Progress in stem cell therapy for HIV/AIDS

Last week the company Sangamo Biosciences announced good results from their HIV/AIDS trial in which they genetically altered patients' own T-cells. CIRM is following this trial closely, since it's the precursor to one being developed by a team of CIRM-funded researchers led by John Zaia at City of Hope that includes Sangamo.

According to Discover Magazine, the company reported last week:

The goal was to see if receiving these altered cells would let patients go off their anti-retroviral drugs. The results, reported at a recent conference in Chicago, were mixed—the cells didn’t always survive long in the fifteen people enrolled. But two patients saw their HIV levels drop 10-fold, and one patient who stopped his anti-retrovirals first saw a spike in virus levels but then had them decline to undetectable levels.

The work funded by CIRM is a next generation version of this trial. In both cases, Sangamo's technology is used to snip the DNA of cells taken from a patient's bone marrow. Those snips introduce a mutation in a gene called CCR5, which makes the protein that the HIV virus uses to enter a cell. No CCR5 gene means HIV can't infect the cells.

Doctors then reintroduce those cells into the patient. The idea is that the patient will then be resistant to the HIV in their bloodstream and eventually can go off drugs. In the recently reported study, the team altered the adult T-cells, which would supply a finite number of resistant T cells. The CIRM study will be altering the blood-forming stem cells, which give rise to T-cells, in hopes of creating a more permanent supply of HIV-resistant T-cells.

This video gives more information about the goal of the CIRM-funded team:


A.A.

CIRM HIV/AIDS disease team technology makes news

Richmond-based Sangamo BioSciences has been making a lot of news lately with their gene editing technology. Theirs is the technique being used in CIRM'S HIV Disease Team Award to John Zaia at The City of Hope (summarized in this San Francisco Business Journal story).

Sangamo's so-called zinc finger technology can recognize a specific location in the DNA, snip it out, and replace it with a different sequence. In the case of HIV, the molecular zinc scissors are being used to create a mutation in a small region of DNA in blood-forming stem cells.

Those cells altered in the lab lack a working copy of the protein CCR5, which the HIV virus uses to enter and destroy immune cells. The team then plans to transplant those altered stem cells into a person, where they create a new immune system that is resistant to HIV infection. Early results from this work in animals look promising and the team is hoping to be able to enter human clinical trials with the technique in the next few years.

This is one of two CIRM disease teams attempting to generate a stem cell-based therapy for HIV/AIDS. The other award, to Irvin Chen at UCLA, is using a different type of molecule to mutate the CCR5.

Ron Leuty of the San Francisco Business Journal had a story yesterday about Sangamo's prospects, which include a trial to treat pain associated with diabetes, called diabetic neuropathy. The technique is also being used in research to treat the blood-clotting disease hemophilia B and to create disease-in-a-dish models of heart disease. Reuty wrote about the heart disease work, being carried out by Sangamo and researchers at the Scripps Translational Science Institute:

Using induced pluripotent stem cells — adult stem cells manipulated to give them embryonic-like qualities — researchers will recreate cells that line the arteries. ...

"Genome editing allows us to do an experiment no one has ever tried — that is, if you change someone's genetics, can you make their cells revert away from acquiring a disease?" Samuel Levy, director of genomic sciences at the Scripps Translational Science Institute, said in a press release.

This video describes how the City of Hope team hopes to use the zinc finger technology in their proposed therapy for HIV.



You can also watch talks by City of Hope research John Zaia, CIRM board member and HIV patient advocate Jeff Sheehy, and HIV advocate Loren Leeds when they spoke to the CIRM governing board about the work.

-A.A.

30th Anniversary of HIV/AIDS, CIRM teams making progress

Thirty years ago the first reports of a mysterious illness began appearing in the media. This illness would eventually become known as AIDS.

CIRM board member Jeff Sheehy recently spoke as part of a KQED Forum radio show about the 30th anniversary of HIV/AIDS. As a long-time AIDS activist, Sheehy has been part of the fight for a cure. In his introduction, Sheehy talked about limitations of the current drug regimen for HIV/AIDS:

“We’re still losing people and I think that gets lost in a lot of this. People have a treatment optimism belief. HIV or medication side effects are shortening lifespans. Things are still tough for people with HIV and one of the things we need to talk about is a cure.”

That cure is looking more hopeful with the announcement of a man who has come to be known as the Berlin patient (we blogged about him here). He received a bone marrow transplant in Berlin from someone who was effectively resistant to HIV infection. That man, Timothy Brown, also became resistant to infection and now doctors are unable to detect HIV in his body.

In the Forum discussion, Steven Deeks, professor of medicine at UCSF and a leader in HIV/AIDS research, pointed out that although Brown’s HIV is now undetectable, his isn’t the treatment that will become a widespread cure. First, there aren’t enough bone marrow donors who are resistant to HIV. The bone marrow transplant itself is also an extremely risky procedure.

Deeks pointed to work being carried out by CIRM grantees who are attempting to engineer a person’s own bone marrow stem cells to carry the mutation that makes the cells resistant to HIV. Sheehy pointed out that CIRM has been alone in funding this type of work:

“It’s been lonely. Thank god for the voters in 2004 who voted for proposition 71[ the proposition that created CIRM]. What surprised me when I got appointed to this board I really didn’t think there was much in HIV that could be done.”

CIRM now funds more than $40 million in HIV/AIDS research (see a list of those awards here), including two disease teams that are both working toward beginning clinical trials in two to three years.

This video features Sheehy and John Zaia from the City of Hope who leads one of those disease teams.



A.A.

Guest blogger Jeff Sheehy - CIRM Grantees Show Progress Towards a “Cure for HIV” in Boston

At the 18th Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, two members of CIRM’s HIV/AIDS Disease Team led by John Zaia at City of Hope presented new research showing the team’s progress toward the clinic.

The team’s overall goal is to use technology developed by Sangamo Biosciences to modify the blood-forming stem cells of people infected with HIV. The modifications would effectively remove the doorway protein—called CCR5—the HIV virus uses to enter immune cells. The less than one percent of the population who lack CCR5 are naturally resistant to HIV infection and one HIV patient in Berlin who received a complete bone marrow transplant from someone born lacking the CCR5 receptor has been functionally “cured” of HIV.

In a presentation on Monday, Sangamo Biosciences released preliminary data from 6 HIV patients in its gene therapy clinical trial targeting T-cells, which are the primary immune cells invaded by the HIV virus. The study uses Sangamo’s zinc finger gene modification technique to remove the CCR5 receptor from T-cells taken from the patients with HIV. Those modified T cells were then returned to the patients’ blood system. The patients saw both survival and expansion of the modified T-cells—a critical finding since this implies some competitive advantage for cells protected by CCR5 deletion over cells that are not protected.

This finding is not itself a cure, since T-cells are just one type of immune cell that HIV attacks. However, it is encouraging for the CIRM funded Disease Team project, which seeks to use the same gene modification technique on a HIV patient’s blood-forming stem cells in the bone marrow. These tissue-specific stem cells give rise to all of the blood cells in the body and modifying them successfully could lead to protection for all of the immune cells that HIV attacks – not just the T cells. A full bone marrow transplant replacing the entire blood-forming stem cell compartment with modified cells carries significant risk, with mortality close to twenty percent. However, partial replacement of the stem cell compartment with CCR5 deleted cells and successful survival and expansion might be a safer and more accessible avenue for replicating the functional cure achieved in the single Berlin patient.

In a presentation Wednesday at CROI supporting this approach, Paula Cannon from USC and a member of the same Disease Team, will expand on her research on the use of hematopoietic stem cells genetically modified with the Sangamo zinc finer technology to remove CCR5 in mice with humanized immune systems. In her previously published study (here's a link to the Nature paper), the partial replacement of the bone marrow stem cell compartment with a minority of gene-modified cells led to competition between modified and unmodified cells with the CCR5 deleted modified cells (here's our blog entry on the work). In the humanized mice, the modified cells were eventually selected to the point where the humanized immune systems of the mice were able to control HIV successfully to a level where HIV is undetectable and without the use of antiretroviral therapies.

Together these two studies suggest that the Sangamo technology is able to effectively remove the CCR5 protein from modified cells, and that those cells are able to resist HIV infection.

Here are a few news reports about the work:
http://www.aidsmeds.com/articles/HIV_Sangamo_CCR5_1667_19952.shtml


http://m.apnews.com/ap/db_8559/contentdetail.htm?contentguid=YVSgAu1f

This video discusses the City of Hope HIV/AIDS disease team:



- Jeff Sheehy is is director for communications at the AIDS Research Institute at UCSF, and a member of the CIRM governing board.

CIRM Innovation: The Patient Advocate Role -- Guest blogger Jeff Sheehy

Duane Roth, my colleague on the CIRM governing board where he serves as one of the vice-chairs, has just published an article, with the title, “The Third Seat at the Table: An Insider’s Perspective on Patient Representatives,” in the Hasting’s Center Report. The Center, an independent, nonpartisan, and nonprofit bioethics research institute, publishes its report six times a year to “explore the ethical, legal, and social issues in medicine, health care, public health, and the life sciences.”

His article, along with one I published in Nature earlier this year (“Advocates deserve room at the decision-making table”) describe one of the critical innovations found in the governance of CIRM: formal, powerful roles for patient advocates.


I serve on the governing board as a patient advocate for HIV/AIDS, and in that role I along with the other patient advocate board members have been able to directly influence the direction of the agency. Our voice has helped shape decisions regarding CIRM policies and funding. As Roth writes, patient advocates can grasp some of the most complex and thorny policy and scientific issues and “tip the scales” in the direction of sound public policy that seeks prudently to accelerate progress towards cures.

In his essay, Roth describes the genesis of active and vocal patient power through the response to AIDS in the 1980s and 90s, “which galvanized patient communities to unprecedented levels of scientific and political involvement.” He also points out the current struggles between advocates and the FDA, where patients with multiple sclerosis and prostate cancer have been frustrated by the agency’s decisions.

Roth forcefully argues for incorporating a formal role for “patient mediators” into the FDA’s product approval processes. “The costs would be negligible, and the payoffs in therapeutic efficiency, and procedural efficiency, and public confidence could be enormous.”

In my Nature article, I link the successful passage of Proposition 71 establishing CIRM to the unprecedented efforts of patient advocates around California and argue that scientists and policymakers have an obligation to include in the decision-making processes those who make their work possible.

As pluripotent (embryonic or iPS) cell approaches enter clinical space, formal inclusion of patient advocates into decision making roles along the lines suggested by Roth is absolutely essential if society is going to judiciously accept the inevitable failures that accompany most clinical research. Cell therapy has the potential to transform medicine, but the risks are as great as the potential.

In HIV/AIDS, we have seen risk mitigated by the unwavering willingness of an active patient and stakeholder community to tolerate failure. The patient communities seeking relief and cures through cell therapy are just as capable of evaluating and accepting risks and failures.

I would argue that Roth’s article with its recommendations is not only timely, but also urgent, and I hope that it inspires a dialogue leading to near term conclusive action to bring patient advocates into the decision-making process regarding new therapies.

- Jeff Sheehy is is director for communications at the AIDS Research Institute at UCSF, and a member of the CIRM governing board.

More on the Berlin patient, stem cells, and a cure for HIV

The response to the story about the Berlin patient who was reported cured of  HIV has been incredible, but in this case it’s also a little troubling. What I see in comments on news stories or in tweets is that we have an uphill battle in terms of educating people about stem cells.

The stem cells used to eliminate this man’s HIV infection were from the bone marrow. Essentially, what he got was just a really great bone marrow transplant, because the transplanted cells were resistant to HIV. The bone marrow houses the blood-forming stem cells that create the entire blood system. Those blood-forming stem cells were the first stem cells to be identified, back in 1998 by Stanford’s Irv Weissman.

CIRM’s two disease teams are working on even more sophisticated -- and safer -- bone marrow transplants that could bring this same cure to thousands of people who need it. (Summaries of those teams are available here and here.)

What concerns me is that many of the comments on news stories or Tweets are tying this HIV therapy to embryonic stem cells or even abortion. Just so we’re clear here, an aborted fetus has no embryonic stem cells. None. Human embryonic stem cells come from IVF embryos left over after a couple completes their family. (Paul Knoepfler of UC Davis has a good description of how those human embryonic stem cell lines are created.) These embryonic stem cells are amazing — they can form any tissue in the body, which can become cures or unlock the mysteries of how diseases form.

In the case on the Berlin patient, it was adult, blood-forming stem cells that were the basis of the cure. For other diseases, the cure may come from embryonic or reprogrammed iPS cells. At this point, we don’t know which cell type will cure which disease. All we know is that we need cures, and like the Chilean miners who dug three rescue holes to have one succeed, we’re working all angles in order to be successful in our quest for cures.

A.A.

Stem cell therapy treats HIV, basis for two CIRM disease teams

There’s a lot of buzz today over a paper in the journal Blood declaring a man who has come to be known as the “Berlin patient” cured of HIV.

The same patient was featured in the New England Journal of Medicine in February 2009. A man infected with HIV needed a bone marrow transplant for his leukemia. The doctors gave him the transplant from a person who was naturally resistant to HIV infection. The donor’s bone marrow cells contained a mutated protein called CCR5, which is required for HIV to enter the cell. This follow-up work presents the results of numerous tests that failed to find evidence of remaining HIV infection.

In the paper, the authors write: "In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient."

This story discusses an interview in a German publication in which the Berlin patient discusses the difficulties he faced during the course of the treatment. Although I don’t read German, the English summary of that interview makes it clear that bone marrow transplant is not an easy answer, and that making the transplantation more tolerable needs to be part of a future therapy.

The Berlin patient is the basis for two different CIRM disease teams. Although the therapy was a success, there aren’t enough donors who lack CCR5 to provide bone marrow for all people with HIV infection. Instead, the CIRM groups are removing the patient’s own bone marrow and attempting two different approaches at manipulating those cells to remove CCR5 function. They will then give the modified bone marrow back to the patients, hopefully providing a life-long resistance to HIV infection.

Here are summaries of the CIRM disease team awards at City of Hope and UCLA. We also have a video about the technique, featuring the lead researcher at City of Hope and HIV/AIDS advocate Jeff Sheehy, who serves on the CIRM governing board.



A.A.

HIV/AIDS video for World AIDS Day

World AIDS Day seems like a good time to revisit a video we made this year featuring CIRM board member Jeff Sheehy, who is a long-time advocate for HIV/AIDS research:



CIRM is funding two teams of researchers working on different approaches to treating HIV/AIDS (one at UCLA and one at City of Hope). Both involve replacing a person’s blood-forming system with cells that are resistant to infection.

For more background on the work, you can watch a Spotlight on HIV/AIDS by one of the disease team leaders, John Zaia of City of Hope.

All of these resources are available on our HIV/AIDS disease page, along with information about the grants we fund that target HIV/AIDS.

Here's hoping that on this day next year we'll be able to talk about progress being made by the two outstanding teams of researchers working to cure this devastating disease.

A.A.

Artist inspired by HIV/AIDS therapies

Miracle of Hope I, Dave Putnam

The promise of a cure for HIV/AIDS has inspired activists, researchers and now artists. The image shown here, by Woodside, CA artist Dave Putnam, was donated to Stanford’s Positive Care Clinic in Atherton, CA. It’s one of three 36” by 48” images making up a new triptych depicting Putnam’s interpretation of the body’s triumph over HIV.

Stanford’s Scope blog describes the images:

The acrylics, which hang in the hallway of the clinic, show a cell that is permeated by multiple black dots. These represent the invasion of the HIV protease enzyme, which is essential to survival of the virus. Blue dots on the canvas are used to capture the image of the fighters – the protease inhibitors that stop cell growth. Gradually, the blue dots spread and overtake the nasty enzyme. In the last painting, a bright yellow canvas shines through, as the enzyme is destroyed (though remnants of the virus remain, as current therapies never completely eradicate it).

If the two CIRM-funded HIV disease teams at UCLA and City of Hope are successful, the disease would most resemble the final, less dramatic image. Both teams are trying to replace the person’s HIV-infected bloodstream with a new blood system that is resistant to the virus. This link provides more information about stem cell approaches to treating HIV/AIDS.




A.A.