believe in hope.

Wishing you health, hope and happiness.



Big bear hug,





Daddy Dab