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.”

Ask UC Irvine neuroscientist Leslie Thompson to describe how Huntington’s disease affects patients, and she replies by turning to her computer. “I can show you,” she says. She clicks on a video of patients she visited in Venezuela. On-screen, a middle-aged man stands on a street corner, swaying as if intoxicated. A woman, no longer able to walk or feed herself, lies dying in her bed.

“That’s the end stage. It’s awful, just awful,” Thompson says, shaking her head. “Huntington’s always ends in death.”

A professor of psychiatry & human behavior and neurobiology & behavior, as well as director of the Interdepartmental Neuroscience Program, Thompson has dedicated the last 20 years of her career to halting Huntington’s — a fatal brain disorder that affects about 30,000 people in the U.S., with another 200,000 at risk of inheriting it. While a postdoctoral researcher at UCI, Thompson helped identify the gene that causes Huntington’s. Now she’s using a powerful new tool to find a cure: stem cells.

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