TAG: "Stem cells"

A sense for biosensors


UC Irvine’s Weian Zhao has created a device that improves detection of bacterial, viral invaders in blood samples.

The Integrated Comprehensive Droplet Digital Detection system invented by Weian Zhao of UC Irvine converts blood samples directly into billions of very small droplets. (Photo by Steve Zylius, UC Irvine)

By Tom Vasich, UC Irvine

As a doctoral student at McMaster University in Hamilton, Ontario, Weian Zhao took part in a Canada-wide research effort to develop bioactive paper that would detect, capture and deactivate waterborne and airborne pathogens.

As part of this project, he helped invent gold nanoparticle-coated paper that could detect common pathogens, such as E. coli, but ultimately, the product didn’t meet his exacting standards of diagnostic speed and sensitivity. With a freshly minted Ph.D. in chemistry, Zhao moved on to a joint postdoctoral fellowship at both the Massachusetts Institute of Technology and Harvard, where he dove into stem cell research, his biosensor work seemingly left north of the border.

But the challenge of creating a technology that could rapidly and selectively identify bacterial and viral invaders in blood samples nagged at the young scientist, even as he joined UC Irvine in 2011 as an assistant professor of pharmaceutical sciences with state-of-the-art lab space in the Sue & Bill Gross Stem Cell Research Center.

And then he met Enrico Gratton. In his Laboratory for Fluorescence Dynamics, the UCI biomedical engineer and colleagues have been developing imaging tools for biomedical applications. Among them is a three-dimensional particle counter that tags low-concentration fluorescent particles in large volumes of solution within several minutes, which drew Zhao’s attention. He knew he was back in the biosensor game.

Employing this particle counter, Zhao created a bloodstream infection test that speeds up diagnosis times with unprecedented accuracy – allowing physicians to treat patients with potentially deadly ailments more promptly and effectively.

Zhao says that the Integrated Comprehensive Droplet Digital Detection system can, in as little as 90 minutes, detect bacteria in milliliters of blood with single-cell sensitivity; no cell culture is needed. He published his latest results in the November issue of Nature Communications.

“We are extremely excited about this technology because it addresses a long-standing unmet medical need in the field,” says Zhao, who also holds a faculty appointment in biomedical engineering. “As a platform technology, it may have many applications in detecting extremely low-abundance biomarkers in other areas, such as cancers, HIV and, most notably, Ebola.”

Bloodstream infections are a major cause of illness and death. In particular, infections associated with antimicrobial-resistant pathogens are a growing health problem in the U.S. and worldwide. According to the Centers for Disease Control & Prevention, more than 2 million people a year globally get antibiotic-resistant blood infections, with about 23,000 deaths. The high mortality rate for blood infections is due, in part, to the inability to rapidly diagnose and treat patients in the early stages.

Recent molecular diagnosis methods, including polymerase chain reaction, can reduce the assay time to hours but are often not sensitive enough to detect bacteria that occur at low concentrations in blood, as is common in patients with incipient blood infections.

The Integrated Comprehensive Droplet Digital Detection technology differs from other diagnostic techniques in that it converts blood samples directly into billions of very small droplets. Fluorescent DNA sensor solution infused into the droplets detects those with bacterial markers, lighting them up with an intense fluorescent signal. Zhao says that separating the samples into so many small drops minimizes the interference of other components in blood, making it possible to directly identify target bacteria without the purification typically required in conventional assays.

“The IC 3D instrument is designed to read a large volume in each measurement, to speed up diagnosis,” Gratton says. “Importantly, using this technique, we can detect a positive hit from hundreds of millions of measurement samples with very high confidence.”

But invention was only the first step. Zhao wants to commercialize IC 3D. At UCI, faculty researchers with an entrepreneurial bent can work with the Institute for Innovation, an interdisciplinary and campuswide center focused on integrating research, entrepreneurship and technology to create real-world applications that benefit the public and drive the economy. The Office of Technology Alliances, part of the institute, helped Zhao patent-protect the IC 3D technology and establish a spin-off company, Velox Biosystems, to test and manufacture a commercial IC 3D device.

Currently, Zhao is focusing on applying IC 3D to cancer treatments – an extension of the research he’s been advancing since joining UCI.

Zhao has been developing stem cell messengers that selectively migrate to cancer sites to deliver tumor-fighting drugs or probes for contrast-enhanced medical imaging. This could, potentially, enable the identification of cancer micro-metastases at their early stages and increase the effectiveness of chemotherapeutic treatments for metastatic cancer while mitigating the symptoms associated with systemic chemotherapy.

For this work, Zhao was included in the MIT Technology Review’s 2012 list of the world’s top innovators under the age of 35, and this year he earned a prestigious National Institutes of Health Director’s New Innovator Award to further his efforts to create stem cell-based detection methods and treatments for cancer.

He’s also collaborating with Dr. Jason Zell, an assistant professor of medicine and co-leader of the Colon Cancer Disease-Oriented Team at UCI’s Chao Family Comprehensive Cancer Center, to use IC 3D to identify biomarkers in colon cancers. This could enable oncologists to gauge the effectiveness of treatment during the cancer’s early stages more accurately than with current methods, which Zell says are not reliable.

Zhao is now seeking business partners to accelerate Velox Biosystems’ growth and hopes to conduct clinical studies of IC 3D’s utility in patient diagnosis and treatment.

“That’s what’s so important about this project,” he says. “We’ve created a multi-platform tool that has the potential to work with a variety of infections and diseases. I’m very excited about its future.”

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Researchers ID protein key to harnessing regenerative power of blood stem cells


Discovery could lead to development of more effective therapies for blood diseases, cancers.

By Peter Bracke, UCLA

UCLA scientists have for the first time identified a protein that plays a key role in regulating how blood stem cells replicate in humans.

This discovery lays the groundwork for a better understanding of how this protein controls blood stem cell growth and regeneration, and could lead to the development of more effective therapies for a wide range of blood diseases and cancers.

The study, which was led by Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member Dr. John Chute, was published online last month ahead of print in the Journal of Clinical Investigation.

Hematopoietic stem cells (HSCs) are the blood-forming cells that have the remarkable capacity to both self-renew and give rise to all of the differentiated cells (fully developed cells) of the blood system. HSC transplantation provides curative therapy for thousands of patients annually. However, little is known about the process through which transplanted HSCs replicate following their arrival in human bone marrow. In this study, the authors showed that a cell surface protein called protein tyrosine phosphatase-sigma (PTP-sigma) regulates the critical process called engraftment, which is how HSCs start to grow and make healthy blood cells after transplantation.

Mamle Quarmyne, a graduate student Chute’s lab and first author of the study, demonstrated that PTP-sigma is produced (expressed) on a high percentage of mouse and human HSCs. She showed further that genetic deletion of PTP-sigma in mice markedly increased the ability of HSCs to engraft in transplanted mice.

In a complementary study, Quarmyne demonstrated that selection of human blood HSCs which did not express PTP-sigma led to a 15-fold increase in HSC engraftment in transplanted immune-deficient mice. Taken together, these studies showed that PTP-sigma suppresses normal HSC engraftment capacity and targeted blocking of PTP-sigma can substantially improve mouse and human HSC engraftment after transplantation.

Chute and colleagues showed further that PTP-sigma regulates HSC function by suppressing a protein, RAC1, which is known to promote HSC engraftment after transplantation.

“These findings have tremendous therapeutic potential since we have identified a new receptor on HSCs, PTP-sigma, which can be specifically targeted as a means to potently increase the engraftment of transplanted HSCs in patients,” said Chute, senior author of the study and professor of hematology/oncology and radiation oncology at UCLA. “This approach can also potentially accelerate hematologic recovery in cancer patients receiving chemotherapy and/or radiation, which also suppress the blood and immune systems.”

Chute’s team is now working with fellow UCLA researchers to test small molecules for their ability to specifically inhibit PTP-sigma on blood stem cells. If these studies are successful, they aim to translate these findings into clinical trials in the near future.

This research was supported by funding from the National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute. Additional funding was provided by the UCLA Broad Stem Cell Research Center through philanthropy and other sources.

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Novel mechanism of RNA regulation in embryonic stem cells discovered


UCLA research suggests new strategy to control cellular identity and fate.

Yi Xing, UCLA

By Stuart Wolpert, UCLA

A team of scientists that included researchers from UCLA has discovered a novel mechanism of RNA regulation in embryonic stem cells. The findings are strong evidence that a specific chemical modification, or “tag,” on RNA plays a key role in determining the ability of embryonic stem cells to adopt different cellular identities.

The team also included scientists from Harvard Medical School, Massachusetts General Hospital and Stanford University.

Published in the journal Cell Stem Cell, the research reveals that depleting or knocking out a key component of the machinery that places this chemical tag — known both as m6A and N6-methyladenosine — on RNA significantly blocks embryonic stem cells from differentiating into more specialized types of cells.

A key property of embryonic stem cells is their ability to differentiate into many specialized types of cells. However, instead of marching toward a specific fate when prompted by signals to differentiate, embryonic stem cells that have reduced ability to place m6A become stuck in a sort of suspended animation, even though they appear healthy.

Yi Xing, a UCLA associate professor of microbiology, immunology and molecular genetics, led the informatics analyses and was a co-corresponding author of the paper. Other corresponding authors were Dr. Cosmas Giallourakis, an assistant professor of medicine at Harvard Medical School and Massachusetts General Hospital, and Dr. Howard Chang, a professor of Stanford University’s School of Medicine and a Howard Hughes Medical Institute investigator.

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How stem cells can be activated to help immune system fight infection


UCLA scientists show crucial role of genes Scalloped and Yorkie.

UCLA researchers have discovered that the Scalloped (above) and Yorkie genes play a key role in how progenitor stem cells are activated to fight infection. (Image by Dr. Julian Martinez-Agosto Lab, UCLA)

By Peter Bracke, UCLA

In a study led by Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member Dr. Julian Martinez-Agosto, UCLA scientists have shown that two genes not previously known to be involved with the immune system play a crucial role in how progenitor stem cells are activated to fight infection.

This discovery lays the groundwork for a better understanding of the role progenitor cells can play in immune system response and could lead to the development of more effective therapies for a wide range of diseases.

The two-year study was published in the current issue of the journal Current Biology.

Progenitor cells are the link between stem cells and fully differentiated cells of the blood system, tissues and organs. This maturation process, known as differentiation, is determined in part by the original environment that the progenitor cell came from, called the niche. Many of these progenitors are maintained in a quiescent state or “standby mode” and are ready to differentiate in response to immune challenges such as stress, infection or disease.

Dr. Gabriel Ferguson, a postdoctoral fellow in Martinez-Agosto’s lab and first author of the study, built upon the lab’s previous research that utilized the blood system of the fruit fly species Drosophila to show that a specific set of signals must be received by progenitor cells to activate their differentiation into cells that can work to fight infection after injury. Ferguson focused on two genes previously identified in stem cells but not in the blood system, named Yorkie and Scalloped, and discovered that they are required in a newly characterized cell type called a lineage specifying cell. These cells then essentially work as a switch, sending the required signal to progenitor cells.

The researchers further discovered that when the progenitor cells did not receive the required signal, the fly would not make the mature cells required to fight infection. This indicates that the ability of the blood system to fight outside infection and other pathogens is directly related to the signals sent by this new cell type.

“The beauty of this study is that we now have a system in which we can investigate how a signaling cell uses these two genes, Yorkie and Scalloped, which have never before been shown in blood, to direct specific cells to be made,” said Martinez-Agosto, associate professor of human genetics. “It can help us to eventually answer the question of how our body knows how to make specific cell types that can fight infection.”

The researchers said that they hope future studies will examine these genes beyond Drosophila and extend to mammalian models, and that the system will be used by the research community to study the role of the genes Yorkie and Scalloped in different niche environments.

“At a biochemical level, there is a lot of commonality between the molecular machinery in Drosophila and that in mice and humans,” Ferguson said. “This study can further our shared understanding of how the microenvironment can regulate the differentiation and fate of a progenitor or stem cell.”

Martinez-Agosto noted, “Looking at the functionality of these genes and their effect on the immune response has great potential for accelerating the development of new targeted therapies.”

Ferguson’s research on this project was supported by a Cellular and Molecular Biology National Institutes of Health predoctoral training grant. Additional funding was provided by the David Geffen School of Medicine at UCLA.

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Researchers ID protein key to development of blood stem cells


Critical step in improving stem cell therapies for blood-related diseases and cancers.

By Peter Bracke, UCLA

Led by Dr. Hanna Mikkola, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA scientists have discovered a protein that is integral to the self-replication of hematopoietic stem cells during human development.

The discovery lays the groundwork for researchers to generate hematopoietic stem cells in the lab that better mirror those that develop in their natural environment. This could in turn lead to improved therapies for blood-related diseases and cancers by enabling the creation of patient-specific blood stem cells for transplantation.

The findings are reported online ahead of print in the journal Cell Stem Cell.

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UCLA researcher pioneers cure for ‘Bubble Baby’ disease


Game-changing stem cell treatment to be tested for sickle cell disease next.

Christian and Alysia Padilla-Vaccaro and their twins, Annabella (left) and Evangelina. With a newly restored immune system, Evangelina lives a normal and healthy life.

By Peter Bracke, UCLA

UCLA stem cell researchers have pioneered a stem cell gene therapy cure for children born with a life-threatening condition called adenosine deaminase–deficient severe combined immunodeficiency, or ADA-deficient SCID. Often called Bubble Baby disease, the condition can be fatal within the first year of life if left untreated.

The groundbreaking treatment was developed by Dr. Donald Kohn, a renowned stem cell researcher and member of the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.

Kohn’s breakthrough was developed over three decades of research aimed at creating a gene therapy that safely restores the immune systems of children with ADA-deficient SCID using the patients’ own cells with no side effects.

To date, 18 children with SCID have been cured of the disease after receiving the therapy in clinical trials at UCLA and the National Institutes of Health.

“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,” said Kohn, a professor of pediatrics and of microbiology, immunology and molecular genetics in the UCLA College. “Instead they are all thriving with fully functioning immune systems.”

Children born with SCID are kept in controlled, isolated environments because without an immune system, ordinary illness and infection could be lethal.

“Other current options for treating ADA-deficient SCID are not always optimal or feasible for many children,” Kohn said. “We can now, for the first time, offer these children and their families a cure, and the chance to live a full, healthy life.”

Defeating ADA-deficient SCID

Children born with SCID, an inherited immunodeficiency, are generally diagnosed when they are about six months old. The disease causes their cells to not create ADA, an enzyme that is critical for producing the healthy white blood cells needed for a normal, fully functioning immune system. About 15 percent of all SCID patients are ADA-deficient.

Currently, there are only two treatment options for children with the disease. They can be injected twice a week with ADA — a lifelong process that is very expensive and often doesn’t return the immune system to optimal levels. Or they can undergo bone marrow transplants from siblings, but bone marrow matches are very rare and can result in the patient’s body rejecting the transplanted cells, which then turn against the child.

Since 2009 and over the course of two multiyear clinical trials, Kohn and his team tested two therapy regimens on 18 children with ADA-deficient SCID. The children’s blood stem cells were removed from their bone marrow and genetically modified to correct the defect.

All 18 patients were cured.

Using a virus delivery system that he developed in his lab in the 1990s, Kohn inserted the corrected gene that produces the missing enzyme into the blood, forming stem cells in the bone marrow. The genetically corrected blood-forming stem cells then produced T cells capable of fighting infection.

Kohn and his colleagues tested, modified and perfected viral delivery as the best method to put the healthy ADA genes back into the bone marrow cells of the patients. With the newly transplanted cells now able to produce the needed enzyme, the research team harnessed the powerful self-renewal potential of stem cells to repopulate the blood stream and the children developed their own new, fully functioning immune systems.

“We were very happy that over the course of several clinical trials and after making refinements and improvements to the treatment protocol, we are now able to provide a cure for babies with this devastating disease using the child’s own cells,” Kohn said.

The researchers’ next step is to seek FDA approval for the gene therapy, with the hope that all children with ADA-deficient SCID will be able to benefit from the treatment. Their cutting-edge research also lays the groundwork for the gene therapy to be tested for treatment of sickle cell disease; clinical trials are set to begin in 2015.

”We’ve been working for the last five years to take the success we’ve had with this stem cell gene therapy for SCID to sickle cell,” Kohn said. “We now have the potential to take the gene that blocks sickling and get it into enough of a patient’s stem cells to block the disease.”

UCLA Dr. Donald Kohn and Evangelina Padilla-Vaccaro

One child’s story

Only weeks after giving birth to fraternal twins in 2012, Alysia Padilla-Vaccaro quickly felt something was wrong with one of her daughters, Evangelina, now 2 years old.

“I was told that it was the stress, or the fear of being a new mom, but I just knew something wasn’t right,” said Padilla-Vaccaro, a resident of Corona, California. “Then I was informed that Evangelina had absolutely no immune system, that anything that could make her sick, would kill her. It was literally the worst time of my life.”

Alysia and her husband, Christian, brought Evangelina to UCLA. Soon after she underwent Kohn’s stem cell gene therapy, Evangelina’s new immune system developed without side effects. Her T cell count began to rise and her ability to fight off illness and infection grew stronger. Then Kohn told Alysia and Christian the good news: For the first time, they could hug and kiss their daughter and take Evangelina outside to meet the world.

“To finally kiss your child on the lips, to hold her, it’s impossible to describe what a gift that is,” Padilla-Vaccaro said. “I gave birth to my daughter, but Dr. Kohn gave my baby life.”

The research was supported by grants from the FDA, the California Institute for Regenerative Medicine and the National Institutes of Health, including the National Heart, Lung and Blood Institute; the National Institute of Allergy and Infectious Diseases; and the National Center for Advancing Translational Science.

Additional funding was provided by UCLA, including the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, the Jonsson Comprehensive Cancer Center, the Children’s Discovery and Innovation Institute, the department of microbiology, immunology and molecular genetics, and the department of pediatrics at the David Geffen School of Medicine.

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Anti-leukemia drug also may work against ovarian cancer


Findings extend anti-cancer potential of monoclonal antibody developed at UC San Diego.

An antibody therapy already in clinical trials to treat chronic lymphocytic leukemia (CLL) also may prove effective against ovarian cancer – and likely other cancers as well, report researchers at the UC San Diego School of Medicine in a study published in today’s (Nov. 17) online early edition of the Proceedings of the National Academy of Sciences (PNAS).

The findings extend the anti-cancer potential of an experimental monoclonal antibody called cirmtuzumab, developed at UC San Diego Moores Cancer Center by Thomas Kipps, M.D., Ph.D., and colleagues. Cirmtuzumab is currently in a first-in-human phase one clinical trial to assess its safety and efficacy in treating CLL.

Cirmtuzumab targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumor growth and metastasis, the latter being responsible for 90 percent of all cancer-related deaths.

Because normal adult cells do not express ROR1, scientists suspect ROR1 is a specific biomarker of cancer cells in general and cancer stem cells in particular. Because it appears to drive tumor growth and disease spread, they believe it also presents an excellent target for anti-cancer therapies. Earlier research by Kipps and colleagues has shown a link between ROR1 and both breast cancer and CLL.

In their latest PNAS paper, Kipps and colleagues investigated whether cirmtuzumab also might be effective against ovarian cancer, which has rebuffed efforts to find a cure or long-term remedy. Most ovarian cancer patients initially respond well to standard chemotherapy, sometimes appearing to become disease-free, but 85 percent relapse within two years after systemic treatment, often with a more aggressive and disseminated form of the disease.

More than 21,000 women are diagnosed with ovarian cancer annually; more than 14,000 die from the disease each year. The 5-year survival rate after diagnosis is 44.6 percent.

The Moores Cancer Center team found that ovarian cancer stem cells, which are thought to be responsible for cancer recurrence and metastasis and are largely resistant to standard chemotherapies, singularly express ROR1. Patients whose tumors had high levels of ROR1 experienced more aggressive forms of ovarian cancer. They had higher rates of relapse and shorter median survival times than patients with lower levels of ROR1.

“ROR1 is used by embryo cells to migrate and to develop new organs,” said Kipps. “Cancer stem cells subsequently use ROR1 for their own growth and dissemination throughout the body. They are essentially the seeds of the cancer. The more seeds a tumor has, the greater its ability to recur after therapy or metastasize.”

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New genetic links in autism revealed


For answers, UC San Diego researchers turn to mice, stem cells and the ‘tooth fairy.’

Alysson Muotri, UC San Diego

With the help of mouse models, induced pluripotent stem cells (iPSCs) and the “tooth fairy,” researchers at the UC San Diego School of Medicine have implicated a new gene in idiopathic or non-syndromic autism. The gene is associated with Rett syndrome, a syndromic form of autism, suggesting that different types of autism spectrum disorder (ASD) may share similar molecular pathways.

The findings are published in today’s (Nov. 11) online issue of Molecular Psychiatry.

“I see this research as an example of what can be done for cases of non-syndromic autism, which lack a definitive group of identifying symptoms or characteristics,” said principal investigator Alysson Muotri, Ph.D., associate professor in the UC San Diego departments of pediatrics and cellular and molecular medicine. “One can take advantage of genomics to map all mutant genes in the patient and then use their own iPSCs to measure the impact of these mutations in relevant cell types. Moreover, the study of brain cells derived from these iPSCs can reveal potential therapeutic drugs tailored to the individual. It is the rise of personalized medicine for mental/neurological disorders.”

But to effectively exploit iPSCs as a diagnostic tool, Muotri said researchers “need to compare neurons derived from hundreds or thousands of other autistic individuals.” Enter the “Tooth Fairy Project,” in which parents are encouraged to register for a “Fairy Tooth Kit,” which involves sending researchers like Muotri a discarded baby tooth from their autistic child. Scientists extract dental pulp cells from the tooth and differentiate them into iPSC-derived neurons for study.

“There is an interesting story behind every single tooth that arrives in the lab,” said Muotri.

The latest findings, in fact, are the result of Muotri’s first tooth fairy donor. He and colleagues identified a de novo or new disruption in one of the two copies of the TRPC6 gene in iPSC-derived neurons of a non-syndromic autistic child. They confirmed with mouse models that mutations in TRPC6 resulted in altered neuronal development, morphology and function. They also noted that the damaging effects of reduced TRPC6 could be rectified with a treatment of hyperforin, a TRPC6-specific agonist that acts by stimulating the functional TRPC6 in neurons, suggesting a potential drug therapy for some ASD patients.

The researchers also found that MeCP2 levels affect TRPC6 expression. Mutations in the gene MeCP2, which encodes for a protein vital to the normal function of nerve cells, cause Rett syndrome, revealing common pathways among ASD.

“Taken together, these findings suggest that TRPC6 is a novel predisposing gene for ASD that may act in a multiple-hit model,” Muotri said. “This is the first study to use iPSC-derived human neurons to model non-syndromic ASD and illustrate the potential of modeling genetically complex sporadic diseases using such cells.”

For more information on the Tooth Fairy Project, visit http://muotri.ucsd.edu.

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Benchmark proposed for better replication of natural stem cell development in lab


UCLA researchers have developed a standard to assess how closely stem cell culture conditions in lab resemble a developing embryo.

Image by Guoping Fan Lab, UCLA

In a study that could provide the foundation for scientists to more precisely replicate natural stem cell development in an artificial environment, researchers at the UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have established a standard to assess how conditions used to procure stem cells in the lab compare to those found in a human embryo.

The study, which was led by Guoping Fan, professor of human genetics at David Geffen School of Medicine at UCLA, was published in the October edition of the journal Cell Stem Cell.

Pluripotent stem cells are cells that can transform into almost any cell in the human body. Scientists have long cultured them in the laboratory (in vitro) using different methods and under a variety of conditions. Though it has been known that culture techniques can affect what kind of cells pluripotent stem cells eventually become, no “gold standard” has yet been established to help scientists determine how the artificial environment can more closely replicate that found in a natural state (in vivo).

“When you have culture conditions that more consistently match a non-artificial environment, you have the potential for a much better reflection of what is going on in actual human development,” said Kevin Huang, postdoctoral fellow in Fan’s lab and a lead author of the study.

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Stem cell therapy coming of age


With first clinical trials, UC San Diego pushes stem cell therapies into new era.

Photos by Erik Jepsen, UC San Diego

In 2004, the therapeutic potential of stem cells persuaded more than 7 million Californians to approve Proposition 71, which allocated a whopping $3 billion for research and development of stem cell-based drugs and therapies that might someday address a medical dictionary’s worth of diseases and conditions.

Now, stem cell research is being put to the test in full force as years of cellular and animal studies make the leap to human clinical trials—a requisite step before any new drug or therapy is approved for market. Nowhere is this progress more visible than at UC San Diego, which in recent weeks has launched the three first stem-cell-based clinical trials in patients to pursue potential treatments for spinal cord injury, Type 1 diabetes and chronic lymphocytic leukemia.

And last week, the California Institute for Regenerative Medicine (CIRM), the state stem cell agency established by Prop.71, named the Sanford Stem Cell Clinical Center at UC San Diego Health System one of three “alpha clinics,” a highly sought-after designation that comes with an $8 million grant to further speed stem cell clinical development. The other two alpha clinic sites are City of Hope hospital near Los Angeles and UCLA, which is partnering with UC Irvine.

“A UC San Diego alpha clinic will provide a vital infrastructure for establishing a comprehensive regenerative medicine clinical hub that can support the unusual complexity of first-in-human stem cell-related clinical trials,” said Dr. Catriona Jamieson, deputy director of the Sanford Stem Cell Clinical Center, director of the UC San Diego Moores Cancer Center stem cell program and the alpha clinic grant’s principal investigator.

“The designation is essential in much the same manner that comprehensive cancer center status is an assurance of scientific rigor and clinical quality. It will attract patients, funding agencies and study sponsors to participate in, support and accelerate novel stem cell clinical trials and ancillary studies for a range of arduous diseases.”

Lawrence Goldstein, director of the UC San Diego Stem Cell Program and Sanford Center

Such work is well underway. Last week, doctors at UC San Diego and Veterans Affairs San Diego Healthcare System, in collaboration with the San Diego-based biotechnology firm ViaCyte, Inc., treated the first patient in an unprecedented phase one-two trial of a stem-cell-derived therapy for patients with Type 1 diabetes. The trial involves implanting specially encapsulated embryonic stem-cell-derived cells under the skin where it’s hoped they will mature into pancreatic beta and other cells able to produce a continuous supply of needed insulin and other substances.

Last month, a 26-year-old woman paralyzed in a car accident a year ago successfully underwent the first experimental procedure to test whether neural stem cells injected at the site of a spinal cord injury is safe and could be an effective treatment. It is hoped that the procedure – the first of four in the phase one trial sponsored by the Sanford Center and Maryland-based Neuralstem Inc. – will ultimately lead to a treatment in which transplanted neural stem cells will develop into new neurons that bridge the gap created by an injury, replace severed or lost nerve connections and restore at least some motor and sensory function.

Also last month, researchers at UC San Diego Moores Cancer Center and the Sanford Center treated the first participant in a novel phase one trial to assess the safety of a monoclonal antibody treatment that targets cancer stem cells in patients with chronic lymphocytic leukemia, the most common form of blood cancer.

“What we are seeing after years of work is the rubber hitting the road,” said Lawrence Goldstein, director of the UC San Diego Stem Cell Program and Sanford Center. “These are three very ambitious and innovative trials. Each followed a different development path; each addresses a very different disease or condition. It speaks to the maturation of stem cell science that we’ve gotten to the point of testing these very real medical applications in people.”

Goldstein noted that the number of patients involved in these first trials is small. Their focus is upon treatment with low doses to assess safety, but also with hope of patient benefit. As these trials progress – and additional trials are launched – Goldstein predicts greater numbers of patients will be enrolled at UC San Diego, the Sanford Center and elsewhere.

Achieving alpha clinic status should help, he said. One element of the new grant is expanded public outreach to raise awareness and understanding of stem cell science, in part to combat what Goldstein calls “stem cell tourism” and the marketing of unproven, unregulated and potentially dangerous therapies.

“Clinical trials are the fastest and safest way to develop therapies that are truly safe and that actually work. You want to prove that a new therapy will work for more than just a single, random patient. These alpha clinic awards not only provide valuable support that will help accelerate experimental stem cell therapies into clinical trials, they also bring with them a ‘stamp of approval’ that our center meets important standards set by peers for testing of stem cell therapy trials.”

The alpha grant reflects CIRM’s continued support for UC San Diego’s stem cell research and development efforts. Since 2004, CIRM has approved 74 awards totaling more than $147 million to UC San Diego stem cell scientists and programs. The three clinical trials launched are just the first of many to come, said alpha clinic principal investigator Jamieson. Other trials for heart failure, amyotrophic lateral sclerosis (Lou Gehrig’s disease) and blindness are in the planning stages.

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Anti-cancer drug found effective vs. common stem cell transplant complication


Trial shows that bortezomib provides better outcomes than existing treatments.

Researchers at UC Davis have found that the drug bortezomib effectively treats chronic graft-versus-host disease (GVHD), a common and debilitating side effect from allogeneic hematopoietic stem cell transplants. The trial showed that bortezomib provides better outcomes than existing treatments and does not impair the immune response against residual cancer cells, or the graft-versus-tumor effect (GVT).

“Bortezomib helped a group of patients who desperately needed a treatment, having failed multiple different therapies,” said UC Davis hematologist and associate professor Mehrdad Abedi, lead author on the paper. “The drug fights chronic graft-versus host disease, and unlike other GVHD therapies such as steroid, cyclosporine or mycophenolate, it treats chronic GVHD without dampening the graft-versus-tumor effect, which can be critically important to help patients avoid relapse. In fact, because bortezomib is an anti-cancer drug, it potentially attacks cancer cells in its own right.”

The trial results were published in October in the journal Blood.

Chronic GVHD strikes patients who have received stem cell transplants from donors, commonly called allogeneic transplants. Although the transplants are close matches, they are not identical, and donor cells can attack the recipient, damaging skin, lungs, kidneys and other organs, which can be life threatening.

Developed by Millennium Pharmaceuticals, bortezomib has been used to treat multiple myeloma, leukemia and lymphoma. The drug also has been studied against acute GVHD, making it a promising option against the chronic version of the disease.

The researchers first studied bortezomib in mice, in which the drug delivered excellent results.

The investigation, in collaboration with William Murphy, professor and acting chair of the Department of Dermatology and a co-senior author, found that bortezomib suppresses the donor immune cells that cause GVHD.

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Two UC centers named stem cell ‘alpha clinics’


Designation will help speed development of treatments.

Image by UCLA Broad Stem Cell Research Center

In a push to further speed clinical development of emerging stem cell therapies, Sanford Stem Cell Clinical Center at UC San Diego Health System and a joint UC Irvine-UCLA alliance were named today (Oct. 23) two of three new “alpha clinics” by the state’s stem cell agency.

The announcement, made at a public meeting in Los Angeles of the California Institute for Regenerative Medicine Governing Board, includes an award of $8 million for each of the three sites. The other alpha grant recipient is the City of Hope hospital near Los Angeles.

“A UC San Diego alpha clinic will provide vital infrastructure for establishing a comprehensive regenerative medicine clinical hub that can support the unusual complexity of first-in-human stem cell-related clinical trials,” said Dr. Catriona Jamieson, associate professor of medicine at UC San Diego School of Medicine, deputy director of the Sanford Stem Cell Clinical Center, director of the UC San Diego Moores Cancer Center stem cell program and the alpha clinic grant’s principal investigator.

“The designation is essential in much the same manner that comprehensive cancer center status is an assurance of scientific rigor and clinical quality. It will attract patients, funding agencies and study sponsors to participate in, support and accelerate novel stem cell clinical trials and ancillary studies for a range of arduous diseases.”

The alpha clinics are intended to create the long-term, networked infrastructure needed to launch and conduct numerous, extensive clinical trials of stem cell-based drugs and therapies in humans, including some developed by independent California-based investigators and companies. These trials are requisite before any new drug or treatment can be approved for clinical use.

Meanwhile, UCLA’s Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research and UC Irvine’s Sue & Bill Gross Stem Cell Research Center will launch a collaborative stem cell clinic. The joint entity will conduct clinical trials of investigational stem cell therapies and provide critical resources and expertise via the creation of a world-class, state-of-the-art infrastructure supporting clinical research.

The grant reviewers lauded the UCLA/UCI consortium’s “impressive and multidimensional team of experienced personnel” that will expand “access to patients, attracting national and international clinical trials and accelerating future trials in the pipeline.”

The initial stem cell trials supported by the UCLA/UCI Alpha Stem Cell Clinic will be two UCLA projects using blood-forming stem cells. The first trial will test a stem cell-based gene therapy for patients with “bubble baby disease,” also called severe combined immune deficiency, in which babies are born without an immune system. Under the direction of Dr. Donald Kohn, the clinical trial will use the baby’s own stem cells with an inserted gene modification to correct the defect and promote the creation of an immune system. The second clinical trial, under the direction of Dr. Antoni Ribas, will use a patient’s own genetically modified blood-forming stem cells to engineer and promote an immune response to melanoma and sarcomas.

“This CIRM Alpha Stem Cell Clinic grant is an important acknowledgement of our cutting-edge research and will help us to advance the design, testing and delivery of effective and safe stem cell-based therapies,” said Dr. Owen Witte, professor and director of the Broad Stem Cell Research Center. “The implementation of a standard of excellence in clinical research will improve healthcare and the lives of patients far beyond the longevity of individual trials.”

Potential clinical studies at UCI, such as those being considered for retinitis pigmentosa and stroke, will also be supported by the clinic.

“UCI has established a strong preclinical stem cell research program, and it’s vital to move ahead to the clinical testing phase,” said Sidney Golub, director of the UCI Sue and Bill Gross Stem Cell Research Center. “To advance treatments in this field, we all have to work together, and that’s what the UCLA-UCI Alpha Stem Cell Clinic program represents.”

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