Published by
Stanford Medicine


Pediatrics, Research, Stanford News, Stem Cells

Near approval: A stem cell gene therapy developed by Stanford researcher

Near approval: A stem cell gene therapy developed by Stanford researcher

It has been a momentous month for Stanford researcher Maria Grazia Roncarolo, MD. Following decades of research in Roncarolo’s lab and the clinic, pharmaceutical company Glaxo SmithKline has applied for final approval by European Medicines Agency (EMA) of a treatment she developed to cure a deadly childhood immune disorder. If approved by the EMA, which is Europe’s equivalent of the U.S. Food and Drug Administration (FDA), the treatment would be the first gene stem cell therapy to be granted approval by a major medical regulatory agency.

The therapy cures a disease called severe combined immune deficiency (SCID), sometimes called the “bubble boy disease,” by inserting a gene into blood stem cells and transplanting the stem cells into the patient’s body. The treatment is still being evaluated by the FDA.

My greatest satisfaction is that kids who were once incurable now have options

If approved, the treatment will no longer be considered an experimental therapy in Europe, and “people will be able to get this treatment as they would any other, and will be able to get their insurance company to pay for it,” Roncarolo told me. The final regulatory review marks the beginning of a new era in which genetically modified stem cells might be used to treat or cure a wide variety of human diseases, she also noted.

Roncarolo developed the treatment while she was scientific director at the San Raffaele Scientific Institute in Milan, Italy. There, she treated kids who were born with an inability to make the enzyme adenosine deaminase (ADA), which leaves them unable to make certain immune cells that protect them from infection. For that reason, children with ADA-SCID are forced to spend their lives in a sterile environment that protects them from infections that most people would easily fight off but are deadly for them.

Roncarolo and her team inserted the gene for ADA into blood stem cells which were transplanted into 18 children with the disease. Once the modified blood stem cells could produce the enzyme, they were able to form the necessary immune cells and the children were able to leave their sterile environment. “Those children have been effectively cured,” Roncarolo said.

Other gene therapies have been developed before, but those therapies modified more mature cells that cannot reproduce themselves. Only stem cells can both make more copies of themselves and also produce more specialized cells. If gene therapy is used to modify cells that are not stem cells, the treatment will only last as long as the cells last. Eventually, mature cells age and die, and the disorder returns.

Last year, Roncarolo was recruited to Stanford to continue her work while serving as co-director of the Institute for Stem Cell Biology and Regenerative Medicine. She is busy researching cures for other congenital immune disorders and developing methods that could lead to stem cell treatments for a wide variety of other diseases.

“My greatest satisfaction is that kids who were once incurable now have options,” Roncarolo said.

Previously: Countdown to Childx: Stanford expert highlights future of stem cell and gene therapies

AHCJ15, Science, Science Policy, Stem Cells

Stanford stem cell experts highlight “inherent flaw” in drug development system

Stanford stem cell experts highlight "inherent flaw" in drug development system

Academic institutions are in a much better position than pharmaceutical companies to make the best decisions about which therapies deserve further development. That was the underlying message from a pair of Stanford researchers at a panel on stem cell science at last weekend’s Association of Health Care Journalism 2015 conference.

“There’s an inherent flaw in our system,” said Irving Weissman, MD, director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. “Companies are driven by the desire for profits rather than the desire to find the best therapy, and they often give up on discoveries too early.”

Weissman cited studies that were done long ago at Stanford and proven in mouse models or human clinical trials that pharmaceutical companies have failed to develop. “In mice, transplantation of purified blood stem cell and insulin producing cells from closely related mice leads to a permanent cure,” Weissman says. “We discovered that 16 years ago, and a therapy is still not available.”

A therapy involving high-dose chemotherapy followed by purified stem cell transplant for stage 4 breast cancer cured a relatively high number of women in a small trial almost 20 years ago but the pharmaceutical company with the rights to the technology decided not to develop the treatment, Weissman says. A larger trial of this therapy is currently being planned at Stanford.

Maria Grazia Roncarolo, MD, co-director of the institute, spoke about her own experience in an academic environment developing therapies for diseases that pharmaceutical companies deem to rare to merit their attention. Only after she showed that a therapy for severe combined immune deficiency could work did pharmaceutical companies get interested.

“Academic researchers should have the ability to test a therapy, to have control of the design and execution of the clinical trials, and pharmaceutical companies should do the production and marketing,” Roncarolo told the journalists attending the session.

Allowing academic institutions to run clinical trials is “a big effort that will require a team, institutional commitment and robust funding,” Roncarolo said. Comparing the situation in the United States to that in Europe, where she has done much of her research, she notes that “in this country there is little funding for proof of concept trials to bring therapies from the lab bench to the bedside.”

Previously: An inside look at drug development, Stanford’s Irving Weissman on the (lost?) promise of stem cells and The largest stem cell research building in the U.S.

Events, Genetics, Patient Care, Pediatrics, Research, Stanford News, Stem Cells

“It’s not just science fiction anymore”: Childx speakers talk stem cell and gene therapy

“It’s not just science fiction anymore": Childx speakers talk stem cell and gene therapy

childx PorteusAt the Childx conference last week there was a great deal of optimism that stem cell and genetic therapies are about to have a huge impact on many childhood diseases. “It’s not just science fiction anymore,” Matthew Porteus, MD, PhD, told the audience. “We can correct mutations that cause childhood disease.”

The session was hosted by Stanford professor Maria Grazia Roncarolo, MD, who until recently was head of the Italy’s Telethon Institute for Cell and Gene Therapy at the San Raffaele Scientific Institute in Milan. Roncarolo pointed out that there are more than 10,000 human diseases that are caused by a single gene defect. “Stem cell and gene therapies can be used to treat cancer and other diseases,” Roncarolo said.

Two such diseases are sickle cell disease and severe combined immune deficiency. In both cases, a single nucleotide change in DNA becomes a deadly defect for children with the bad luck to have them. Porteus is working on very new genome editing technologies that allow clinicians to go in and fix those DNA typos and cure diseases.

Stanford dermatology researcher Anthony Oro, MD, PhD is working to do something similar with skin cells for a painful blistering disease called epidermolysis bullosa. Children with EB lack a functional gene for one of the proteins that anchors the layers of skin together. Oro and Stanford Institute for Stem Cell Biology and Regenerative Medicine scientist Marius Wernig, MD, PhD, are taking defective skin cells from patients, transforming them into embryonic-like stem cells, fixing the gene defect, and then growing them back into skin stem cells and then layers of skin ready for transplantation. Oro says that they have shown that they can do this in a scalable way in mice, and they hope to start a clinical trial in humans soon.

One of the challenges to genetic therapy is that it often requires putting the gene into blood stem cells to deliver it to the body, but the high dose chemotherapy or radiation that is necessary to remove the bodies own blood stem cells and make way for the transplanted cells is very dangerous in itself. Researchers like Stanford researcher Hiromitsu Nakuchi, MD, PhD, are exploring gentler ways to make space in the body for the transplanted cells. He has discovered that simply by feeding mice a diet deficient in a particular amino acid, blood stem cells begin to die. Other cells in the body don’t seem to be as strongly affected. A dietary solution may eventually allow clinicians to avoid using the highly toxic treatments that have traditionally been used for blood stem cell transplant.

Continue Reading »

Research, Science, Stanford News, Stem Cells

Researchers celebrate 25th anniversary of major stem cell discovery

Researchers celebrate 25th anniversary of major stem cell discovery

A new era of stem cell science began 25 years ago. At that time, Stanford researcher Irving Weissman, MD, and his colleagues announced in Science that they had purified hematopoietic stem cells from a mouse. This was the first “adult” (tissue specific) stem cell isolated in purified form from any species. In order to isolate the stem cells, the researchers had to identify the key cell-surface proteins that differentiated the stem cells from closely related cells and separate them from each other. They also had to develop new transplant models to show that the stem cells could produce every single type of blood an immune cell needed by the body.

Since then, researchers at Stanford and elsewhere have learned to identify and purify blood stem cells and other types of stem cells in humans, opening the door to creating stem cell therapies that researchers hope will be able to cure many intractable diseases. Today, we’re honoring this achievement as part of the observation of World Stem Cell Awareness Day.

Previously: Very small embryonic like stem cells may not exist, say Stanford researchers, Stanford’s Irving Weissman on the (lost?) promise of stem cells and Stanford study shows stem cell treatment improves survival of patients with metastatic breast cancer

Immunology, Research, Science, Stanford News, Videos

Ocean organism settles down, digests its proto-brain and loses its individuality

Ocean organism settles down, digests its proto-brain and loses its individuality

Last week, Science published a research report from Stanford scientists on the discovery of a single gene in a primitive marine organism that determines whether that organism recognizes wayward cells as being part of themselves or foreign. What’s interesting scientifically is that this is a very primitive immune system, and if we understand exactly how it works and how it evolved, we might learn something about how our own immune system recognizes foreign cells. It could eventually lead to new understanding about how to repel disease-causing organisms or how to successfully transplant organs.

That finding is impressive, but I also found myself fascinated by the strange organism they were studying: Botryllus schlosseri. This ocean-dwelling creature has two life stages. In the larval stage it swims about freely and has a primitive brain and notochord (like a proto-spinal cord). But eventually it attaches itself to a rock with other Botryllus organisms, dissolves its proto-brain, and buds off identical individuals to share life under a sheltering tunic. Domestic Botryllus bliss.

It gets stranger. These individual Botryllus organisms share a common circulatory system that pumps fluid through their colony. This circulating fluid carries cells from one individual to another. When two adjacent related colonies touch, they can fuse and form a joint circulatory system, allowing cells from one colony to implant themselves in the other. Circulating stem cells can then potentially replicate themselves throughout the fused colonies, replacing the cells of the recipient Botryllus until they are clones of the donor.

Luckily, they haven’t become advanced enough to engage in psychotherapy. No life cycle is long enough to work out those issues.

Big data, Research, Stanford News, Technology, Videos

Stanford computer scientist shows stem cell researchers the power of big data

Stanford computer scientist shows stem cell researchers the power of big data

Not long ago, Stanford computer scientist Debashis Sahoo, PhD, told investigators at the Stanford Institute for Stem Cell Biology and Regenerative Medicine that in a few seconds he could find many of the important stem cell genes that the researchers were used to finding only after spending millions of dollars and years in the lab. “We laughed and said, ‘That’s impossible,'” recalls Irving Weissman, MD, director of the institute, in a recent video. But Weissman went ahead and gave Sahoo information about two key genes – and within a few seconds, Sahoo had used his desktop computer to scour the world’s public gene databases, analyzed that information with the computer algorithm he had designed, and come up with over a dozen genes new genes that were involved in the development of certain kinds of cells. That search, Weissman estimates, saved his team a decade of work and about $2.5 million.

More details are shared in the video above. And as a reminder, big data – and the ways in which people like Sahoo are mining through vast amounts of publicly available information to further research and advance health care – is the focus of a Stanford/Oxford conference being held here later this month.

Previously: Atul Butte discusses why big data is a big deal in biomedicine and Mathematical technique used to identify bladder cancer marker

Cancer, Research, Stanford News, Stem Cells

Blood cancers shown to arise from mutations that accumulate in stem cells

Blood cancers shown to arise from mutations that accumulate in stem cells

How and why do some cells in our bodies become cancerous?  Can any cell become cancerous, or only certain kinds of cells? Those are longstanding questions with big implications for treating and preventing cancer.

In the case of leukemias, Stanford researchers finally have an answer to the first question: Mutations accumulate slowly in blood stem cells, the cells that produce all the cells of the blood and immune system. This had been a controversial theory of some experts, and the team proved it correct by comparing mutations found in leukemia cells with mutations found in blood stem cells from the same patient. As I explain in a release today:

When the researchers compared mutations in these seemingly normal blood stem cells with the leukemia cells, they could reconstruct exactly which mutations led to the leukemia, and the order in which the mutations arose. They did this by looking for blood-forming stem cells with a single mutation, which they knew must be the first, then finding other stem cells with that first mutation plus one other, which they could then identify as the second. They continued to do this until they found examples of stem cells at each stage of mutation accumulation, leading up to the full set of mutations found in the actual leukemia cell.

Individual mutations can occur in mature blood and immune cells too, but these cells will die off naturally before they get the whole set of mutations needed to cause cancer. Only the stem cells, which last a lifetime, are around long enough to accumulate all the mutations.

This information is important for treating leukemia (and perhaps other cancers, if the same pattern applies). Leukemia can initially be treated with chemotherapy to kill the cancer cells, but patients will often relapse – the cancer comes back, often more deadly than before. One possibility is that relapse occurs because a few leukemia cells survived the chemotherapy, in which case the solution might be increase the potency of the chemotherapy. But if relapse occurs because the stem cells are creating new leukemia cells, then it really won’t matter how effective chemotherapy is because the mutated stem cells are acting as a reservoir for the disease. Co-principal author Ravi Majeti, MD, PhD, said this area will be the focus of the next phase of the team’s research.

This study appears in Science Translational Medicine.

Previously: Leukemia prognosis and cancer stem cells

Cardiovascular Medicine, Image of the Week, Stanford News

Image of the Week: "Heart cells"

Image of the Week: "Heart cells"

As I reported in this week’s issue of Inside Stanford Medicine, Scott Metzler, PhD, is a researcher who not only studies the early development of the heart, but also suffers from a serious heart defect called Tetralogy of Fallot. Since hearts are a leitmotif of Metzler’s life, it seems appropriate that heart-shaped images, like this one, recently popped up under his microscope.

Metzler has been studying the action of apelin, a protein that seems to offer some protection against heart disease. Metzler observed that when heart muscle cells are exposed to apelin, the protein clusters at one point on the cell and pulls that spot down toward the center of the cell, making that spot pucker. In the microscope, from the side, these cells start to look like little hearts.

Photo courtesy of Scott Metzler

Medicine and Society, Technology

Medicine is about to be “Schumpetered" – and go through its biggest shake-up in history

Medicine is about to be “Schumpetered" - and go through its biggest shake-up in history

Eric Topol, MD, director of the Scripps Translational Science Institute in La Jolla, Calif., was at the Stanford Cardiovascular Institute talking yesterday about the transformative power of digital technology and social networks in medicine. He noted that economist Joseph Schumpeter described more than 50 years ago how old ways of doing things are destroyed as new technologies take over. “Medicine is about to go through the biggest shake-up in history,” Topol predicted. “We are about to get Schumpetered.”

Displaying a graph of people’s increasing interaction with digital devices, he talked about the rise of the iPod, the Blackberry phone, the iPhone and now social networking, and the accelerating changes they have made in how we live our lives. Add those devices to the increasing amount of digital information available about our biological and physiological states, and “we are about to hit the inflection point” in how all medicine is done.

Topol foresees a world in which people will know an enormous amount about their own genes, biochemistry and physiological state, and have the ability to monitor changes in real time and transmit that information to physicians far away. There are already wireless devices that record and transmit information about blood pressure, heart rate, physical activity and sleep state. Doctors can carry an echocardiogram device in their pockets. Very soon, Topol said, we’ll have inexpensive implanted sensors that will be able to spot cancer cells floating in the bloodstream or spot a developing heart attack, giving us enough warning to do something about it.

The new technology will enable many patients to be at home instead of in the hospital because they can be monitored from afar. “Why do we need hospitals except for intensive care visits?” Topol asked. “Why do we need clinics when we can do it wirelessly?”

Putting these information technologies to work will also finally allow medicine to move from a populations-based approach to individualized medicine. As an example, Topol cited the case of Nicholas Volker, who at three years old had undergone more than 100 operations because a mystery illness was eating away at his digestive tract. As a last resort, doctors sequenced his whole genome and found one gene mutation that was causing the problem. A stem cell transplantation from cord blood cured him.

I, for one, am looking forward to these changes. I think they’ll result in a system in which we’re more connected to our health needs and more connected to people around us. And I think we’ll have generally better health care – as long as we don’t lose the personal connection to physicians.

Cancer, Research, Stanford News, Stem Cells

Cancer stem cell researchers are feeling the need for speed

Cancer stem cell researchers are feeling the need for speed

Stanford researchers just announced that by using a new antibody against a cell protein called CD47, along with an existing anti-cancer antibody, they were able to cure well over half of a group of mice with human non-Hodgkin’s lymphoma. (Their paper appears in the journal Cell.) This is particularly promising because there is an abundance of CD47 on many other human cancers – such as breast, bladder, skin, brain and lung cancer – and the potential benefit might be extended to these other malignancies.

I had been hearing about this result around the labs for a while, and when I learned in early August that the research would be published I was excited that we would soon be able to talk about it publicly. But that excitement was tempered by a sad counterpoint.

That same week I read in a local newspaper a story about a non-Hodgkins lymphoma patient, Vallejo, Calif. police sergeant Brian Carter. Carter, a 36-year old father of two young boys, had been diagnosed last year and had beaten back the cancer with chemotherapy. But the leukemia returned this year, stronger than before, and at the time I read the story, Carter was searching for a compatible donor for a bone marrow transplant. Happily, I’ve since learned that a matched donor had been found and his chances of successful treatment are good, but there are many people around the world in the same situation who won’t be so lucky.

I see the same mixed feelings all the time among cancer stem cell researchers. Many of the researchers are also physicians who treat patients, and they know existing cancer therapies are not effective enough for many – which is why they went into the lab in the first place. They’re excited to be making real progress, but at the same time they know research can only move so fast.

As for this promising research, science has not progressed to the point where people can be treated. But “we want to bring this to patients as quickly as we can,” MD/PhD student Mark Chao and co-first author of the release, said in a release. Plans are already in the works to create a human version of the anti-CD47 antibody and prepare for a clinical trial within a couple years, which is about as fast as the process can go.

Stanford Medicine Resources: