Gene editing in blood stem cells just got easier

Genome editing is a field of science that’s been around for awhile, but has experienced an explosion of activity and interest in recent years. Chances are that even your grandmother has heard about the recent story where for the first time, gene editing saved a one-year-old girl from dying of leukemia.

Microsoft word versus genome editing

To give you an idea of what this technique involves, think back to the last time you had to write a report. You let all your ideas flow out onto the page, but then realize that certain sentences or paragraphs need to be rearranged, removed, or added. So you copy, paste, and move stuff around with your mouse and keyboard until you’re satisfied.

Image source: Broad Institute

Image source: Broad Institute

Tools for editing the genome (which contain all of our genes) work a similar way, but they cut and paste DNA sequences in the human genome instead of words on a page. Scientists have figured out how to use these “genetic scissors” to delete genes (so they no longer have function) and to correct disease-causing mutations (by pasting in the normal DNA sequence of a gene to restore function). Both these abilities make genome editing a highly valuable tool for scientists to model diseases and to develop therapies to treat them.

There are multiple tools that researchers are currently using to modify the human genome. The main ones are fancifully named ZFNs, TALENs, and CRISPRs. All three use engineered proteins called nucleases to cut strands of DNA at specific locations in the genome. A cell’s DNA repair machinery will then either glue the DNA strands back together (this typically results in the loss of DNA and gene function), or repair the break by copying and pasting in the missing sequence of DNA from a template (you can correct disease-causing mutations this way by providing a donor template). We don’t have time to get into more details about how these tools work, but you can learn more by reading this fact sheet from Science Media Centre.

Some cells are more stubborn than others

While genome editing technologies offer many advantages for modifying human genes, it’s not a perfect science. There are still many limitations and roadblocks that need to be addressed to make sure that these tools can be safely and effectively used as therapies in humans.

Besides the obvious worry about “off-target effects” (when the genetic scissors cut random sections of DNA, which can cause big problems), another issue with genome editing tools is that some types of cells are harder to genetically modify than others.

Such is the case with blood stem cells, also known as hematopoietic stem and progenitor cells (HSPCs), that live in our bone marrow and make all the different blood cells in our body. Initial studies reported difficulty in delivering genome editing tools into human HSPCs, which is a problem if you want to use these tools to help cure patients suffering from genetic blood or immune diseases.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Have no fear, blood-stem cell editing is here

We are happy to inform you that a CIRM-funded study published today in Nature Biotechnology has developed a solution to the problem of hard-to-edit blood stem cells. Scientists from the USC Keck School of Medicine and from Sangamo BioSciences developed a new delivery method that allows for efficient genome editing of human HSPCs using zinc finger nucleases (ZFNs).

They used a viral delivery system to deliver ZFNs to distinct locations in the genome of HSPCs and successfully inserted a gene sequence that made the cells turn green under a fluorescent microscope. The virus they used was a harmless form of an adeno-associated virus (AAV), which can enter certain cells and delivery the researcher’s DNA cargo with a very low chance of altering or inserting its own DNA into the HSPC genome.

Using an AAV that was exceptionally good at entering HPSCs, they virally delivered ZFNs to specific gene locations in HSPCs that had been isolated from human blood and from fetal liver tissue. They found that delivering the ZFNs as mRNA molecules allowed the protein versions they turned into to be temporarily expressed in HSPCs. This produced a high rate of gene insertion (ranging from 15-40% of cells treated), while keeping off-target effects and cell death low. Even the most hard-to-edit HSPCs, called the primitive HSPCs, were modified. This result was really exciting because no other study has reported gene editing with this level of efficiency in this primitive population of blood stem cells.

The tools work but what about the cells?

After proving that they were able to successfully edit the genomes of HSPCs with high efficiency, they next asked whether the modified cells could grow in culture and create new blood cells when transplanted into mice.

While their method to deliver ZFNs into the HSPCs did cause some of the cells to die (around 20%), the majority that survived were able to multiply in a dish and specialize into various blood cells when grown in cultures. When the modified HSPCs were taken a step further and transplanted into immune-deficient mice (meaning their immune system is compromised and won’t attack transplanted cells), they not only survived, but they also specialized into many different types of blood cells while still retaining their genomic modifications.

Now here is where I want to give the researchers a high five. They decided that once wasn’t enough, and challenged their modified HSPCs to a second round of transplantation. They collected the bone marrow from mice that received the first transplant of modified HSPCs, and transferred it into another immune-deficient mouse. Five months later, they found that the modified cells were still there and had generated other blood cell types. Because these modified HSPCs lasted for so long and through two rounds of transplants, the authors concluded that they had successfully edited the primitive, long-term repopulating HSPCs.

Next stop, the clinic?

In summary, this study offers a new and improved method to genetically modify blood stem cells in all their forms.

So what’s next? The obvious hope is the clinic.


HIV (yellow) infecting a human immune cell. Photo credit: Seth Pincus, Elizabeth Fischer and Austin Athman, NIH.

It’s a likely future as the study was conducted in collaboration with Sangamo BioSciences. They specialize in ZFN-mediated gene therapy and have a number of preclinical therapeutic programs, many of which focus on genetic diseases that affect the blood and immune system, as well as ongoing clinical trials using ZFNs to treat patients with HIV/AIDs. (One of these trials is funded by CIRM, read more here).

In a USC press release, Dr. Michael Holmes, VP of Research at Sangamo and co-senior author on the paper hinted at future clinical applications:

Michael Holmes, Sangamo BioSciences

Michael Holmes, Sangamo BioSciences


Our results provide a strategy for broadening the application of gene editing technologies in HSPCs. This significantly advances our progress towards applying gene editing to the treatment of human diseases of the blood and immune systems.



Co-senior author and USC Professor Dr. Paula Cannon echoed Dr. Holmes:

Gene therapy using HSPCs has enormous potential for treating HIV and other diseases of the blood and immune systems.

One last question

A question that I had after reading this exciting study was whether other genome editing tools such as CRISPR could produce better results in blood stem cells using a similar viral delivery method.

CRISPR is described as a faster, cheaper, and easier gene editing technology compared to ZFNs and TALENS (for a comparison, check out this fun article by The Jackson Laboratory). And many scientists, both in academia and industry, are pushing CRISPR gene editing towards clinical applications.

When I asked Paula Cannon about which gene editing technology, ZFNs or CRISPRs, is better for therapeutic development, she said:

Paula Cannon, USC Professor

Paula Cannon, USC Professor

In terms of advantages, CRISPRs are easier to work with initially, and this makes them a great lab research tool. But when it comes to developing something for a clinical trial, its much more of a long game, so that initial advantage disappears. The ZFNs I work with have been previously optimized and are well characterized, and the CCR5 ZFNs are already in the clinic so they have a big advantage in that regard when you are trying to develop something for the next clinical application.

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Stem cell stories that caught our eye: cancer fighting virus, lab-grown guts work in dogs, stem cell trial to cure HIV

Here are some stem cell stories that caught our eye this past week. Some are groundbreaking science, others are of personal interest to us, and still others are just fun.

Cancer fighting virus approved for melanoma

(Disclaimer: While this isn’t a story about stem cells, it’s pretty cool so I had to include it.)

The term “virus” generally carries a negative connotation, but in some cases, viruses can be the good guys. This was the case on Tuesday when our drug approval agency, the US Food and Drug Administration (FDA), approved the use of a cancer fighting virus for the treatment of advanced stage melanoma (skin cancer).

The virus, called T-VEC, is a modified version of the herpesvirus, which causes a number of diseases and symptoms including painful blisters and sores in the mouth. Scientists engineered this virus to specifically infect cancer cells and not healthy cells. Once inside cancer cells, T-VEC does what a virus normally does and wreaks havoc by attacking and killing the tumor.

The beauty of this T-VEC is that in the process of killing cancer cells, it causes the release of a factor called GM-CSF from the cancer cells. This factor signals the human immune system that other cancer cells are nearby and they should be attacked and killed by the soldiers of the immune system known as T-cells. The reason why cancers are so deadly is because they can trick the immune system into not recognizing them as bad guys. T-VEC rips off their usual disguise and makes them vulnerable again to attack.

T-VEC recruits immune cells (orange) to attack cancer cells (pink) credit Dr. Andrejs Liepins/SPL

T-VEC recruits immune cells (orange) to attack cancer cells (pink). Photo credit Dr. Andrejs Liepins/SPL.

This is exciting news for cancer patients and was covered in many news outlets. Nature News wrote a great article, which included the history of how we came to use viruses as tools to attack cancer. The piece also discussed options for improving current T-VEC therapy. Currently, the virus is injected directly into the cancer tumor, but scientists hope that one day, it could be delivered intravenously, or through the bloodstream, so that it can kill hard to reach tumors or ones that have spread to other parts of the body. The article suggested combining T-VEC with other cancer immunotherapies (therapies that help the immune system recognize cancer cells) or delivering a personalized “menu” of cancer-killing viruses to treat patients with different types of cancers.

As a side note, CIRM is also interested in fighting advanced stage melanoma and recently awarded $17.7 million to Caladrius Biosciences to conduct a Phase 3 clinical trial with their melanoma killing vaccine. For more, check out our recent blog.

Lab-grown guts work in mice and dogs

If you ask what’s trending right now in stem cell research, one of the topics that surely would pop up is 3D organoids. Also known as “mini-organs”, organoids are tiny models of human organs generated from human stem cells in a dish. To make them, scientists have developed detailed protocols that sometimes involve the use of biological scaffolds (structures on which cells can attach and grow).

A study published in Regenerative Medicine and picked up by Science described the generation of “lab-grown gut” organoids using intestine-shaped scaffolds. Scientists from Johns Hopkins figured out how to grow intestinal lining that had the correct anatomy and functioned properly when transplanted into mice and dogs. Previous studies in this area used flat scaffolds or dishes to grow gut organoids, which weren’t able to form proper functional gut lining.

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

Lab-grown guts could help humans with gut disorders. (Shaffiey et al., 2015)

What was their secret recipe? The scientists took stem cells from the intestines of human infants or mice and poured a sticky solution of them onto a scaffold made of suture-like material. The stem cells then grew into healthy gut tissue over the next few weeks and formed tube structures that were similar to real intestines.

They tested whether their mini-guts worked by transplanting them into mice and dogs. To their excitement, the human and mouse lab-grown guts were well tolerated and worked properly in mice, and in dogs that had a portion of their intestine removed. Even more exciting was an observation made by senior author David Hackham:

“The scaffold was well tolerated and promoted healing by recruiting stem cells. [The dogs] had a perfectly normal lining after 8 weeks.”

The obvious question about this study is whether these lab-grown guts will one day help humans with debilitating intestinal diseases like Crohn’s and IBS (inflammatory bowel disorder). Hackam said that while they are still a long way from taking their technology to the clinic, “in the future, scaffolds could be custom-designed for individual human patients to replace a portion of an intestine or the entire organ.”

Clinical trial using umbilical cord stem cells to treat HIV

This week, the first clinical trial using human umbilical cord stem cells to treat HIV patients was announced in Spain. The motivation of this trial is the previous success of the Berlin Patient, Timothy Brown.

The Berlin patient can be described as the holy grail of HIV research. He is an American man who suffered from leukemia, a type of blood cancer, but was also HIV-positive. When his doctor in Berlin treated his leukemia with a stem cell transplant from a bone-marrow donor, he chose a special donor whose stem cells had an inherited mutation in their DNA that made them resistant to infection by the HIV virus. Surprisingly, after the procedure, Timothy was cured of both his cancer AND his HIV infection.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

Berlin patient Timothy Brown. Photo credit: Griffin Boyce/Flickr.

The National Organization of Transplants (ONT) in Spain references this discovery as its impetus to conduct a stem cell clinical trial to treat patients with HIV and hopefully cure them of this deadly virus. The trial will use umbilical cord blood stem cells instead of bone-marrow stem cells from 157 blood donors that have the special HIV-resistance genetic mutation.

In coverage from Tech Times, the president of the Spanish Society of Hematology and Hemotherapy, Jose Moraleda, was quoted saying:

“This project can put us at the cutting edge of this field within the world of science. It will allow us to gain more knowledge about HIV and parallel offer us a potential option for curing a poorly diagnosed malignant hematological disease.”

The announcement for the clinical trial was made at the Haematology conference in Valencia, and ONT hopes to treat its first patient in December or January.

UCLA Scientists Find 3000 New Genes in “Junk DNA” of Immune Stem Cells

Genes and Junk

Do you remember learning about Junk DNA when you took Biology in high school? The term was used to described 98% of the human genome that doesn’t make up its approximately 22,000 genes. We used to think that Junk DNA didn’t serve a purpose, but that was before we discovered special elements called non-coding RNAs that call Junk DNA their home. But we’re getting ahead of ourselves, so let’s take a step back.

Genes are sequences of DNA that contain the blueprints for the proteins that make your cells and organs function. Before a gene can become a protein, its transformed into a molecule called an RNA. RNAs contain messages that tell a cell’s machinery what types of protein to make and how many.

Not Junk After All

Now back to “Junk DNA”… scientists thought that because this mass of DNA sequences was never turned into protein, it served no purpose. It turns out that they couldn’t be farther from the facts.

There are actually sequences of DNA in our genomes that are blueprints for RNAs that never become proteins. Scientists call them “non-coding” RNAs, and they play very important roles in the body such as replicating DNA and regulating gene expression – deciding which genes are turned on and which are turned off.

Another important function that non-coding RNAs control is cell differentiation, or the maturation of immature cells into adult cells. Differentiation is a complicated process, and because non-coding RNAs are relatively new to the scientific world, we haven’t figured out their exact roles in the differentiation of stem cells into adult cells.

Understanding Immune Cell Development

In a study published this week in Nature Immunology, UCLA scientists reported the discovery of 3000 new genes that make a type of non-coding RNA called a long non-coding RNA (lncRNA) that regulates the differentiation of stem cells into mature immune cells like B and T cells, which play a key role in fighting infection. This important study was funded in part by CIRM.

UCLA scientists David Casero and Gay Crooks with the sequencing machine that separated the genetic information within the bone marrow and thymus gland tissue stem cells. (Image credit: Mirabai Vogt-James, UCLA Broad Stem Cell Research Center)

UCLA scientists David Casero and Gay Crooks with the sequencing machine used to identify the 3000 new genes. (Image credit: Mirabai Vogt-James, UCLA Broad Stem Cell Research Center)

Using sequencing technology and bioinformatics, they mapped the RNA landscape (known as the transcriptome) of rare stem cells isolated from human bone marrow (hematopoietic stem cells) and the thymus (lymphoid progenitor cells). They identified over 9000 genes that produced lncRNAs that were important for moderating various stages of immune cell development. Of this number, over 3000 were genes whose lncRNAs hadn’t been found before.

First author, David Casero explained the importance of their discovery in a UCLA press release:

Our findings are exciting because they provide a huge and unique resource for the whole immunology community. We will now be able to drill down on the specific LncRNA genes that seem to be most important at each stage of immune cell development and understand how they function individually and together to control the process.


Co-senior author and UCLA professor Gay Crooks explained that the goal of their work was to gain a better understanding of how the immune system develops in order to battle serious diseases that affect it and open up avenues for generating better cell therapies.

If we can understand how the immune system is generated and maintained during life, we can find ways to improve production of immune cells for potential therapies after chemotherapy, radiation and bone marrow transplant, or for patients with HIV and inherited immune deficiencies. In addition, by understanding the genes that control this process we can better understand how they are changed in cancers like leukemia and lymphoma.


Final Words

While this study focused on the role of lncRNAs in the development of the immune system and the differentiation of immune stem cells, the technology in this study can be used to understand the development of other systems and organs.

Scientists are already publishing papers on the role of lncRNAs in the differentiation of stem cells in the brain and heart, and further work in this field will undoubtedly uncover many new and important lncRNA genes. If the pace keeps up, the term “Junk DNA” will need to be retired to the junk yard.


Image source

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Gene Therapy Beats Half-Matched Stem Cell Transplant in Side-by-Side Comparison to Treat ‘Bubble Baby’ Disease

If you are born with Severe Combined Immunodeficiency (SCID), your childhood is anything but normal. You don’t get to play with other kids, or be held by your parents. You can’t even breathe the same air. And, without treatment, you probably won’t live past your first year.

The bubble boy.  Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

The bubble boy. Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

This is the reality of SCID, also called “Bubble Baby” disease, a term coined in the 1970s when the only way to manage the disease was isolating the child in a super clean environment to avoid exposure to germs. The only way to treat the disorder was with a fully matched stem cell transplant from a bone marrow donor, ideally from a sibling. But as you may have guessed, finding a match is extraordinarily rare. Until recently, the next best option was a ‘half-match’ transplant—usually from a parent. But now, scientists are exploring a third, potentially advantageous option: gene therapy. Late last year, we wrote about a promising clinical trial from UCLA researcher (and CIRM Grantee) Donald Kohn, whose team effectively ‘cured’ SCID in 18 children with the help of gene therapy. Experts still consider a fully matched stem cell transplant to be the gold standard of treatment for SCID. But are the second-tier contenders—gene therapy and half-matched transplant—both equally as effective? Until recently, no one had direct comparison. That all changes today, as scientists at the Necker Children’s Hospital in Paris compare in the journal Blood, for the first time, half-matched transplants and gene therapy—to see which approach comes out on top. The study’s lead author, Fabien Touzot, explained the importance of comparing these two methods:

“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”

So the team monitored a group of 14 SCID children who had been treated with gene therapy, and compared them to another group of 13 who had received the half-matched transplant. And the differences were staggering. Children in the gene therapy group showed an immune system vastly improved compared to the half-matched transplant group. In fact, in the six months following treatment, T-cell counts (an indicator of overall immune system health) rose to almost normal levels in more than 75% of the gene therapy patients. In the transplant group, that number was just over 25%. The gene therapy patients also showed better resilience against infections and had far fewer infection-related hospitalizations—all indictors that gene therapy may in fact be superior to a half-matched transplant. This is encouraging news say researchers. Finding a fully matched stem cell donor is incredibly rare. Gene therapy could then give countless families of SCID patients hope that their children could lead comparatively normal, healthy lives. “Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” explained Touzot. “These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach.” Hear more about how gene therapy could revolutionize treatment strategies for SCID in our recent interview with Donald Kohn:

Avoiding drug trial tragedies: new stem cell-based test predicts dangerous drug toxicity

In 2006 Ryan Wilson, a healthy 20 year old Londoner, volunteered for a first-in-human clinical trial to help test the safety of a new drug, TGN1412, intended to treat rheumatoid arthritis and leukemia. The cash he’d get in exchange for his time would help fund his upcoming vacation.

Instead, he nearly died.

Screen Shot 2015-03-11 at 11.37.42 AM

The TGN1412 drug trial disaster got a lot of high profile news coverage in 2006. (image credit: BBC News)

Even though the drug amount injected in his body was 500 times lower than the dose found to be safe in animals, Wilson experienced a catastrophic immune reaction, called a cytokine storm, that led to heart, kidney and liver failure, pneumonia and the loss of his toes and three fingers to dry gangrene. The other five healthy volunteers were also severely injured.

TGN1412’s devastating effect was unfortunately missed in preclinical laboratory and animal studies prior to the human trial. Unlike the pills in your medicine cabinet which are made up of synthesized chemicals, TGN1424 belongs to a growing class of medicines called biologics which come from biological sources such as proteins, DNA, sugars and cells. There is a concern that once a biologic is injected in a patient, the immune system may mount a strong attack all over the body. If that happens, too many immune cells, or white blood cells, are activated and release proteins, called cytokines, which in turn activate more immune cells and the reaction spirals into a dangerous cytokine storm like in Ryan Wilson’s case.

Clearly this tragedy begs for tests that can better predict drug toxicity in humans well before the first trial participants step into the clinic. On Monday a research team from the Imperial College London reported in the journal FASEB that they have done just that using human blood stem cells.

The team’s novel test is not so different than previous ones. Both tests are carried out in a petri dish using two human cell types: white blood cells and endothelial cells, a component of blood vessels. Both tests are also designed to mimic the human immune system’s response to biologics by measuring the release of cytokines.


Endothelial cells grown from blood stem cells. (credit: Imperial College London)

But the Imperial College London team’s test differs from others in one important way: both the white blood cell and endothelial cell types come from the same individual. First they collect a donor’s blood stem cells and specialize them into endothelial cells. Then white blood cells are also collected from the same donor.

The prior tests, on the other hand, rely on cells from two different donors. Because the two cell types aren’t necessarily tissue-matched, the white blood cells may already be primed for an immune response even before a biologic is added to the test. In fact, these prior tests weren’t able to distinguish between a biologic known to cause a limited immune response versus TGN1424, known to cause a cytokine storm. The newly developed test, however, accurately predicts both the toxic cytokine storm caused by TGN1424 and the absence of a response by several approved biologics, such as the breast cancer drug Herceptin.

In a college news release, Jane Mitchell, the senior author on the report, sees the big picture importance of her lab’s work:

“As biological therapies become more mainstream, it’s more likely that drugs being tested on humans for the first time will have unexpected and potentially catastrophic effects. We’ve used adult stem cell technology to develop a laboratory test that could prevent another disaster like the TGN1412 trial.”

Their results also highlight the often-overlooked power of stem cells to not just deliver therapies but to help develop safer ones.

Stem Cell Stories that Caught Your Eye: The Most Popular Stem Cellar Stories of 2014

2014 marked an extraordinary year for regenerative medicine and for CIRM. We welcomed a new president, several of our research programs have moved into clinical trials—and our goal of accelerating treatments for patients in need is within our grasp.

As we look back we’d like to revisit The Stem Cellar’s ten most popular stories of 2014. We hope you enjoyed reading them as much as we did reporting them. And from all of us here at the Stem Cell Agency we wish you a Happy Holidays and New Year.

10. UCSD Team Launches CIRM-Funded Trial to Test Safety of New Leukemia Drug

9. Creating a Genetic Model for Autism, with a Little Help from the Tooth Fairy

8. A Tumor’s Trojan Horse: CIRM Researchers Build Nanoparticles to Infiltrate Hard-to-Reach Tumors

7. CIRM funded therapy for type 1 diabetes gets FDA approval for clinical trial

6. New Videos: Living with Crohn’s Disease and Working Towards a Stem Cell Therapy

5. Creativity Program Students Reach New Heights with Stem Cell-Themed Rendition of “Let it Go”

4. Scientists Reach Yet Another Milestone towards Treating Type 1 Diabetes

3. Meet the Stem Cell Agency President C. Randal Mills

2. Truth or Consequences: how to spot a liar and what to do once you catch them

1. UCLA team cures infants of often-fatal “bubble baby” disease by inserting gene in their stem cells; sickle cell disease is next target

Searching for a Cure for HIV/AIDS: Stem Cells and World AIDS Day


It’s been 26 years since the first World AIDS Day was held in 1988—and the progress that the international scientific community has made towards eradicating the disease has been unparalleled. But there is much more work to be done.

One of the most promising areas of HIV/AIDS research has been in the field of regenerative medicine. As you observe World AIDS Day today, we invite you to take a look at some recent advances from CIRM-funded scientists and programs that are well on their way to finding ways to slow, halt and prevent the spread of HIV/AIDS:

Calimmune’s stem cell gene modification study continues to enroll patients, show promise:
Calimmune Approved to Treat Second Group in HIV Stem Cell Gene Modification Study

Is a cure for HIV/AIDS possible? Last year’s public forum discusses the latest on HIV cure research:

Town Hall: HIV Cure Research

The Stem Cell Agency’s HIV/AIDS Fact Sheet summarizes the latest advances in regenerative medicine to slow the spread of the disease.

And for more on World AIDS Day, follow #WorldAIDSDay on Twitter and visit

10 Years/10 Therapies: 10 Years after its Founding CIRM will have 10 Therapies Approved for Clinical Trials

In 2004, when 59 percent of California voters approved the creation of CIRM, our state embarked on an unprecedented experiment: providing concentrated funding to a new, promising area of research. The goal: accelerate the process of getting therapies to patients, especially those with unmet medical needs.

Having 10 potential treatments expected to be approved for clinical trials by the end of this year is no small feat. Indeed, it is viewed by many in the industry as a clear acceleration of the normal pace of discovery. Here are our first 10 treatments to be approved for testing in patients.

HIV/AIDS. The company Calimmune is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease.

Spinal cord injury patient advocate Katie Sharify is optimistic about the latest clinical trial led by Asterias Biotherapeutics.

Spinal cord injury patient advocate Katie Sharify is optimistic about the clinical trial led by Asterias Biotherapeutics.

Spinal Cord Injury. The company Asterias Biotherapeutics uses cells derived from embryonic stem cells to heal the spinal cord at the site of injury. They mature the stem cells into cells called oligodendrocyte precursor cells that are injected at the site of injury where it is hoped they can repair the insulating layer, called myelin, that normally protects the nerves in the spinal cord.

Heart Disease. The company Capricor is using donor cells derived from heart stem cells to treat patients developing heart failure after a heart attack. In early studies the cells appear to reduce scar tissue, promote blood vessel growth and improve heart function.

Solid Tumors. A team at the University of California, Los Angeles, has developed a drug that seeks out and destroys cancer stem cells, which are considered by many to be the reason cancers resist treatment and recur. It is believed that eliminating the cancer stem cells may lead to long-term cures.

Leukemia. A team at the University of California, San Diego, is using a protein called an antibody to target cancer stem cells. The antibody senses and attaches to a protein on the surface of cancer stem cells. That disables the protein, which slows the growth of the leukemia and makes it more vulnerable to other anti-cancer drugs.

Sickle Cell Anemia. A team at the University of California, Los Angeles, is genetically modifying a patient’s own blood stem cells so they will produce a correct version of hemoglobin, the oxygen carrying protein that is mutated in these patients, which causes an abnormal sickle-like shape to the red blood cells. These misshapen cells lead to dangerous blood clots and debilitating pain The genetically modified stem cells will be given back to the patient to create a new sickle cell-free blood supply.

Solid Tumors. A team at Stanford University is using a molecule known as an antibody to target cancer stem cells. This antibody can recognize a protein the cancer stem cells carry on their cell surface. The cancer cells use that protein to evade the component of our immune system that routinely destroys tumors. By disabling this protein the team hopes to empower the body’s own immune system to attack and destroy the cancer stem cells.

Diabetes. The company Viacyte is growing cells in a permeable pouch that when implanted under the skin can sense blood sugar and produce the levels of insulin needed to eliminate the symptoms of diabetes. They start with embryonic stem cells, mature them part way to becoming pancreas tissues and insert them into the permeable pouch. When transplanted in the patient, the cells fully develop into the cells needed for proper metabolism of sugar and restore it to a healthy level.

HIV/AIDS. A team at The City of Hope is genetically modifying patients’ own blood-forming stem cells so that they can produce immune cells—the ones normally destroyed by the virus—that cannot be infected by the virus. It is hoped this will allow the patients to clear their systems of the virus, effectively curing the disease

Blindness. A team at the University of Southern California is using cells derived from embryonic stem cell and a scaffold to replace cells damaged in Age-related Macular Degeneration (AMD), the leading cause of blindness in the elderly. The therapy starts with embryonic stem cells that have been matured into a type of cell lost in AMD and places them on a single layer synthetic scaffold. This sheet of cells is inserted surgically into the back of the eye to replace the damaged cells that are needed to maintain healthy photoreceptors in the retina.

UCLA team cures infants of often-fatal “bubble baby” disease by inserting gene in their stem cells; sickle cell disease is next target

Poopy diapers, ear-splitting cries, and sleepless nights: sure, the first few weeks of parenthood are grueling but those other moments of cuddling and kissing your little baby are pure bliss.

The bubble boy.  Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

The bubble boy. Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

That wasn’t the case for Alysia and Christian Padilla-Vacarro of Corona, California. Close contact with their infant daughter Evangelina, born in 2012, was off limits. She was diagnosed with a genetic disease that left her with no immune system and no ability to fight off infections so even a minor cold could kill her.

Evangelina was born with Severe Combined Immunodeficiency (SCID) also called “bubble baby” disease, a term coined in the 1970s when the only way to manage the disease was isolating the child in a super clean environment to avoid exposure to germs. Bone marrow transplants from a matched sibling offer a cure but many kids don’t have a match, which makes a transplant very risky. Sadly, many SCID infants die within the first year of life.

Until now, that is.

Today, a UCLA research team led by Donald Kohn, M.D., announced a stunning breakthrough cure that saved Evangelina’s life and all 18 children who have so far participated in the clinical trial. Kohn—the director of UCLA’s Human Gene Medicine Program—described the treatment strategy in a video interview with CIRM (watch the video below):

“We collect some of the baby’s own bone marrow, isolate the [blood] stem cells, add the gene that they’re missing that their immune system needs and then transplant the cells back to them. “

Inserting the missing gene, called ADA, into the blood stem cells restores the cells’ ability to produce a healthy immune system. And since the cells originally came from the infant, there’s no worry about the possible life-threatening complications from receiving non-matched donor cells.

This breakthrough didn’t occur overnight. Kohn and colleagues have been plugging away for over twenty years carrying out trials, observing their limitations and going back to lab to improve the technology. Their dedication has paid off. As Kohn states in a press release:

“All of the children with SCID that I have treated in these stem cell clinical trials would have died in a year or less without this gene therapy, instead they are all thriving with fully functioning immune systems.”

Alysia Padilla-Vacarro and daughter Evangelina on the day of her gene therapy treatment. Evangelina, now two years old, has had her immune system restored and lives a healthy and normal life. [Credit: UCLA Broad Center of Regenerative Medicine and Stem Cell Research.]

Alysia Padilla-Vacarro and daughter Evangelina on the day of her gene therapy treatment. Evangelina, now two years old, has had her immune system restored and lives a healthy and normal life. [Credit: UCLA Broad Center of Regenerative Medicine and Stem Cell Research.]

For the Padilla-Vacarro family, the dark days after Evangelina’s grave diagnosis have given way to a bright future. Alysia, Evangelina’s mom, poignantly recalled her daughter’s initial recovery:

”It was only around six weeks after the procedure when Dr. Kohn told us Evangelina can finally be taken outside. To finally kiss your child on the lips, to hold her, it’s impossible to describe what a gift that is. I gave birth to my daughter, but Dr. Kohn gave my baby life.”

The team’s next step is to get approval by the Food and Drug Administration (FDA) to provide this treatment to all SCID infants missing the ADA gene.

At the same time, Kohn and colleagues are adapting this treatment approach to cure sickle cell disease, a genetic disease that leads to sickle shaped red blood cells. These misshapen cells are prone to clumping causing debilitating pain, risk of stroke, organ damage and a shortened life span. CIRM is providing over $13 million in funding to support the UCLA team’s clinical trial set to start early next year.

For more information about CIRM-funded sickle cell disease research, visit our fact sheet.

What everybody needs to know about CIRM: where has the money gone

It’s been almost ten years since the voters of California created the Stem Cell Agency when they overwhelmingly approved Proposition 71, providing us $3 billion to help fund stem cell research.

In the last ten years we have made great progress – we will have ten projects that we are funding in or approved to begin clinical trials by the end of this year, a really quite remarkable achievement – but clearly we still have a long way to go. However, it’s appropriate as we approach our tenth anniversary to take a look at how we have spent the money, and how much we have left.

Of the $3 billion Prop 71 generates around $2.75 billion was set aside to be awarded to research, build laboratories etc. The rest was earmarked for things such as staff and administration to help oversee the funding and awards.

Of the research pool here’s how the numbers break down so far:

  • $1.9B awarded
  • $1.4B spent
  • $873M not awarded

So what’s the difference between awarded and spent? Well, unlike some funding agencies when we make an award we don’t hand the researcher all the cash at once and say “let us know what you find.” Instead we set a series of targets or milestones that they have to reach and they only get the next installment of the award as they meet each milestone. The idea is to fund research that is on track to meet its goals. If it stops meetings its goals, we stop funding it.

Right now our Board has awarded $1.9B to different institutions, companies and researchers but only $1.4B of that has gone out. And of the remainder we estimate that we will get around $100M back either from cost savings as the projects progress or from programs that are cancelled because they failed to meet their goals.

So we have approximately $1B for our Board to award to new research, which means at our current rate of spending we’ll have enough money to be able to continue funding new projects until around 2020. Because these are multi-year projects we will continue funding them till around 2023 when those projects end and, theoretically at least, we run out of money.

But we are already working hard to try and ensure that the well doesn’t run dry, and that we are able to develop other sources of funding so we can continue to support this work. Without us many of these projects are at risk of dying. Having worked so hard to get these projects to the point where they are ready to move out of the laboratory and into clinical trials in people we don’t want to see them fall by the wayside for lack of support.

Of the $1.9B we have awarded, that has gone to 668 awards spread out over five different categories:

CIRM spending Oct 2014

Increasingly our focus is on moving projects out of the lab and into people, and in those categories – called ‘translational’ and ‘clinical’ – we have awarded almost $630M in funding for more than 80 active programs.


Under our new CIRM 2.0 plan we hope to speed up the number of projects moving into clinical trials. You can read more about how we plan on doing there in this blog.

It took Jonas Salk almost 15 years to develop a vaccine for polio but those years of hard work ended up saving millions of lives. We are working hard to try and achieve similar results on dozens of different fronts, with dozens of different diseases. That’s why, in the words of our President & CEO Randy Mills, we come to work every day as if lives depend on us, because lives depend on us.