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.

CIRM sends Patient advocates to international stem cell meeting

Today stem cell scientists and patient advocates are descending on Toronto for the annual meeting of the International Society for Stem Cell Research. Among those registering and preparing for three days of science is Don Reed, who is one of 20 patient advocates who received a CIRM stipend to attend. 

On his blog today, Reed writes about his trip to Toronto and the important role of patient advocates in promoting science:

Patient advocates like my son Roman Reed are the emotional muscle behind research for cure. It is not easy for a paralyzed person to travel, but he will be there, listening and learning, and speaking.

Because there will be funding fights ahead, both nationally, and in every state.

When a politician says, “We can’t afford to fund the research”—someone must be there to say: “We cannot afford NOT to fund the research—and here’s why.” That someone is us. If it is just the scientists talking, it is all too easy for politicians to ignore them.

Think of he numbers. There are only a handful of top research scientists. Politically, they are negligible. If they only talk to each other, they might as well pack up their test tubes and go home, because they will never get public funding.

But there are millions of patients and family– patient advocates. Working together, we cannot be ignored.

From its inception, CIRM has recognized the importance of patient advocate voices in scientific decision-making, including ten such advocates on our governing board (bios of all board members are available here). Jeff Sheehy, patient advocate board member for HIV/AIDS blogged about his role on our board:

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 [vice chair Duane] 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.

ISSCR is kicking off the meeting tonight with a public symposium consisting of patient advocates and scientists discussing progress being made in spinal cord injury (featuring Reed's son Roman Reed), multiple sclerosis and blood disorders. Hopefully those advocate voices will help drive home the importance of continued funding for stem cell research.

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.