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:


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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.

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Techniques for tracking stem cells necessary for possible therapies

Last week The Scientist carried a story addressing a topic near and dear to the heart of anyone trying to develop a therapy based on transplanting stem cells, whether they are embryonic, adult, or iPS cells: Where do the cells go once they are transplanted?

The problem is this — if you, as a scientist, transplant stem cells near some damage that you are hoping they will repair, you've got to hope those cells actually make it to the damaged tissue. If they make a run for the liver when you are trying to treat the heart, or simply sit in a lump where you implanted them, those cells aren't going to fulfill their mission.

The story quotes CIRM grantee Joseph Wu of Stanford University who has SEED and Basic Biology III Awards to detect stem cells implanted into the heart and to develop stem cell transplantation therapies for hypertrophic cardiomyopathy.

“If you want to understand what happens to these stem cells, it’s important to track the fate of these cells without having to kill the animal,” says Joseph Wu, a cardiologist at Stanford University School of Medicine in Palo Alto, California. Stem cell transplants may settle down, proliferate, and differentiate as desired; they may form dangerous tumors; or they may simply falter and die.

The issue is also one CIRM grantee Paul Knoepfler of the University of California, Davis, touched on in his blog last week, saying:

Once these cells, which have spent weeks in a lab environment, are injected into a person, what happens next?

This is arguably the most important question in the regenerative medicine field, but there are few answers. We are literally mostly in the dark about what cells do after transplant, but there are some things that can be predicted pretty confidently.

He goes on to discuss some of what's known about the issue using Geron's clinical trial as an example.

In their article, the Scientist discusses a few techniques scientists are using (including some nice images) to address the question of where the cells go. The story includes a technique being used by CIRM grantee Eduardo Marban at Cedars-Sinai Medical Institute, who has a Disease Team Award to develop a therapy for heart disease.

This is the type of research that comes to mind when people who don't follow the science comment on the lack of cures. CIRM is funding a broad range of science, some of which is primarily dedicated developing new therapies, and some of which is working to understand these kinds of basic questions that need to be addressed before those therapies can become widespread.

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Celebrating National Cancer Research Month with a cancer stem cell round-up

In celebration of National Cancer Research Month, our colleagues at Sanford-Burnham Medical Research Institute have posted a series of blog entries about cancer research at their institute. The latest installment includes CIRM grantee Robert Wechsler-Reya, who moved to California from Duke University on a CIRM Research Leadership Award.

According to their blog:

Dr. Robert Wechsler-Reya, who directs the Tumor Development Program in Sanford-Burnham’s Cancer Center, has spent many years studying how “good” processes can also cause disease. He is particularly interested in how mechanisms that are normal in embryonic development can cause cancer when turned on in children and adults.

“We work on the relationship between development and cancer, particularly in the brain,” says Dr. Wechsler-Reya. “We’re interested in how normal stem cells and progenitor cells make decisions like when to divide, when to differentiate and what to differentiate into. We’re interested in how those decisions go wrong in cancer.”

To-date, CIRM has awarded more than $130 million to cancer research, including grantees working to understand the role of cancer stem cells in the disease and other teams working to develop therapies. Among our Disease Team projects, which have the goal of reaching clinical trials by 2014, CIRM funded two teams working on therapies for glioma (City of Hope and UCSF), two working on therapies for leukemia (Stanford and UCSD), and one working on solid tumors (UCLA).

Here are a few resources CIRM offers for people trying to get information about stem cells and cancer.

• Information about stem cells and glioma
• Information about stem cells and leukemia
• Information about stem cells and solid tumors

We also produced this video with CIRM grantee Catriona Jamieson at Moore's UCSD Cancer Center at the University of California, San Diego. Jamieson has a therapy in clinical trial for a pre-cancerous blood condition. The work that led to that trial was funded in part by a CIRM SEED grant.



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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.

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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.



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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.

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ACT files to test embryonic stem cell-based therapy for macular degeneration

Advanced Cell Technology has filed an application with the FDA to begin an early phase trial of an embryonic stem cell-based therapy for macular degeneration. If the company name sounds familiar, that’s because it’s the same company that on November 22 received FDA approval to begin a trial for Stargardt’s macular degeneration. Both trials are testing the same cells. In a press release, the company said:

Company scientists view the use of the same hESC derived RPE cells for both trials as the most efficacious approach, as it permits the Company to leverage its experience with the FDA that it gained through the process of obtaining approval for the Stargardt’s clinical trial to expedite the approval of its clinical trial in Dry AMD.

As with the company’s Stargardt’s trial and Geron’s spinal cord injury trial, this new trial will be assessing safety in a very small number of patients — standard practice for any new therapy being tested. After proving safety in a phase I trial, a larger trial will assess whether or not the potential therapy is effective.

It’s exciting to see embryonic stem cell derived therapies reaching patients. In general, more trials fail than succeed and we don’t know in advance which ones are going to work. That’s why there are hundreds of cancer trials going on around the country, and why we need hundreds of stem cell trials too. Hopefully CIRM’s macular degeneration disease team led by Mark Humayun at USC won’t be far behind ACT with their own version of an embryonic stem cell-based therapy for macular degeneration. And hopefully, one of them will provide a cure for the roughly 30 million people worldwide who are losing or have lost vision due to the disease.

Here’s a video about the CIRM disease team project:



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Vision loss trial based on embryonic stem cells begins

The FDA has given the green light to the second trial based on embryonic stem cells — this one for a genetic form of blindness called Stargardt’s Macular Degeneration. The treatment, developed by Advanced Cell Technology, involves replacing the the layer of the retina damaged by the disease, called the retinal pigment epithelium, with new RPE cells derived from embryonic stem cells.

This approach is similar to one under development by a CIRM macular degeneration disease team led by Mark Humayun at the University of Southern California.

Nature wrote about the ACT trial:

In the trial, 12 individuals at several US medical centres will receive injections of the cells directly into the eye to test the safety of the procedure. (Although the disease begins to take its toll at around 6 years of age, the trial will start with patients who are over 18.)

The small size of the trial is typical for a Phase I/II trial, which is primarily looking to ensure that the technique is safe before testing it in more people. Nature went on to quote ACT’s chief scientific officer Robert Lanza:

The advantage, of course, is that we’re talking about a very small number of cells going into a very local area,” he says. Using instruments that can track a single retinal cell in the eye in real time, the researchers will also be able to easily monitor patients’ progress.

“Also, with the eyes there are very objective tests for visual acuity,” he notes, “so we can measure performance gains very objectively.” Tracking improvement after spinal cord injury, on the other hand, is notoriously tricky.

This video features Mark Humayun discussing his macular degeneration work:




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Patient advocates vital to stem cell research progress

Nature Medicine carried a piece Friday by CIRM governing board member Jeff Sheehy, writing about the importance of having a patient advocate voice in biomedical research. Sheehy, who is living with HIV, is a long-time advocate for HIV/AIDS research. He has been on the CIRM board since the beginning in November 2004, and is a vocal participant in CIRM working groups including the group that makes research funding recommendations to the full board (the Grants Working Group), for which he is vice-chair.

Sheehy writes:

The presence of vocal, engaged patient advocates has added an indispensable dimension to the proceedings. In measuring research quality, advocates tend to focus on a project's ability to benefit people—not just drive scientific curiosity—which keeps even basic biomedical research grounded in its ability to produce concrete health benefits.

CIRM’s governing board includes 12 patient advocates representing HIV/AIDS, MS, diabetes (type 1 and type 2), heart disease, spinal cord injury, cancer, Alzheimer’s disease, Parkinson’s disease and autism. Sheehy goes on to say:

... CIRM is made up of patient advocates from a wide spectrum of diseases and conditions who work together to advance therapies across the board. And contrary to critics' assertions, these advocates have not narrowly focused on their own diseases, but have uniformly advocated for the best approaches for moving basic research towards the clinic. They support each other.

Patient advocates serve a powerful role even if they aren’t directly involved in funding decisions. Don Reed has been a vocal supporter of stem cell research since his son Roman Reed suffered a spinal cord injury. He is sponsor of the Roman Reed Spinal Cord Injury Research Act that funds spinal cord research in California, founder and co-chair of Californians for Cures and blogger on his own site www.stemcellbattles.org and for the Huffington Post.

In a recent Huffington Post blog entry about the World Stem Cell Summit he wrote about the importance of patient advocates staying involved in stem cell research at a political level, in order to maintain the U.S. leadership in stem cell research:

But unless we in the patient advocacy community can encourage Congress to pass a stem cell research protection act the dream will have been stolen.

CIRM came about in part because of the passion and support of patient advocates like Sheehy and Reed, and they continue to be a crucial part of the success of CIRM and of the progress made in stem cell research.

Here's Sheehy advocating for a stem cell therapy for HIV/AIDS. CIRM has funded two disease teams (City of Hope and UCLA) focusing on developing therapies for the disease.

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.




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Hope for CIRM leukemia disease team

The clock is ticking on the 14 CIRM Disease Team projects issued last October, which are working under a four-year deadline to hit the clinic. The $20 million acute myeloid leukemia project headed up by Irv Weissman of Stanford University just reported some promising progress.

Weissman and his team are developing a chemotherapy drug that binds to a protein found on leukemia stem cells, killing the cells. The protein, called CD47, is also found on other cancer stem cells.

The work, which was published in the Sept. 3 issue of Cell, was focused on non-Hodgkins lymphoma. The group gave mice with non-hodgkins lymphoma the molecule that blocks CD47 in addition to another antibody, and cured the disease in 60 percent of cases.

According to a Stanford press release:

The researchers point out that, although the CIRM grant focuses on investigating anti-CD47 therapies for acute myeloid leukemia, the drug development process will result in an antibody that could also be used for other cancers. They focused their preliminary investigations on non-Hodgkin’s lymphoma because they were curious as to how the anti-CD47 antibody would work with rituximab, which also binds to human lymphoma cells.

The release goes on to say that the researchers hope to try the therapy in other cancers:

The researchers are moving forward to conduct tests on other CD47-expressing cancer cells, which include acute leukemia, bladder and several other cancer stem cells. They speculate that they might see a similar synergistic effect between anti-CD47 and other cancer-specific monoclonal antibodies currently in clinical use. They are also moving ahead as quickly as possible to bring the anti-CD47 antibody treatment to trials in human patients.

Recently, CIRM disease teams targeting brain tumors (blogged about here) and HIV/AIDS (blogged about here) have also had some preliminary success.

You can learn more about the CIRM disease team program in our October press release.

If you aren’t familiar with cancer stem cells, here’s a video with Catriona Jameison, a cancer stem cell scientist at University of California, San Diego, talking about their role in cancer.



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Stem cells treat life-threatening skin condition

This week researchers at the University of Minnesota published a paper showing that stem cells from the bone marrow can help kids with a blistering skin condition called epidermolysis bullosa. The disease is horrible. Lacking a protein to anchor skin in place, the children's blister at the slightest touch -- on their skin, in their throat, inside their eyelids, and anywhere else skin forms.

The group gave the kids a bone marrow transplant, replacing their own blood system with cells that make the form of collagen lacking in kids with the disease. It worked. In a press release, John Wagner, M.D., director of pediatric blood and marrow transplantation and clinical director of the Stem Cell Institute, said:

“To understand this achievement, you have to understand how horrible this disease actually is. From the moment of birth, these children develop blisters from the slightest trauma which eventually scar. They live lives of chronic pain, preventing any chance for a normal life. My hope is to do something that might change the natural history of this disease and enhance the quality of life of these kids.”

A Canadian CBS news story quotes Pediatric dermatologist Dr. Elena Pope, medical director of the EB clinic at Toronto's Hospital for Sick Children, as saying:

"It's extremely, extremely exciting for us who are working in this area to actually see some steps forward."

CIRM funds a disease team headed by Alfred Lane at Stanford Univerversity, who is also working toward a stem cell-based therapy for the disease. His team is creating reprogrammed iPS cells from the children's skin, inserting a good copy of the mutated gene, and transplanting the resulting skin cells back onto the children. 

CIRM's epidermolysis bullosa disease team: Anthony Oro,
Gerhard Bauer, Alfred Lane, Marius Wernig

Whichever approach is successful long-term, it's nice to see progress being made for this truly horrible disease. 

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