UC Irvine staffer works to end Huntington’s disease.

Frances Saldana, UC Irvine

For two decades, UC Irvine has been on the forefront of Huntington’s disease research and care, and Frances Saldaña is working to keep it that way.

By day, she manages the Corporate Partners program for The Paul Merage School of Business. But Saldaña is better known as a focused and driven advocate for the patients and family members who must endure the terrible consequences of this incurable neurodegenerative disorder.

She shares their pain. Saldaña has lost a husband and her younger daughter to Huntington’s disease, and her other two children are in the late stages of it. “HD is cruel and unfair,” she says. “And we have to end it.”

So along with friends Jean Abdalla and Linda Pimental, who have also lost family members to the disease, Saldaña founded HD CARE to raise awareness and funds for UC Irvine research and clinical care. It’s an official support group of the campus’s Institute for Memory Impairments & Neurological Disorders (UCI MIND), which explores new research and treatments for a spectrum of neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

“Frances is a tireless promoter of HD research and care, and her enthusiasm is infectious,” says Leslie Thompson, a UC Irvine professor of psychiatry & human behavior and neurobiology & behavior who’s recognized as one of the world’s pre-eminent HD researchers. “Her impact is profound.”

Huntington’s disease – a progressive, genetic brain disorder – causes the degeneration of neurons in certain areas of the brain. It’s a familial disease passed from parent to child through a genetic mutation. Symptoms include uncontrolled movements, loss of intellectual capabilities and emotional disturbances. In the U.S. alone, at least 30,000 people have HD, and more than 150,000 others have a 50 percent risk of developing it.

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Findings could have implications for developing new treatments for Parkinson’s, Alzheimer’s.

Confocal micrograph of a primary human fibroblast cell grown in culture stained blue for actin, a highly abundant protein that makes up the cytoskeleton of cells.Energy-producing mitochondria are shown in green.

Repression of a single protein in ordinary fibroblasts is sufficient to directly convert the cells – abundantly found in connective tissues – into functional neurons. The findings, which could have far-reaching implications for the development of new treatments for neurodegenerative diseases like Huntington’s, Parkinson’s and Alzheimer’s, will be published online in advance of the Jan. 17 issue of the journal Cell.

In recent years, scientists have dramatically advanced the ability to induce pluripotent stem cells to become almost any type of cell, a major step in many diverse therapeutic efforts. The new study focuses upon the surprising and singular role of PTB, an RNA-binding protein long known for its role in the regulation of alternative RNA splicing.

In in vitro experiments, scientists at the UC San Diego School of Medicine and Wuhan University in China describe the protein’s notable regulatory role in a feedback loop that also involves microRNA – a class of small molecules that modulate the expression of up to 60 percent of genes in humans. Approximately 800 miRNAs have been identified and characterized to various degrees.

One of these miRNAs, known as miR-124, specifically modulates levels of PTB during brain development. The researchers found that when diverse cell types were depleted of PTB, they became neuronal-like cells or even functional neurons – an unexpected effect. The protein, they determined, functions in a complicated loop that involves a group of transcription factors dubbed REST that silences the expression of neuronal genes in non-neuronal cells.

According to principal investigator Xiang-Dong Fu, Ph.D., professor of cellular and molecular medicine at UC San Diego, it’s not known which neuronal signal or signals turn on the loop, which in principle can happen at any point in the circle. But the ability to artificially manipulate PTB levels in cells, inducing them to become neurons, offers tantalizing possibilities for scientists seeking new treatments for an array of neurodegenerative diseases.

It is estimated that over a lifetime, 1 in 4 Americans will suffer from a neurodegenerative disease, from Alzheimer’s and Parkinson’s to multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).

“All of these diseases are currently incurable. Existing therapies focus on simply trying to preserve neurons or slow the rate of degeneration,” said Fu. “People are working with the idea of replacing lost neurons using embryonic stem cells, but there are a lot of challenges, including issues like the use of foreign DNA and the fact that it’s a very complex process with low efficiency.”

Fu explained that REST is expressed in cells everywhere except in neurons. PTB is itself a target of miR-124, but also acts as a break for this microRNA to attack other cellular targets that include REST, which is responsible for repressing miR-124.

In non-neuronal cells, REST keeps miR-124 down and PTB enforces this negative feedback loop, but during neural induction, miR-124 is induced, which diminishes PTB, and without PTB as a break, REST is dismantled, and without REST, additional miR-124 is produced. This loop therefore becomes a positive feed forward, which turns non-neuronal cells into neurons.

“If we learn how to manipulate PTB, which appears to be a kind of master regulator, we might eventually be able to avoid some of these problems by creating new neurons in patients using their own cells adjacent deteriorating neurons,” said Fu.

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Initial results in mice could lead to new way to fight neurodegenerative diseases.

Mitochondria are labeled red and green, and the nucleus is blue, in this neuron isolated from a Huntington's disease mouse model.

There’s new hope in the fight against Huntington’s disease. A group of researchers that includes scientists from the U.S. Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab) have designed a compound that suppresses symptoms of the devastating disease in mice.

The compound is a synthetic antioxidant that targets mitochondria, an organelle within cells that serves as a cell’s power plant. Oxidative damage to mitochondria is implicated in many neurodegenerative diseases including Alzheimer’s, Parkinson’s and Huntington’s.

The scientists administered the synthetic antioxidant, called XJB-5-131, to mice that have a genetic mutation that triggers Huntington’s disease. The compound improved mitochondrial function and enhanced the survival of neurons. It also inhibited weight loss and stopped the decline of motor skills, among other benefits. In short, the Huntington’s mice looked and behaved like normal mice.

Based on their findings, the scientists believe that XJB-5-131 is a promising therapeutic compound that deserves further investigation as a way to fight neurodegenerative diseases.

They report their research in a paper that appears online Nov. 1 in the journal Cell Reports.

“The compound was very successful. More research is needed, but it has the real potential to make an impact in treating neurodegenerative disorders,” says Cynthia McMurray of Berkeley Lab’s Life Sciences Division. She conducted the research with other Berkeley Lab researchers, including Zhiyin Xun, and scientists from the University of Pittsburgh.

Huntington’s disease is a genetic disorder in which neurons in certain parts of the brain waste away. Symptoms of the disease typically appear in mid-life. These include loss of muscle coordination and cognitive decline. There is no cure. Currently, patients are prescribed antidepressants or compounds that reduce the loss of motor coordination, neither of which delays the disease’s progression.

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Grants target CLI, Huntington’s, osteoporosis, melanoma, spinal cord injury.

The California Institute for Regenerative Medicine has approved funding for projects to be led by (from left) Nancy Lane, Vicki Wheelock, John Laird and Jan Nolta of UC Davis.

The University of California received or shared five grants totaling $93.1 million today (July 26) from the state’s stem cell agency to speed therapies to patients suffering from Huntington’s disease, critical limb ischemia, osteoporosis, melanoma and spinal cord injury. Three grants went to UC Davis researchers, one to UCLA and one was shared by UC Irvine.

The California Institute for Regenerative Medicine awarded a total of $150 million to help move promising stem cell-based therapies from laboratory research to human clinical trials.

Overall, CIRM’s governing board has awarded more than $1.5 billion in stem cell grants, with more than half of the total going to the University of California or UC-affiliated institutions.

CIRM Disease Team Therapy Development Awards:

UC Davis: $53.1 million, including grants of:

• $20 million, led by Nancy Lane, targeting osteoporosis, a bone disease
• $19 million, led by Jan Nolta and Vicki Wheelock , targeting Huntington’s disease, a genetic brain disorder
• $14.1 million, led by John Laird and Jan Nolta, targeting critical limb ischemia, a severe blockage of the arteries

UC Irvine: $20 million for a grant shared by Aileen Anderson and Brian Cummings of UC Irvine and Nobuko Uchida of StemCells Inc., targeting cervical spinal cord injury

UCLA: $20 million for a grant led by Antoni Ribas, targeting melanoma, the most dangerous type of skin cancer

For more information:
CIRM release

Pair helps remove, prevent misfolding of proteins that cause neurodegeneration.

In a paper published in today’s (July 11) online issue of Science Translational Medicine, researchers at the UC San Diego School of Medicine have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington’s disease.

The findings explain a fundamental aspect of how the disease wreaks havoc within cells and provides “clear, therapeutic opportunities,” said principal investigator Albert R. La Spada, M.D., Ph.D., professor of cellular and molecular medicine, chief of the Division of Genetics in the Department of Pediatrics and associate director of the Institute for Genomic Medicine at UC San Diego.

“We think the implications are significant,” said La Spada. “It’s a lead we can vigorously pursue, not just for Huntington’s disease, but also for similar neurodegenerative conditions like Parkinson’s disease and maybe even Alzheimer’s disease.”

In Huntington’s disease, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells, leading to progressive deterioration of involuntary movement control, cognitive decline and psychological problems. More than 30,000 Americans have Huntington’s disease. There are no effective treatments currently to either cure the disease or slow its progression.

La Spada and colleagues focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function.

“It’s all about energy,” La Spada said. “Neurons have a constant, high demand for it. They’re always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity.”

Previous studies by La Spada and others discovered that the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha. “This study confirms that,” La Spada said. More surprising was the discovery that elevated levels of PGC-1alpha in a mouse model of Huntington’s disease virtually eliminated the problematic misfolded proteins.

Specifically, PGC-1alpha influenced expression of another protein vital to autophagy — the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival.

“Mitochondria get beat up and need to be recycled,” La Spada said. “PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. We were unaware of this connection before, because TFEB is a relatively new player, though clearly emerging as a leading actor. We discovered that even without PGC-1alpha induction, TFEB can prevent htt aggregation and neurotoxicity.”

In their experiments, Huntington’s disease mice crossbred with mice that produced greater levels of PGC-1alpha showed dramatic improvement. Production of misfolded proteins was essentially eliminated and the mice behaved normally. “Degeneration of brain cells is prevented. Neurons don’t die,” said La Spada.

PGC-1alpha and TFEB provide two new therapeutic targets for Huntington’s disease, according to La Spada. “If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time. If we could achieve the level of increased function necessary to eliminate misfolded proteins, we might nip the disease process in the bud. That would go a long way toward treating this devastating condition.”

Co-authors are Taiji Tsunemi, Travis D. Ashe and Bradley E. Morrison, Department of Pediatrics, UC San Diego; Kathryn R. Soriano, Jonathan Au and Vincent A. Damian, Department of Laboratory Medicine, University of Washington; Ruben A. Vazquez Roque, Department of Pathology, UC San Diego; Eduardo R. Lazarowski, Department of Medicine, University of North Carolina; and Eliezer Masliah, Departments of Pathology and Neurosciences, UC San Diego.

Funding for this research came, in part, from the Hereditary Disease Foundation, the CHDI and the National Institutes of Health (grant numbers R01 AG033083, R01 NS065874, P01 HL034322, R01 AG018440, R01 NS057096 and R01 AG022074).

UC Irvine, UCSF-affiliated scientists develop model to speed drug development.

Steve Finkbeiner, Gladstone Institutes

>>Related coverage: UC Irvine release

Scientists at UC Irvine, the UC San Francisco-affiliated Gladstone Institutes and an international team of researchers have generated a human model of Huntington’s disease — directly from the skin cells of patients with the disease.

For years, scientists have studied Huntington’s disease primarily in postmortem brain tissue or laboratory animals modified to mimic the disease. Today (June 28), in Cell Stem Cell, the international team shows how they developed a human model of Huntington’s disease, which causes a diverse range of neurological impairments. The new model should help scientists better understand the development of Huntington’s — and provide better ways to identify and screen potential therapeutics for this devastating disease.

This new model comes at a time of concentrated federal efforts to accelerate solutions for diseases — including a number of debilitating conditions that touch only small percentages of the population. Last year, the National Institutes of Health consolidated its efforts to attack rare diseases under the new National Center for Translational Sciences.

Huntington’s is such a rare disease, although it is the most common inherited neurodegenerative disorder. It afflicts approximately 30,000 people in the United States — with another 75,000 people carrying the gene that will eventually lead to it. Caused by a mutation in the gene for a protein called huntingtin, the disease damages brain cells so that people with Huntington’s progressively lose their ability to walk, talk, think and reason.

“An advantage of this human model is that we now have the ability to identify changes in brain cells over time — during the degeneration process and at specific stages of brain-cell development,” said Gladstone Senior Investigator Steve Finkbeiner, M.D., Ph.D. “We hope this model will help us more readily uncover relevant factors that contribute to Huntington’s disease and especially to find successful therapeutic approaches.”

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Single treatment produces long-term improvement in animal models, researchers discover.

Stained mouse neurons

With a single drug treatment, researchers at the Ludwig Institute for Cancer Research at the UC San Diego School of Medicine can silence the mutated gene responsible for Huntington’s disease, slowing and partially reversing progression of the fatal neurodegenerative disorder in animal models.

The findings are published in the June 21 print issue of the journal Neuron.

Researchers suggest the drug therapy, tested in mouse and non-human primate models, could produce sustained motor and neurological benefits in human adults with moderate and severe forms of the disorder. Currently, there is no effective treatment.

Huntington’s disease afflicts approximately 30,000 Americans, whose symptoms include uncontrolled movements and progressive cognitive and psychiatric problems. The disease is caused by the mutation of a single gene, which results in the production and accumulation of toxic proteins throughout the brain.

Don W. Cleveland, Ph.D., professor and chair of the UC San Diego Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research, and colleagues infused mouse and primate models of Huntington’s disease with one-time injections of an identified DNA drug based on antisense oligonucleotides (ASOs). These ASOs selectively bind to and destroy the mutant gene’s molecular instructions for making the toxic huntingtin protein.

The singular treatment produced rapid results. Treated animals began moving better within one month and achieved normal motor function within two. More remarkably, the benefits persisted, lasting nine months, well after the drug had disappeared and production of the toxic proteins had resumed.

“For diseases like Huntington’s, where a mutant protein product is tolerated for decades prior to disease onset, these findings open up the provocative possibility that transient treatment can lead to a prolonged benefit to patients,” said Cleveland. “This finding raises the prospect of a ‘huntingtin holiday,’ which may allow for clearance of disease-causing species that might take weeks or months to re-form. If so, then a single application of a drug to reduce expression of a target gene could ‘reset the disease clock,’ providing a benefit long after huntingtin suppression has ended.”

Beyond improving motor and cognitive function, researchers said the ASO treatment also blocked brain atrophy and increased lifespan in mouse models with a severe form of the disease. The therapy was equally effective whether one or both huntingtin genes were mutated, a positive indicator for human therapy.

Cleveland noted that the approach was particularly promising because antisense therapies have already been proven safe in clinical trials and are the focus of much drug development. Moreover, the findings may have broader implications, he said, for other “age-dependent neurodegenerative diseases that develop from exposure to a mutant protein product” and perhaps for nervous system cancers, such as glioblastomas.

Co-authors are first author Holly B. Kordasiewicz, Melissa M. McAlonis, Kimberly A. Pytel and Jonathan W. Artates, Ludwig Institute for Cancer Research and UC San Diego Department of Cellular and Molecular Medicine; Lisa M. Stanek, Seng H. Cheng and Lamya S. Shihabuddin, Genzyme Corporation; Edward V. Wancewicz, Curt Mazur, Gene Hung and C. Frank Bennett, Isis Pharmaceuticals; and Andreas Weiss, Novartis Institutes for BioMedical Research.

Funding for this research came, in part, from the CHDI Foundation.

Stem cells show promise for delivering gene therapy for the currently incurable disease.

Jan Nolta, UC Davis

A team of researchers at the UC Davis Institute for Regenerative Cures has developed a technique for using stem cells to deliver therapy that specifically targets the genetic abnormality found in Huntington’s disease, a hereditary brain disorder that causes progressive uncontrolled movements, dementia and death. The findings, now available online in the journal Molecular and Cellular Neuroscience, suggest a promising approach that might block the disease from advancing.

“For the first time, we have been able to successfully deliver inhibitory RNA sequences from stem cells directly into neurons, significantly decreasing the synthesis of the abnormal huntingtin protein,” said Jan A. Nolta, principal investigator of the study and director of the UC Davis stem cell program and the UC Davis Institute for Regenerative Cures. “Our team has made a breakthrough that gives families affected by this disease hope that genetic therapy may one day become a reality.”

Huntington’s disease can be managed with medications, but currently there are no treatments for the physical, mental and behavioral decline of its victims. Nolta and other experts think the best chance to halt the disease’s progression will be to reduce or eliminate the mutant huntingtin (htt) protein found in the neurons of those with the disease.  RNA interference (RNAi) technology has been shown to be highly effective at reducing htt protein levels and reversing disease symptoms in mouse models.

“Our challenge with RNA interference technology is to figure out how to deliver it into the human brain in a sustained, safe and effective manner,” said Nolta, whose lab recently received funding from the California Institute for Regenerative Medicine to develop an RNAi delivery system for Huntington’s disease. “We’re exploring how to use human stem cells to create RNAi production factories within the brain.”

Huntington’s disease affects more than a quarter of a million Americans. The disorder can be passed down through families even if only one parent has the abnormal huntingtin gene. The disease is caused by a mutation in the gene, which is comprised of an abnormally repeating building block of DNA that appears on the fourth chromosome. While the building block pattern normally repeats up to 28 times on the chromosome, too many repeats cause an abnormal form of protein – known as the huntingtin protein – to be made. The huntingtin protein accumulates in the brain, causing the disease’s devastating progression. Individuals usually develop symptoms in middle age if there are more than 35 repeats. A more rare form of the disease occurs in youth when the abnormal DNA pattern repeats many more times.

The UC Davis research team showed for the first time that inhibitory RNA sequences can be transferred directly from donor cells into target cells to greatly reduce unwanted protein synthesis from the mutant gene. To transfer the inhibitory RNA sequences into their targets, Nolta’s team genetically engineered mesenchymal stem cells (MSCs), which were derived from the bone marrow of unaffected human donors. Over the past two decades, Nolta and her colleagues have shown MSCs to be safe and effective vehicles to deliver enzymes and proteins to other cells. She said finding that MSCs can also transfer RNA molecules directly from cell to cell, in amounts sufficient to reduce levels of a mutant protein by over 50 percent in the target cells, is a discovery that has never been reported before and offers great promise for a variety of disorders.

“Not only is finding new treatments for Huntington’s disease a worthwhile pursuit on its own, but the lessons we are learning are applicable to developing new therapies for other genetic disorders that involve excessive protein development and the need to reduce it,” said Nolta, who recently received a prestigious Transformative Research Grant from the National Institutes of Health to study how mesenchymal stem cells can transfer microRNA and other factors into the cells of damaged tissues, and how that process can be harnessed to treat injuries and disease. “We have high hopes that these techniques may also be utilized in the fight against some forms of amyotrophic lateral sclerosis (Lou Gehrig’s disease) as well as Parkinson’s and other conditions.”

The article, “Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington’s disease affected neuronal cells for reduction of huntingtin,” was co-authored by Scott D. Olson, now with University of Texas Health Sciences Center at Houston. Other authors were Amal Kambal, now at Washington University in St. Louis; and Kari Pollock, Gaela-Marie Mitchell, Heather Stewart, Stefanos Kalomoiris, Whitney Cary, Catherine Nacey and Karen Pepper, with the UC Davis Institute for Regenerative Cures. Funding for the research was provided by the California Institute for Regenerative Medicine and Team KJ.

Finding could offer new avenues for treating a variety of similar conditions.

Steven Finkbeiner

Scientists at the Gladstone Institutes have discovered how a form of the protein linked to Huntington’s disease influences the timing and severity of its symptoms, offering new avenues for treating not only this disease, but also a variety of similar conditions.

In a paper being published today in Nature Chemical Biology, the laboratory of Gladstone Senior Investigator Steven Finkbeiner, M.D., Ph.D., singles out one form of a misfolded protein in neurons that best predicts whether the neuron will die. Neuronal death is key to the development of Huntington’s symptoms — including erratic behavior, memory loss and involuntary muscle movement. This research underscores the value of the cross-disciplinary work done at Gladstone — a leading and independent biomedical–research organization — while revealing techniques that scientists anywhere can apply to conditions involving misfolded proteins, such as Alzheimer’s disease and type 1 diabetes.

“Effective treatments for diseases such as Huntington’s and Alzheimer’s have been slow to develop,” said Finkbeiner, whose research at Gladstone investigates the interactions between genes, neurons and memory. “We hope that our newfound understanding of precisely which misfolded proteins contribute to disease symptoms will speed up drug development for sufferers.”

Huntington’s, an ultimately fataldisease that affects more than a quarter of a million people nationwide,is caused by mutations in the gene that creates the huntingtin, or htt, protein. As the mutated gene produces htt, a segment of the protein called polyglutamine is mistakenly expanded, distorting htt’s natural shape and function. As a result, the misfolded protein malfunctions and can be toxic.

Previous researchinto Huntington’s found that misfolded proteins in the brain lead to the dysfunction and subsequent death of neurons. In this study, Finkbeiner set out to find which misfolded htt types were the most toxic. In laboratory experiments on mice, he and his colleagues screened numerous antibodies that each bind uniquely to one type of misfolded htt in order to identify and tag each type. These antibodies acted as molecular tracking devices that Finkbeiner monitored with an automated microscope and specialized software, both of which his lab created. Experiments revealed that one of the antibodies, 3B5H10, bound to a form of htt closely linked to neuron death and, therefore, disease progression.

“Now that our experiments have identified — at a cellular level — when neurons will die, it will be easier to develop drugs that target the toxic form of htt that causes Huntington’s symptoms,” said Finkbeiner, who is also a professor of neurology and physiology at the University of California, San Francisco, with which Gladstone is affiliated.

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UC Santa Cruz researchers awarded for research that has potential to improve human health.

(From left) Nicholas Shikuma, Kelly Peach and Walter Bray, UC Santa Cruz

A team of UC Santa Cruz researchers searching for drugs to fight cholera won the Deloitte QB3 Award for Innovation, presented by representatives of QB3 and Deloitte Thursday (Oct. 27) at a ceremony at UC San Francisco Mission Bay.

The team — graduate students Kelly Peach and Nicholas Shikuma, with research specialist Walter Bray — developed a high-throughput screening method to identify drugs that prevent Vibrio cholerae, the cholera pathogen, from forming biofilms: thin, tough sheets in which bacteria are shielded from antibiotics.

Biofilms are also a source of infection following operations to implant medical devices, and the team’s method could equally be applied to screen for drugs that disrupt other bacteria.

The $10,000 Award for Innovation, given to a graduate student, postdoc, staff scientist or team working in QB3 laboratories at UC Berkeley, UC Santa Cruz and UCSF, recognizes research that has the potential to improve human health.

The competition began in June when QB3 faculty nominated 38 candidates. By September, a jury panel drawn from industry, venture capital, academia and the media had narrowed the field to five. QB3 then invited the entire Berkeley, UCSF and Santa Cruz campus communities to vote, “American Idol” style, for the ultimate winner. (San Francisco Business Times reporter Ron Leuty covered the competition.) Santa Cruz featured its team in a news article on its website, while on Twitter, the universities (and the Gladstone Institutes) waged a sporadic battle for votes. In the end more than 1500 votes were cast—over half of them for the Santa Cruz team.

In a paper published this year in the journal Molecular Biosystems, the Santa Cruz team explained that biofilms are involved in over 60 percent of bacterial infections in humans. Bacteria often lie dormant in biofilms, encased in material that protects them from a host’s immune response — or drugs. Most antibiotics target cells that are actively dividing, so bacteria in a biofilm can sit out a course of treatment and emerge later to multiply. Drugs that disrupt biofilms make bacteria more vulnerable. Ideally, disruptors would be used in “cocktails” with antibiotics to kill free-floating bacteria.

Cholera remains a major Third World pathogen; an outbreak following the 2010 earthquake in Haiti sickened half a million and killed over 5,000. Biofilms are crucial to the virulence of V. cholerae, but no therapeutics exist to disrupt them. In a step toward solving this problem, Bray, Peach, Shikuma, and colleagues developed a technique to grow cholera biofilms in 384-well plates, and an automated method that uses fluorescence microscopy to measure how much biofilm is present in each well. Theirs is the first reported technique in the scientific literature to use images to analyze V. cholerae biofilms.

In a demonstration run, from a relatively small library of 3080 compounds, the team identified 29 compounds that disrupt cholera biofilm without killing the cells. The 29 compounds are “leads” — starting points for a company to test and refine into an actual drug therapy through many rounds of screens and clinical trials.

The work brought together scientists in three QB3 labs at UC Santa Cruz: those of Roger Linington, Scott Lokey and Fitnat Yildiz. Nadine Gassner, currently the grant program administrator at QB3-Santa Cruz, also contributed.

Four other finalists were in the running:

• Jonathan Galazka, a UC Berkeley graduate student, for engineering a strain of yeast that digests two types of sugar, thus speeding our path to biofuels and improving our access to clean, reliable, and affordable energy sources

• Patrick Goodwill, Ph.D. , a UC Berkeley research associate, for a magnetic particle imaging technique that could enable real-time angiography without radiation or iodine tracer

• Ellen Yeh, M.D., Ph.D., a resident fellow at UCSF, for identifying a potential drug target in the malaria parasite

• Daniel Zwilling, Ph.D., a postdoc, and Lily Huang, a research assistant, both at UCSF and the Gladstone Institutes, for discovering a potential treatment to slow neural breakdown in Alzheimer’s and Huntington’s diseases.

UC teams receive seven awards to accelerate new therapies — UC Davis five, UCLA two.

(From left) Gerhard Bauer, Jan Nolta and John Laird, UC Davis

The California Institute for Regenerative Medicine (CIRM), the state stem cell agency, today approved research planning grants for five UC Davis Health System teams that are working to develop human clinical trials to treat illnesses such as Huntington’s disease, vascular disease, osteoporosis, HIV/AIDS and airway disease in children. Two UCLA teams also received awards. The awards are specifically designed to support collaborative research that will bring potential therapies to the Food and Drug Administration for approval within four years.

“These grants are extremely important to California and to the field of regenerative medicine,” said Jan Nolta, professor of internal medicine and director of the UC Davis Institute for Regenerative Cures. “They enable our teams of scientists and clinicians to plan stem cell clinical trials that will offer treatments to patients who currently have few if any other medical options.”

Stem cells offer the unique potential to restore tissue and repair damage caused by injury or disease. Developing new therapies can normally take 12 or more years. CIRM funding helps advance the most promising approaches for early phase clinical trials. Today’s grants, which range from $71,000 to $110,000, are the first in a two-step process toward applying for full research awards that will be available early next year and worth up to $20 million each.

Known as Disease Team Therapy Development Awards, the grants went to UC Davis stem cell research teams working on five different health disorders:

Huntington’s disease: Nolta and Vicki Wheelock, clinical professor of neurology and director of the UC Davis Huntington’s Disease Clinic, lead a team preparing for a phase I clinical trial using adult stem cells to treat people with the devastating neurodegenerative condition of Huntington’s disease. Study participants will receive stem cells known as mesenchymal stem cells, which are derived from a healthy donor’s bone marrow. These stem cells will be engineered to secrete a neural growth factor, which the UC Davis team believes will have restorative effects by encouraging new neurons to develop in the brains of Huntington’s disease patients.

Critical limb ischemia: People with poor circulation, often caused by diabetes, and facing the risk of amputation, will benefit from the work of a team led by John Laird, director of the UC Davis Vascular Center. The group is developing specially engineered mesenchymal stem cells to treat critical limb ischemia — a condition occurring when blood flow to the feet or legs is restricted. This clinical trial will use donor stem cells that have been engineered to secrete the same vascular growth factor needed to form new blood vessels following an injury or when vessels have been blocked. The stem cells are expected to migrate into low-oxygen tissue areas, where they will wrap around damaged blood vessels and help restore circulation.

Severe airway obstruction in children: Pioneering throat surgeon Martin Birchall and stem cell scientist Alice Tarantal are developing an innovative tissue-engineering therapy for children suffering from severe airway obstruction, an extraordinarily difficult-to-manage and life-threatening condition that affects approximately 200 children a year in California. The team plans to use a patient’s own stem cells — in this case stem/progenitor cells — to create a bioengineered airway that can be implanted to reverse the obstruction. Birchall, who was a part of the surgical team at UC Davis that performed the world’s second-documented larynx transplant last year, says that bioengineered airways using a patient’s own stem cells — known as an autogolous transplant — would not require lifelong, harmful anti-rejection medications and could be used for people of all ages, including those with chronic obstructive pulmonary disease.

HIV/AIDS: Another CIRM award is going to the UC Davis disease team investigating a unique stem cell gene therapy for HIV. Led by Mehrdad Abedi, a professor of hematology and oncology, and Gerhard Bauer, director of the UC Davis Good Manufacturing Practice facility, this clinical trial will use an individual’s own blood-forming, or hematopoietic, stem cells that have been genetically modified to express three different anti-HIV genes. Because blood-forming stem cells have the ability to self-renew, the team believes that this treatment will enable a patient’s immune system to be repopulated with HIV-resistant cells after transplantation. Abedi and Bauer say this stem cell-based therapy may require only a single treatment to cure an HIV-infected individual.

Osteoporosis: Nancy Lane, professor of internal medicine and director of the UC Davis Musculoskeletal Diseases of Aging Research Group, leads a team targeting osteoporosis — the debilitating disease affecting an estimated 10 million Americans. Lane’s group is developing a clinical trial to test a synthetic molecule that has been engineered to direct transplanted mesenchymal stem cells to the surface of bones, helping create new bone formation. A successful therapy would help address the many problems associated with osteoporosis, in which bones become thin, weak and brittle and break more easily, especially in women over the age of 50.

“Our goal is to provide better options for people who have incurable genetic disorders like Huntington’s disease or whose disease has progressed beyond the capabilities of our best medical practices, like critical limb ischemia and osteoporosis,” said Nolta, who added that UC Davis currently has several small, stem cell clinical trials already under way. “Regenerative medicine offers new hope, and today’s planning grants represent a crucial step in being able to turn stem cells into cures.”