Human neural stem cells restore motor function in mice with chronic spinal cord injury

UCI study is first to show reversal of long-term hind-limb paralysis

A UC Irvine study is the first to demonstrate that human neural stem cells can restore mobility in cases of chronic spinal cord injury, suggesting the prospect of treating a much broader population of patients.

Previous breakthrough stem cell studies have focused on the acute, or early, phase of spinal cord injury, a period of up to a few weeks after the initial trauma when drug treatments can lead to some functional recovery.

The UCI study, led by Aileen Anderson and Brian Cummings of the Sue and Bill Gross Stem Cell Research Center, is significant because the therapy can restore mobility during the later chronic phase, the period after spinal cord injury in which inflammation has stabilized and recovery has reached a plateau. There are no drug treatments to help restore function in such cases.

The study appears in the open-access, peer-reviewed journal PLoS ONE and is available online.

The Anderson-Cummings team transplanted human neural stem cells into mice 30 days after a spinal cord injury caused hind-limb paralysis. The cells then differentiated into neural tissue cells, such as oligodendrocytes and early neurons, and migrated to spinal cord injury sites. Three months after initial treatment, the mice demonstrated significant and persistent recovery of walking ability in two separate tests of motor function when compared to control groups.

“Human neural stem cells are a novel therapeutic approach that holds much promise for spinal cord injury,” said Anderson, associate professor of physical medicine & rehabilitation and anatomy & neurobiology at UCI. “This study builds on the extensive work we previously published in the acute phase of injury and offers additional hope to those who are paralyzed or have impaired motor function.”

“About 1.3 million individuals in the U.S. are living with chronic spinal cord injury,” added Cummings, associate professor of physical medicine & rehabilitation and anatomy & neurobiology. “This latest study provides additional evidence that human neural stem cells may be a viable treatment approach for them.”

The research is the latest in a series of collaborative studies conducted since 2002 with StemCells Inc. that have focused on the use of StemCells’ human neural stem cells in spinal cord injury and resulted in multiple co-authored publications. StemCells Inc., based in Palo Alto, Calif., is engaged in the research, development and commercialization of stem cell therapeutics and tools for use in stem cell-based research and drug discovery.

According to Dr. Stephen Huhn, vice president and head of the central nervous system program at StemCells Inc., “the strong preclinical data we have accumulated to date will enable our transition to a clinical trial, which we plan to initiate in 2011.”

Desirée Salazar of UC San Diego, Nobuko Uchida of StemCells Inc. and Frank P.T. Hamers of the Tolbrug Rehabilitation Centre in ’s-Hertogenbosch, Netherlands, also contributed to the study, which received National Institutes of Health and California Institute for Regenerative Medicine support.

Clinical trial of UCI-created stem cell treatment gets FDA go-ahead

Hub of hope and healing

What excites Nan Luke about the new Sue & Bill Gross Hall: A CIRM Institute at UC Irvine isn’t the spacious clinic or pristine laboratories, offices and meeting rooms. It’s the interaction that will take place there between patients like herself and researchers. Both are driving the effort to see if and how stem cells can treat a host of human diseases, disorders and injuries.

Dedicated May 14, the institute will serve as a hub for stem cell research and education in the region and house the Sue & Bill Gross Stem Cell Research Center. The $80-million, 100,000-square-foot building was designed to facilitate contact between patients in the first-floor clinic and rehabilitation center and stem cell researchers in first-, second- and third-floor labs.

“As a multiple sclerosis patient and advocate, I’m extremely heartened that every day, when researchers come to work, they’ll see what’s happening in the clinic and be reminded of what’s at stake,” says Luke, an Irvine attorney and board member of the National Multiple Sclerosis Society’s Pacific South Coast chapter. “It’s also exciting for the patients, who will feel, ‘Wow, we’re here all together in this new facility, and we matter.’”

UCI scientists have been striving to unlock the potential of stem cells for more than 30 years. Today at least 60 campus researchers in medicine, biology, engineering and other disciplines work collaboratively to advance stem cell research and teaching. They’ve made the university an international leader in the field, offering hope to millions who suffer from about 70 conditions stem cells may be able to treat.

The centerpiece of their efforts is Sue & Bill Gross Hall, the result of a successful public-private partnership to transform modern medicine. CIRM — the California Institute for Regenerative Medicine, created in 2004 through Proposition 71 to fund stem cell research — allocated $27.2 million to the project. Laguna Beach philanthropists Sue and Bill Gross made an initial $10-million gift that the campus leveraged to attract CIRM support.

“It’s fantastic that we’ve moved ahead so quickly,” says Peter Donovan , director of the Sue & Bill Gross Stem Cell Research Center. “Historically, UCI has had a tremendous research faculty and environment for collaborative work in regenerative medicine. We know stem cell research represents hope to millions of people, and we aspire to fully deliver on its potential.”

UCI’s recent stem cell efforts include:

• A pioneering therapy developed by renowned neuroscientist Hans Keirstead that restores bodily function lost to spinal cord injury, which could form the basis of the first federally approved embryonic stem cell clinical trial in humans;
• Research led by Frank LaFerla , Institute for Memory Impairments and Neurological Disorders director, showing for the first time that neural stem cells rescue memory in mice with advanced Alzheimer’s disease;
• Molecular biologist Tom Lane and colleagues’ exploration of stem cells’ utility in regenerating MS-ravaged nerve tissue;
• Development of new human stem cell lines by neurobiologist Leslie M. Thompson to better understand and treat Huntington’s disease.

Fueling this work are the input and encouragement of people like Luke, a member of the Sue & Bill Gross Stem Cell Research Center’s patient advocacy committee — a group of nine Orange County residents who either suffer from a disease or have a family member who does.

“What fills me with hope about stem cells is that the research deals with the basics of the human body and can be applied to different illnesses and injuries,” says Luke, who has had MS for 20 years. “I’m excited knowing a finding that improves the quality of life for someone with a spinal cord injury could possibly help people with MS or Parkinson’s.”

“The advocates keep us focused on what this is all about,” says Susan V. Bryant, vice chancellor for research and a member of CIRM’s governing board. “They’ve been very influential and have positively changed our approach to translating our research into potential therapies. Once you make that connection with the advocacy community, it’s impossible not to take it into account. You want to buckle down and keep pushing.”

Immune system helps transplanted stem cells navigate in central nervous system

UCI study provides blueprint for enhanced treatment of inflammatory diseases like MS

By discovering how adult neural stem cells navigate to injury sites in the central nervous system, UC Irvine researchers have helped solve a puzzle in the creation of stem cell-based treatments: How do these cells know where to go?

Tom Lane and Kevin Carbajal of the Sue & Bill Gross Stem Cell Research Center found the answer with the body's immune system.

Their study not only identifies an important targeting mechanism in transplanted stem cells but also provides a blueprint for engineering stem cell-based therapies for multiple sclerosis and other chronic neurological diseases in which inflammation occurs. Results appear in this week's early online edition of the Proceedings of the National Academy of Sciences.

"Previously, we've seen that adult neural stem cells injected into the spinal column knew, amazingly, exactly where to go,"said Lane, Chancellor's Fellow and professor of molecular biology & biochemistry. "We wanted to find what directed them to the right injury spots."

The researchers used adult neural stem cells to treat mice with a disease similar to MS that destroys myelin, the protective tissue coating on nerves, causing chronic pain and loss of motor function. Adult neural stem cells have shown the ability to change -- or differentiate -- into oligodendrocytes, the building blocks of myelin, and repair or replace affected tissue.

In the mice, inflammatory cells -- reacting to the virally induced nerve damage -- were observed activating receptors on the adult neural stem cells. These CXCR-4 receptors, in turn, recruited chemokine proteins called CXCL-12 that guided the stem cells to specific sites. Chemokines are produced in acute and chronic inflammation to help mobilize white blood cells.

As the stem cells migrated through the central nervous system, they began to transform into the precursor cells for oligodendrocytes. Latching onto their repair sites, they continued the differentiation process. Three weeks after the initial treatment, 90 percent of the cells had grown into fully formed oligodendrocytes.

In earlier work, Lane and colleagues demonstrated that adult neural stem cell treatments improved motor function in mice with chronic MS symptoms.

"In this study, we've taken an important step by showing the navigational cues in an inflammatory environment like MS that guide stem cells,"said Lane. "Hopefully, these cues can be incorporated into stem cell-based treatments to enhance their ability to repair injury."

Chris Schaumburg and Joy Kane of UCI and Dr. Robert Strieter of the University of Virginia participated in the study, which received support from the National Institutes of Health and the National Multiple Sclerosis Society.

Lane recently received a Collaborative MS Research Center Award from the National Multiple Sclerosis Society to assemble a team to investigate the use of cell replacement therapy to regenerate MS-ravaged nerve tissue.

UCI researchers create retina from human embryonic stem cells

Complex tissue structure - a first - offers hope to millions with degenerative eye disorders.

UC Irvine scientists have created an eight-layer, early stage retina from human embryonic stem cells, the first three-dimensional tissue structure to be made from stem cells.

It also marks the first step toward the development of transplant-ready retinas to treat eye disorders such as retinitis pigmentosa and macular degeneration that affect millions.

"We made a complex structure consisting of many cell types," said study leader Hans Keirstead of the Reeve-Irvine Research Center and the Sue & Bill Gross Stem Cell Research Center at UCI. "This is a major advance in our quest to treat retinal disease."

In previous studies on spinal cord injury, the Keirstead group originated a method by which human embryonic stem cells could be directed to become specific cell types, a process called differentiation. Results of those studies are leading to the world's first clinical trial using a stem cell-based therapy for acute spinal cord injury.

In this study, the Keirstead team utilized the differentiation technique to create the multiple cell types necessary for the retina. The greatest challenge, Keirstead said, was in the engineering. To mimic early stage retinal development, the researchers needed to build microscopic gradients for solutions in which to bathe the stem cells to initiate specific differentiation paths.

"Creating this complex tissue is a first for the stem cell field," Keirstead said. "Dr. Gabriel Nistor in our group addressed a really interesting scientific problem with an engineering solution, showing that gradients of solutions can create complex stem cell-based tissues."

The retina is the inside back layer of the eye that records the images a person sees and sends them via the optic nerve from the eye to the brain. Retinal diseases are particularly damaging to sight. More than 10 million Americans suffer from macular degeneration, the leading cause of blindness in people over 55. About 100,000 have retinitis pigmentosa, a progressive, genetic disorder that usually manifests in childhood.

"What's so exciting with our discovery," Keirstead said, "is that creating transplantable retinas from stem cells could help millions of people, and we are well on the way."

The UCI researchers are testing the early-stage retinas in animal models to learn how much they improve vision. Positive results would lead to human clinical trials.

The study appears online in the Journal of Neuroscience Methods. Nistor, Magdalene J. Seiler, Fengrong Yan and David Ferguson contributed to the effort, supported by The Lincy Foundation and private donations to the Keirstead group.

The FDA has approved a stem cell therapy based on work led by UCI biologist Hans Keirstead. The treatment for acute spinal cord injury will become the world's first embryonic stem cell therapy tested in humans.

FDA and Geron Corp. Reach Agreement on Spinal Injury Drug Trial Pioneered at UC Irvine

Oct 30 - Stem cell research company Geron Corp (GERN.O) said it reached an agreement with U.S. health regulators which may enable it to restart the early stage trials of its cell therapy to treat complete thoracic spinal cord injury.

The treatment was pioneered at UC Irvine by Dr. Hans Keirstead, as part of a joint UC Discovery grant with Geron Corporation. The trial represents the first embryonic stem cell treatment tested in humans and has initially focused on acute thoracic spinal cord injuries.

Recent results from a cervical rodent study published by Dr. Keirstead and doctoral candidate and lead author Jason Sharp in Stem Cells discovered that stem cells not only rebuild myelin, but prevent tissue death and trigger nerve fiber re-growth. The cells also suppress the immune response, causing an increase in anti-inflammatory molecules.

UCI scientist Hans Keirstead hopes the data will prompt the FDA to authorize clinical testing of the treatment in people with both types of spinal cord damage. About 52 percent of spinal cord injuries are cervical and 48 percent thoracic.

In August, the U.S. Food and Drug Administration (FDA) placed a clinical hold on Geron's investigational new drug application after some of the animals developed cysts in the injury site.

While the early stage trial still remains on clinical hold, a recent agreement with the FDA outlines what is necessary to move the spinal cord injury program forward, Merriman Curhan Ford analyst Joe Pantginis said in a note to clients.

"Geron, which expects to re-initiate the early stage trial in the third quarter of 2010, said the FDA has advised that positive data from an ongoing preclinical study using its product can be used to support both release of the clinical hold and the drug's expansion to cervical patients.

Adopted from source - Anand Basu, Reporter, Bangalore Thompson Reuters 2009.

UCI behind world's first embryonic stem cell study in humans

FDA approves Geron Corp. clinical trial for spinal cord injury treatment therapy developed at UC Irvine that made paralyzed rats walk again will become the world's first embryonic stem cell treatment tested in humans.

The U.S. Federal Drug Administration has approved the therapy, based on work by a research team led by Hans Keirstead, co-director of the UCI Sue and Bill Gross Stem Cell Research Center, for a clinical trial in patients with acute spinal cord injury.

Geron Corp. of Menlo Park, Calif., will conduct the clinical trial.

"This trial was approved only after rigorous safety testing and consultation of countless experts in the field," Keirstead said. "Any benefit to the patient, even an incremental one, would be a resounding victory."

The therapy contains human embryonic stem cells destined to become spinal cord cells called oligodendrocytes. These are the building blocks of myelin, the biological insulation for nerve fibers that is critical for maintaining electrical conduction in the central nervous system. When myelin is stripped away, through injury or disease, paralysis can occur.

In laboratory tests, Keirstead and his colleague, Dr. Gabriel Nistor, developed a technique for prompting human embryonic stem cells to develop into oligodendrocyte cells.

Injected into rats with spinal cord injuries, the precursor cells turned into oligodendrocytes and migrated to the injured area of the spinal cord. As the cells wrapped around damaged neurons, new myelin tissue formed, allowing electrical conduction to resume and the rats to walk again.

This success, published in the Journal of Neuroscience in 2005, was the subject of dozens of media stories, including a "60 Minutes" segment.

According to Geron, patients eligible for the phase-one trial must have a certain type of spinal cord damage and be willing to receive injections 7-14 days after injury. Geron has selected up to seven U.S. medical centers that may participate in the study.

UCI has a robust stem cell research program that has received more than $52 million from the California Institute for Regenerative Medicine. UCI's scientists are pioneers in regeneration, large-scale production of specialized cells with very high purity, and methods for treating damaged tissues

UCI recently broke ground for a four-story building dedicated to stem cell research. When finished in 2010, the building will house the stem cell center, dozens of laboratory-based and clinical researchers, a stem cell techniques course, a master's program in biotechnology with an emphasis on stem cell research, and programs and activities for patients and public education.

-- Jennifer Fitzenberger, University Communications

UCI AWARDED $27.2 MILLION FOR NEW STEM CELL BUILDING

UC Irvine was awarded $27.2 million from the state to build a new stem cell research facility that will unify and strengthen the campus's fast-growing stem cell biology program and serve as a hub for research in Southern California.

When completed, the three-story, 61,600-square-foot building will house the UCI Sue and Bill Gross Stem Cell Research Center, as many as 26 laboratory-based and clinical researchers, a stem cell techniques course for young scientists, a master's program in biotechnology with an emphasis on stem cell research, and an array of programs and activities that involve and educate patients and the general public.

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UC Irvine researchers have discovered a dramatically improved method for genetically manipulating human embryonic stem cells, making it easier for scientists to study and potentially treat thousands of disorders ranging from Huntington's disease to muscular dystrophy and diabetes.

The technique for the first time blends two existing cell-handling methods to improve cell survival rates and increase the efficiency of inserting DNA into cells. The new approach is up to 100 times more efficient than current methods at producing human embryonic stem cells with desired genetic alterations.

"The ability to generate large quantities of cells with altered genes opens the door to new research into many devastating disorders," said Peter Donovan, professor of biological chemistry and developmental and cell biology at UCI, and co-director of the UCI Sue and Bill Gross Stem Cell Research Center. "Not only will it allow us to study diseases more in-depth, it also could be a key step in the successful development of future stem cell therapies.

This study appears online this week in the journal Stem Cells.

Donovan and Leslie Lock, assistant adjunct professor of biological chemistry and developmental and cell biology at UCI, previously identified proteins called growth factors that help keep cells alive. Growth factors are like switches that tell cells how to behave, for example to stay alive, divide or remain a stem cell. Without a signal to stay alive, the cells die.

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