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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Findings suggest therapeutic target for treating fatal disease.

Robert Farese Jr.

Scientists at the UC San Francisco-affiliated Gladstone Institutes and the Stanford University School of Medicine have discovered how modifying a gene halts the toxic buildup of a protein found in nerve cells. These findings point to a potential new tactic for treating a variety of neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) — a fatal disease for which there is no cure.

The Gladstone and Stanford scientists began their experiments independently before realizing that combining their efforts could strengthen their results. Their discovery — which involved the work of both neuroscientists and geneticists — underscores the importance of collaborative and cross-disciplinary research when dealing with complex neurodegenerative diseases such as ALS.

ALS usually strikes between the ages of 40 and 75, ravaging the body’s motor neurons — nerve cells that control muscle movement. This causes muscle weakness, difficulty swallowing and breathing, paralysis and, ultimately, death — often just three to five years after diagnosis. At any given time, as many as 30,000 Americans are living with ALS — which afflicts physicist Stephen Hawking and which killed baseball legend Lou Gehrig.

In a paper published today (Oct. 29) online in Nature Genetics, researchers in the laboratories of Aaron D. Gitler, Ph.D., associate professor at Standord, and Gladstone senior investigators Robert V. Farese Jr., M.D. and Steve Finkbeiner, M.D., Ph.D., describe how shutting off a gene called Dbr1 in yeast cells and in neurons obtained from rats can protect both cell types from the toxic effects of TDP-43 — a protein that plays a key role in ALS.

“Mutations in the gene that produces TDP-43 can cause this protein to build up in cells,” said Farese, who is also a professor at UCSF. “Over time, TDP-43 accumulation inside motor neurons can reach toxic levels and bind to RNAs — small bits of genetic material that act as an intermediary between genes and proteins. One theory is that this binding interferes with the RNAs’ normal functions and impairs the overall health of cells. Eventually, the neurons degrade and die, contributing to the rapid progression of ALS symptoms.”

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Discovery reveals set of target genes that could lead to development of new drug treatments.

Principal investigator Gene Yeo, UC San Diego

Two proteins previously found to contribute to ALS, also known as Lou Gehrig’s disease, have divergent roles. But a new study, led by researchers at the Department of Cellular and Molecular Medicine at the UC San Diego School of Medicine, shows that a common pathway links them.

The discovery reveals a small set of target genes that could be used to measure the health of motor neurons, and provides a useful tool for development of new pharmaceuticals to treat the devastating disorder, which currently has no treatment or cure.

Funded in part by the National Institutes of Health and the California Institute for Regenerative Medicine (CIRM), the study is published in the advance online edition of Nature Neuroscience on Sept. 30.

ALS is an adult-onset neurodegenerative disorder characterized by premature degeneration of motor neurons, resulting in a progressive, fatal paralysis in patients.

The two proteins that contribute to the disease — FUS/TLS and TDP-43 — bind to ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins. In normal cells, both TDP-43 and FUS/TLS are found in the nucleus where they help maintain proper levels of RNA. In the majority of ALS patients, however, these proteins instead accumulate in the cell’s cytoplasm — the liquid that separates the nucleus from the outer membrane, and thus are excluded from the nucleus, which prevents them from performing their normal duties.

Since the proteins are in the wrong location in the cell, they are unable to perform their normal function, according to the study’s lead authors, Kasey R. Hutt, Clotilde Lagier-Tourenne and Magdalini Polymenidou. “In diseased motor neurons where TDP-43 is cleared from the nucleus and forms cytoplasmic aggregates,” the authors wrote, “we saw lower protein levels of three genes regulated by TDP-43 and FUS/TLS. We predicted that this, based on our mouse studies, and found the same results in neurons derived from human embryonic stem cells.”

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UCLA research could shed light on a variety of neurodegenerative diseases, such as ALS.

Bennett Novitch, UCLA

In an effort to identify the underlying causes of neurological disorders that impair motor functions such as walking and breathing, UCLA researchers have developed a novel system to measure communication between stem cell-derived motor neurons and muscle cells in a Petri dish.

The study provides an important proof of principle that functional motor circuits can be created outside the body using these neurons and cells and that the level of communication, or synaptic activity, between them can be accurately measured by stimulating the motor neurons with an electrode and then tracking the transfer of electrical activity into the muscle cells to which the neurons are connected.

When motor neurons are stimulated, they release neurotransmitters that depolarize the membranes of muscle cells. This allows calcium and other ions to enter the cells, causing them to contract. By measuring the strength of this activity, one can get a good estimation of the overall health of motor neurons.

That estimation could shed light on a variety of neurodegenerative diseases, such as spinal muscular atrophy and amyotrophic lateral sclerosis (Lou Gehrig’s disease), in which communication between motor neurons and muscle cells is thought to unravel, said the study’s senior author, Bennett G. Novitch, an assistant professor of neurobiology and a scientist with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

The findings of the study appear May 4 in PLoS ONE, a peer-reviewed journal of the Public Library of Science.

“Now that we have this method to measure the strength of the communications between motor neurons and muscle cells, we may be able to begin exploring what happens in the earliest stages of motor neuron disease, before neuronal death becomes prevalent,” Novitch said. “This can help us to pinpoint where things begin to go wrong and provide us with new clues into therapeutic interventions that could improve synaptic communication and promote neuronal survival.”

Novitch said the synaptic communication activity his team was able to create and measure using muscle cells and motor neurons derived from mouse embryonic stem cells looks very similar to what is seen in a mouse, validating that their model is a realistic representation of what is happening in a living organism.

“That gives us a good starting point to try to model what happens in cells that harbor genetic mutations that are associated with neurodegenerative diseases,” he said. “To do that, we had to first define an activity profile of normal synaptic communication. Some research suggests that a breakdown in this communication can be an early indication of disease progression or possibly an initiating event. Neurons that cannot effectively transmit information to muscle cells will eventually withdraw their contacts, causing both the neurons and muscle cells to degenerate over time. Hopefully, we can now create disease models that will allow us to study what is happening.”

In this study, Novitch and his team, led by Joy Umbach, an associate professor of molecular and medical pharmacology at UCLA, used mouse embryonic stem cells to create the motor neurons, and they used previously established lines of muscle precursors to produce muscle fibers. They put both cells together in a Petri dish, and the cells were cultured in such a way as to encourage communication. Novitch said the team wanted to see if they would naturally form synaptic contacts and whether or not there was neural transmission between them.

In less than a week, the neurons had reached out to the muscle cells and assembled the protein networks needed for synaptic communication, Novitch said.

To measure the connections between the cells, the scientists used a technique called dual patch-clamp recording. Pipettes containing stimulating and recording electrodes are inserted into the membranes of the motor neurons and muscle cells, with special care being taken not to injure them. With this method, the researchers were able send an electrical current into the motor neurons and measure responses in the muscle cells, as well as visualize the muscular contractions.

“The in vitro system developed here might accordingly be expanded to assess the underlying cellular and molecular mechanisms that contribute to this decline in synaptic input to motor neurons,” the study states. “Thus, in addition to their utility for helping to answer fundamental biological questions, these co-cultures have clear applications in addressing problems of medical significance.”

Going forward, Novitch and his team hope to recreate and confirm the work using human stem cell-derived motor neurons and muscle cells and to measure the synaptic communications with newly developed optical recording methods, which are less invasive than the patch-clamp techniques used in this study.

The study was funded by the California Institute for Regenerative Medicine, the UCLA Broad Stem Cell Research Center, the Muscular Dystrophy Association, the UCLA Cellular and Molecular Biology Training Program, and the Ruth L. Kirschstein National Research Service Award.

The Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research: UCLA’s stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 200 members, the Broad Stem Cell Research Center is committed to a multidisciplinary, integrated collaboration among scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed toward future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine at UCLA, UCLA’s Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science.

UC San Diego explores complex interactions of lipids, inflammation in insulin resistance.

Christopher Glass, UC San Diego

In the online May 2 issue of the journal Cell Metabolism, researchers at the UC San Diego School of Medicine publish three distinct articles exploring:

• the complex interactions of lipids and inflammation in insulin resistance
• the roles of omega 3 fatty acids and a particular gene in fighting inflammation
• how elevated levels of a particular protein might delay the muscle-destroying effects of amyotrophic lateral sclerosis.

Type 2 diabetes has reached epidemic proportions around the world, fueled in large part by the equally alarming expansion of obesity as a global health problem. But while it’s well-known that obesity is the most common cause of insulin resistance – the primary metabolic abnormality in type 2 diabetes – researchers have only recently begun to effectively parse the underlying, complicated relationships between lipids (fats and related molecules essential to cell structure and function) and chronic tissue inflammation (a key cause of obesity-induced insulin resistance).

In a wide-ranging perspective article published in Cell Metabolism, Christopher K. Glass, M.D., Ph.D., a professor in the departments of cellular and molecular medicine, and medicine at the UC San Diego, and Jerrold M. Olefsky, M.D., associate dean for scientific affairs and distinguished professor of medicine at UC San Diego, survey where the science stands, describing, for example, the pro-inflammatory effects of saturated fatty acids and the anti-inflammatory benefits of omega 3 fatty acids. They also discuss how inflammation impacts lipid metabolism at the cellular, tissue, organ and whole-body levels.

In a second, related article, Olefsky and colleague Da Young Oh, an assistant project scientist, discuss the critical role of a gene called GPR120 in inhibiting pro-inflammatory macrophages while simultaneously boosting the anti-inflammatory benefits of omega 3 fatty acids. They argue that new research highlights the importance of GPR120 as an attractive target for new drugs that could increase insulin sensitivity and, perhaps, have anti-obesity effects as well.

Finally, Don W. Cleveland, Ph.D., professor and chair of the Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research at UC San Diego and colleagues report the effects of elevated levels of a gene- regulating protein in mouse cells afflicted by a form of amyotrophic lateral sclerosis or ALS.

In humans, ALS is a progressive, adult-onset neurodegenerative disorder characterized by selective motor neuron and muscle loss that ultimately results in fatal paralysis. Among the key players in muscle function is a transcriptional activator protein called PGC-1alpha, which helps enhance various aspects of muscle cell function, including metabolism and mitochondrial biogenesis.

Cleveland and colleagues report that elevated levels of PGC-1alpha in the muscles of a mouse model of inherited ALS helps maintain health and function, though it does not extend survival time. The researchers suggest that increasing PCG-1alpha activity in muscle could be a new and attractive therapeutic target for maintaining, improving and extending physical abilities in ALS patients.

Winners include David Barba, Rohit Loomba, William Mobley, Howard Taras.

David Barba

Brain stimulation surgery for patients with Parkinson’s disease; promoting liver health on a national level; leading one of the nation’s top ALS clinics; and designing a law that protects the rights of students with epilepsy: these are significant reasons why four UC San Diego School of Medicine doctors were honored during the 18th annual Combined Health Agencies Health Hero Awards breakfast on March 15 at The Prado in Balboa Park.

Each year, the Combined Health Agencies’ 24 health nonprofit members each choose a person or company that works daily to improve the lives of local residents affected by chronic illness. This year, four winners who were recognized are UC San Diego physicians David Barba, M.D.; Rohit Loomba, M.D.; William Mobley, M.D., Ph.D.; and Howard Taras, M.D.

Since 2005, Barba, clinical professor of surgery in the Division of Neurological Surgery at UC San Diego Health System, has been involved with the Parkinson’s Association of San Diego. He routinely performs brain stimulation surgery on many patients with Parkinson’s disease and has demonstrated hisleadership by organizing a sold-out patient symposium securing top quality speakers in the field. Barba is currently establishing a UC San Diego system for those working on Parkinson’s research to be in direct contact with each other.

The American Liver Foundation considers Loomba, assistant professor of clinical medicine in the Division of Gastroenterology and the Division of Epidemiology in the Department of Family and Preventive Medicine, a collaborative partner as he serves on the National Board of Directors, and the non-profit local Speakers Bureau promoting prevention and care.

As Chair of the Department of Neurosciences at UC San Diego School of Medicine, Mobley garners national support from physicians and clinicians to join the UC San Diego ALS and Motor Neuron Treatment and Research Center team to raise the level of care and treatment of patients with ALS in San Diego. Through Mobley’s reputation and expertise, the ALS Clinic is quickly becoming known as a place where patients can receive the best care possible in their fight against what is commonly known as Lou Gehrig’s disease.

Taras, professor of pediatrics in the Division of Child Development and Community Health, is being recognized by the Epilepsy Foundation for his instrumental work in the passing of SB 161, a bill signed into law in 2011 that protects the rights of students with epilepsy. He has testified numerous times at California State Legislative hearings and spent hundreds of hours educating legislators and the public about the issue of emergency seizure rescue medications. Through this legislation, life-saving medication can be administered to students at school to prevent further brain damage or death.

“We are humbled by the service of these physicians and grateful to have UC San Diego Health System in our community,” said Susan Day, president of Combined Health Agencies.

This year’s event is possible by the generous support of community sponsors UC San Diego Health System, PhRMA, GlaxoSmithKline, Johnson & Johnson, BIOCOM, Rady Children’s Hospital-San Diego, Sonnenberg & Company CPAs, and The San Diego Business Journal.

Combined Health Agencies has been United Way’s health partner in the United Way/CHAD Campaign since 1974. As a federation of 24 local health charities, Combined Health Agencies is focused on improving the quality of life for individuals and families who are faced with chronic health conditions.

Richard Olney dies at 64.

Richard Olney

Richard K. Olney, M.D., founding director of the ALS Treatment and Research Center at UC San Francisco and a pioneer in clinical research on amyotrophic lateral sclerosis (ALS), has died at age 64, following his own eight-year battle with the disease.

Olney used the tragic irony of his diagnosis – which occurred 18 years after he began focusing on ALS as a physician and researcher – to create public awareness about the condition. He did many interviews with the national and local press beginning in 2004, the year he was diagnosed, even as his condition deteriorated dramatically.

ALS, commonly known as Lou Gehrig’s disease, is a progressive, fatal disease in which motor neurons in the brain and spinal cord degenerate. Patients gradually lose control of their muscles, while their minds generally remain intact.

Current research focuses on what genetic and environmental factors may make people susceptible to the disease, which is not contagious. Olney did not have a family history of ALS.

Throughout his 25-year career, most of it at UCSF, Olney, UCSF professor of neurology, was interested in the diagnosis and management of motor neuron diseases, which include ALS. He joined the UCSF faculty in 1985 and his increasing clinical focus on ALS led to his establishment of UCSF’s ALS clinic in 1993, with one nurse and a physical therapist.

In 1999, the clinic became the UCSF ALS Center and Olney served as its first director, a post he held until August 2004 when the disease’s progression forced him to resign.

Under his leadership, the center grew to its current caseload of more than 375 patients, providing services in multiple disciplines, involving a neurologist, a nurse, a physical therapist, a respiratory therapist, an occupational therapist, a speech pathologist, a dietician, a communication specialist, a social worker and representatives from the ALS Association and the Muscular Dystrophy Association (MDA), who advise patients and families about available support programs.

In 2001, the center received the prestigious designation of “ALS Center of Excellence,” from the ALS Association and the MDA, making it one of only 16 such centers in the United States at the time. The designation, held by only two centers in California, is granted to those programs that offer advanced diagnostics and comprehensive patient care, provide access to the latest drug trials, and conduct clinical research aimed at identifying therapies.

Olney was known internationally for his excellence as a physician, teacher and clinical researcher. In his role as an investigator, he studied potential drug therapies and the disruption in nerve signaling that occurs in ALS and other neuromotor diseases. He refined the statistical method for measuring the rate of ALS progression and, together with UCSF neurologists Catherine Lomen-Hoerth, M.D., Ph.D., and Bruce Miller, M.D., director of the UCSF Memory and Aging Center, defined the links between ALS with features of other neurodegenerative diseases, such as fronto-temporal dementia (FTD).

In the year before his diagnosis, Olney and Lomen-Hoerth – now the director of the ALS Treatment and Research Center at UCSF and Olney’s personal physician – developed a clinical trial to investigate whether two drugs used to combat AIDS and cancer might slow or halt the progression of ALS in some patients.

In January 2005, Olney became the first test subject in this clinical trial. Because it was a placebo-controlled, “blinded” study, neither he nor Lomen-Hoerth, would know for six months if he was receiving the drug.

“It was typical of Rick to put the value of the medical research before himself and not take the drugs outside the boundaries of the trial,” Lomen-Hoerth said. “He knew it was highly unlikely that a treatment would be found during his lifetime, but nothing was going to stop him from doing whatever he could to advance the research.”

When the blinded period of the clinical trial ended, Olney and Lomen-Hoerth learned he had received it. “It may have helped,” Lomen-Hoerth said. “It’s hard to know. Early-stage clinical trials like this involve low doses that are designed to test drug safety, as opposed to efficacy.”

“He’s an inspiration to a whole generation of students who studied under him,” she added. Lomen-Hoerth completed her National Institutes of Health-funded post-doctoral fellowship at UCSF under Olney’s mentorship in 1999.

“His life and career inspires us all to redouble our efforts to find answers to this cruel neurological problem, and to continue to provide best patient care for our patients with ALS,” said Stephen L. Hauser, M.D., chairman of the UCSF Department of Neurology. “The ALS Center at Moffitt-Long Hospital, and the new Neuroscience Research Building at Mission Bay, will carry on in Rick’s magnificent tradition. He always will be remembered as an inspiration to physicians and scientists of UCSF and beyond who are dedicated to finding answers to ALS. We were very lucky to have had him in our midst.”

Lucie Bruijn, Ph.D., chief scientist of the ALS Association, remembered Olney “not only as a courageous person with ALS, but someone who was an outstanding clinician and scientist who made major contributions both for patients and the scientific field.

“He has been an inspiration to those of us who work every day toward the goal of finding meaningful therapies for ALS. It is an honor to have known him personally and the ALS Association is proud to have funded his important studies to identify genetic and environmental influences that impact the disease.”

In 2005, Olney helped to raise awareness about ALS by appearing in a public service announcement produced by the ALS Association.

Olney is survived by his wife of 38 years, Paula, and two children, Amy Koch Olney Dobbs (husband Ryan Dobbs), an occupational therapist at California Pacific Medical Center, and Nicholas T. Olney (wife Caroline Olney) and grandson Richard Knox Olney, all of the Bay Area. Nicholas, inspired by his father’s illness, decided to become a physician. He graduated from UCSF School of Medicine last spring, is carrying out his internship in internal medicine, and will conduct his residency in neurology at UCLA.

Even though Olney became significantly immobilized by his disease, having lost virtually all muscle control and communicating only by moving his pupils across a computer tablet, he remained actively engaged in his family, watching his two children marry, serving as his son’s best man, and participating in the life of his grandchild, who was born last spring and named in his honor.

Olney was the author of numerous research articles, associate editor of Muscle Nerve, and a member of the editorial boards forAnnals of Neurology, Clinical Neurophysiology, and the Journal of Clinical Neurophysiology. He also served as a member of the board of directors of the American Association of Electrodiagnostic Medicine and as a councilor of the neuromuscular section of the American Academy of Neurology.

Olney graduated Phi Beta Kappa from the University of Oklahoma with a bachelor’s degree in Chemistry, Mathematics, and Zoology with highest honors in 1968. He received his medical degree from Baylor College of Medicine in Houston in 1973. He attended UCLA for his training in psychiatry and University of Oregon Health Sciences Center for his training in neurology.

A private memorial service will be held.

Donations to the ALS Center at UCSF should be made payable to the UCSF Foundation, Box 45339, San Francisco, CA 94145-0339. The memo line should state: “Rick Olney ALS Endowment (S0406).”

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care.

Related news:

Sampling of the many news articles featuring Richard Olney following his diagnosis:

San Francisco Chronicle
“Dr. Richard Olney in last stages, study of disease”
April 25, 2011
www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2011/04/25/MNHL1J5LEV.DTL

San Francisco Chronicle
“Cruel irony – Gehrig’s disease expert stricken
Shocking diagnosis after decades caring for ALS patients”
Nov. 29, 2004
www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2004/11/29/MNGQ4A35ST1.DTL

The New York Times
“Longtime expert on ALS now knows it all too well”
Feb. 22, 2005
www.nytimes.com/2005/02/22/health/22als.html

People magazine
“Stricken by the disease he was trying to cure”
March 28, 2005
www.people.com/people/archive/article/0,,20147225,00.html

CBS Sunday Morning
The Doctor and the disease
“Doctor battles ALS, the disease he spent a lifetime researching”
May 22, 3005
www.cbsnews.com/stories/2005/05/22/sunday/main697074.shtml

San Francisco Chronicle
“Researcher with ALS finds solace in expertise”
March 22, 2008
www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2008/03/22/MNH7VK56V.DTL

San Francisco Chronicle
“Dying doctor’s noble choice Stricken SF neurologist enters own ‘placebo’ trial”
Jan. 17, 2005
www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2005/01/17/MNG24ARHTM1.DTL

Lab discoveries shift to tests of therapies.

David Rowitch, UC San Francisco

For more than a decade, stem cell science has raised hopes of cures for a host of diseases and illnesses. Now, the research pace has picked up with lab discoveries moving to tests of therapies for patients.

The ultimate goal of human stem cell research has always been to harness the potential power of these cells to treat and cure intractable diseases.

By transplanting millions of healthy stem cells into patients with a specific defect — be it paralysis, multiple sclerosis, ALS or others that are crippling and devastating — clinicians expect these pluripotent cells to develop into normal mature cells and take over critical functions of damaged tissue.

An accelerating research pace has prepared the way for the first stages of clinical trials, and UC scientists have paved the way to some of the first tests of stem cell therapies.

In 2009, a treatment developed by UC Irvine neuroscientist Hans Keirstead became the world’s first human embryonic stem cell therapy approved by the FDA for early-stage clinical trials. The treatment, now being carried out by Geron Corp., is designed to lessen the impact of severe spinal cord injuries by replacing lost myelin, the substance that normally insulates nerve cells and promotes communication between them.

In preliminary research with embryonic stem cells, the scientists were able to derive cells that could develop into healthy myelin-producing cells. Injected into animals, these cells went on to produce functioning myelin, allowing electrical conduction to resume in the nerves and enabling injured animals to walk again.

With this aim, three patients with severe spinal cord damage have been injected with human embryonic stem cells. If successful, the procedure will restore the communication between neurons, and thereby restore their ability to walk and move normally.

The early human trials test the safety of the procedure. The patient treatments began in October 2010. No adverse signs have been reported.

“Things are looking good,” Kierstead reports.

Treating a severe childhood disorder

Defective myelination of nerves also is observed in multiple sclerosis, cerebral palsy and a rare and fatal brain disorder called Pelizaeus-Merzbacher disease (PMD). This disorder is caused by a defective gene on the X chromosome that boys inherit from their mothers. Children affected with the severe form of PMD can’t walk or talk, and often die between ages 5 and 7.

Clinical trials were approved in 2009 for a stem cell therapy to treat PMD. This trial uses adult rather than embryonic stem cells. Both types have the remarkable ability to develop into many different cell types in the body. While embryonic stem cells are thought to be capable of specializing into any type of cell, adult stem cells are more limited — mainly able to differentiate into cell types from the tissue they are drawn from. But because of their more focused specialization, they may be less likely to be rejected after transplantation.

“This (PMD) is a tragic disease, and I think the families are aware that these early trials may not help their children,” said UCSF physician-scientist David Rowitch. “But they recognize that it might help other children, and they’re very dedicated. I’m so impressed by how involved and engaged the families are in supporting the trials.”

“These early clinical trials are aimed at determining the safety of the stem cells being tested, a critical first step toward developing any effective therapy,” said Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

In PMD, as in spinal cord injury, specialized cells called oligodendrocytes fail to make myelin. Rowitch and colleagues are collaborating with StemCells Inc. in a clinical trial, testing the safety of injecting PMD patients with adult neural stem cells that can lead to healthy oligodendrocytes. They hope normal oligodendrocytes might be able to provide the needed myelin. Results of the clinical trial will be assessed in 2012.

“We are not trying to kill off the defective cells, but to restore the brain’s ability to produce a supply of normal myelin by providing healthy oligodendrocyte precursors,” said Rowitch, principal investigator on the trial and a pediatric specialist and chief of neonatology at UCSF Children’s Hospital. Rowitch also is a Howard Hughes Medical Institute Investigator in UCSF’s Broad Center. “These cells have the capacity to identify areas of the brain lacking myelin, so if they can survive after transplantation they may be able to form myelin in the brain of PMD patients.”

In the study, UCSF neurosurgeon and co-principal investigator in the trial Nalin Gupta transplanted “adult” neural stem cells directly into the brain of four patients.

Critical to monitoring the treatment’s progress, the trial calls for patients to receive MRI scans of their brains before the treatment and then every three months for a year to assure that the new cells do not cause widespread brain inflammation or other problems.

In addition, neurologist Jonathan Strober, also co-principal investigator, monitors the patients’ symptoms to identify any signs of clinical improvement or deterioration.

If the trial shows evidence of safety and of myelin production, it could point the way to a whole new approach to treating of PMD and other childhood brain disorders, said Rowitch says.

“We still have much to learn about human stem cells therapies, but I hope we can look back on this time as the very beginning of a wave of treatments for intractable diseases,” said UCSF’s Kriegstein.

‘Borrowing’ a patient’s stem cells

In both the UC Irvine and UCSF clinical trials, a specific type of normal donor stem cell is introduced to patients. These precursors are expected to develop into healthy adult cells, restoring normal functions. Another type of treatment strategy involves removing millions of disease-carrying stem cells and genetically “curing” them — correcting the disease-causing genetic defect — and then transplanting the healthy cells back into the patient.

A UCLA team is developing such a gene therapy to cure sickle cell disease (SCD), the debilitating disorder that affects nearly 100,000 Americans, weakening many and often killing them before the age of 40. The genetic disease causes red blood cells to take on a sickle shape, clogging blood vessels and producing episodes of excruciating pain.

Most people with SCD have some type of brain blood vessel problem by the time they are 20, and about one in seven have severe strokes. Current medical treatments can provide short-term relief, but the disease leads to progressive deterioration in organ function. In even its milder forms, SCD prevents a normal blood supply, starving cells of oxygen and leading to episodes of severe bone and abdominal pain, breathing problems and progressive kidney damage.

Like many genetic disorders, SCD affects certain populations more than others. The single inherited defect in a single gene that causes the disease occurs more frequently in African Americans, with one in 500 people afflicted. About 5 percent of SCD patients in California are Hispanic Americans.

Donald Kohn, director of the Human Gene Medicine Program at UCLA and a scientist with UCLA’s Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, received a $9 million “Disease Team” grant from the California Institute for Regenerative Medicine (CIRM) to develop a stem cell treatment for the disease. For SCD patients, his team seeks to genetically correct their bone marrow adult hematopoietic stem cells — those cells that give rise to all types of blood cells — by adding a hemoglobin gene that blocks the sickling of the red blood cells. The healthy stem cells then will be transplanted back into the patients.

The strategy has the potential to permanently cure the illness with far less toxicity and risk than a bone marrow transplant from another person.

Kohn and his colleagues have shown in the laboratory that they can take cells from an SCD patient and genetically alter them to prevent sickling. After additional laboratory research, they will seek FDA approval to demonstrate that genetically corrected human bone marrow stem cells can be transplanted into SCD patients  and enable them to make normal red blood cells.

Kohn feels confident that his team can meet its target: human clinical trials within four years.

“This will be the sixth gene therapy clinical trial I have directed,” he said. “It’s a technically complex project, but I think the timeline is realistic. There is a desperate need for new approaches. It’s a very bad disease for many patients, and current therapies haven’t made patients much better.”

Astrocytes for ALS

A UC San Diego program to develop a treatment for amyotrophic lateral sclerosis, or Lou Gehrig’s Disease, received about $11 million in a CIRM-funded Disease Team grant. Larry Goldstein, professor of cellular and molecular medicine and director of the UC San Diego Stem Cell Program, heads the effort. Like UCLA’s Kohn, Goldstein plans to advance this research to a therapy that can move to clinical trials in just a few years.

People with ALS experience a rapidly progressive weakness, muscle atrophy and severe respiratory deficit among other grim effects, and most die after two to five years. The disease is caused by degeneration of neurons in the spinal cord and the brain.

No cures for ALS have been developed, but Goldstein and colleagues at UC San Diego and other institutions have found strong evidence that the disease not only damages neurons but also astrocytes, a type of cell known to provide critical support for neurons. The team’s studies in a rat version of ALS shows that injecting healthy versions of astrocytes into the spinal cord may rescue motor neurons and stop, or at least slow down, the devastating damage.

“It’s the death of motor neurons that leads to paralysis, but we think damaged astrocytes are a key part of the disease,” Goldstein says. “They normally provide nutrients to neurons and maintain an environment that is essential for neurons to survive and function properly.”

Goldstein’s team wants to tweak human embryonic stem cells to become astrocyte precursors, and transplant these stem cells into spinal cords of ALS patients to at least partially restore normal function.

The team must convert stem cells to astrocyte precursors in a quantity large enough to be clinically useful. Millions are needed. Research with animals should help determine roughly how many stem cells would be needed for humans.

As director of UC San Diego’s stem cell program, Goldstein supports efforts to streamline these early days of research-into-treatments. His ALS project will use a single embryonic cell line for many different patients in order to retain control of safety and efficacy. One cellular product can be extensively tested and used on many patients, he says.

Goldstein champions the use of human stem cells to allow researchers to seek treatments by studying “diseases in a dish.”

“Animal models are important for understanding the basic principles of cell function, but animals are not human, and diseases impact different types of organisms differently,” he says.  “By testing drugs and other treatments directly on human cells we are very hopeful we can more quickly get to the payoff of therapies and cures.”

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Five-year grant also will train research specialists in neurodevelopmental disorders.

Craig McDonald, UC Davis

After a highly competitive selection process, UC Davis has been awarded a five-year, $750,000 federal grant to train 10 specialists in research related to the rehabilitation of patients with neuromuscular and neurodevelopmental disorders.

The grant from the National Institute of Disability and Rehabilitation Research, an agency within the U.S. Department of Education, underscores UC Davis’ reputation as an international leader in the study of conditions such as muscular dystrophy and autism.

“This critical funding will help us address the severe shortage of experienced, qualified rehabilitation researchers in the areas of neuromuscular and neurodevelopmental disorders,” said Craig McDonald, chair of the Department of Physical Medicine and Rehabilitation and an internationally recognized expert in the clinical management and rehabilitation of muscular dystrophies. “While the subspecialties of neuromuscular and neurodevelopmental disorders have historically attracted clinicians, the training of clinical scientists in these disciplines has been neglected, creating a profound shortage of qualified researchers.”

Neurodevelopmental and neuromuscular disorders are highly complex diseases that can have a tremendous impact on health, quality of life and life expectancy. Because of their unrelenting, progressive nature, many of the disorders create enormous psychological, emotional and financial burdens for patients, families and caregivers.

More than 5 percent of the population suffers from genetic and acquired neuromuscular disorders such as muscular dystrophy, Lou Gehrig’s disease (ALS) and peripheral neuropathy, which represent major causes of mortality and morbidity in American children and adults. Similarly, neurodevelopmental disorders such as autism and fragile X syndrome also have a significant impact on human health, altering both the developing and mature nervous system, and affecting emotion, learning ability, cognition, social interactions and communication. Once considered rare, autism-spectrum disorders are now known to affect more than 1 in 150 persons — and possibly as many as 1 in 91.

While McDonald is the principal investigator of the grant, he said the training program will be a collaboration leveraging stellar resources within UC Davis’ Clinical and Translational Science Center, together with training programs directed by Jay Han, associate professor of physical medicine and rehabilitation, and Robin Hansen, professor of pediatrics and director of clinical programs at the UC Davis MIND Institute.

“This project is a real example of collaborative, interdisciplinary research at UC Davis and one reason why this institution has been able to excel in team science and clinical translational research,” McDonald said.

Under the grant, each trainee will complete a two-year comprehensive program to develop specialized and interdisciplinary research skills in the field. Trainees will be either physicians, postdoctoral fellows or allied health professionals and will follow a “hands-on,” individualized research training plan, supervised by an experienced group of mentors.

Over time, McDonald said, the training will help UC Davis “accelerate the translation of new knowledge acquired through basic science into clinical therapeutics and rehabilitation interventions that will enhance the health, function and quality of life for those with these disabling disorders.”

In addition to the training grant, the Department of Physical Medicine and Rehabilitation recently received two additional NIH grants related to muscular dystrophy research, totaling almost $2 million over four years. One grant will fund ancillary studies linked to a multi-center natural history study of Duchenne muscular dystrophy currently led by UC Davis. The second grant will help researchers generate much-needed data on novel biomarkers as outcome measures for future clinical trials.

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Discovery will “significantly improve our understanding of these diseases.”

Adam Boxer, UC San Francisco

Frontotemporal dementia and amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease — two fatal neurodegenerative disease with distinct symptoms — are triggered by a common mutation in many cases, according to researchers who say they have identified the mutated gene.

In the study, reported in the Sept. 21 online issue of Neuron, the scientists described the discovery of a genetic mutation that is accountable for almost 12 percent of familial FTD and more than 22 percent of familial ALS samples studied.

They also report that the defect is the strongest genetic risk factor found to date for the more common, non-inherited, sporadic forms of these diseases. It was found in 3 percent of sporadic FTD and 4 percent of sporadic ALS samples in the largest clinical patient series.

The study was led by scientists at the Mayo Clinic in Florida, in collaboration with researchers at UCSF, the University of British Columbia and UCLA. The finding emerged from the identification and study of a family stricken by both ALS and FTD, reported last year. In that study, led by the UCSF scientists and published in the Journal of Neurology, Neurosurgery and Psychiatry, the researchers honed in on the region in which the gene was located.

“Both clinically and at the molecular level this discovery is going to significantly improve our understanding of these diseases,” said co-author Adam Boxer, M.D., Ph.D., of the UCSF Memory and Aging Center, the lead author on the 2010 paper. The discovery makes it possible to develop a diagnostic test for the mutation, as well as to create animal models that may be used to help unravel the molecular mysteries connecting the mutation to the diseases, he said.

In the current study, a detailed molecular genetic characterization of the family that Boxer described was done in the laboratory of senior author Rosa Rademakers, Ph.D., from the Mayo Clinic. She and colleagues identified the gene and the specific mutation within it.

The mutation consists of from hundreds to thousands of extra copies of a six-letter DNA sequence GGGGCC strung end to end within a region of human chromosome nine. The mutation occurs within a gene of unknown function called C9ORF72.

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“Molecular cap” blocks processes that lead to form amyloid fibers common in certain degenerative diseases.

A new advance by UCLA biochemists has brought scientists one step closer to developing treatments that could delay the onset of Alzheimer’s disease and prevent the sexual transmission of HIV.

The researchers report that they have designed molecular inhibitors that target specific proteins associated with Alzheimer’s disease and HIV to prevent them from forming amyloid fibers, the elongated chains of interlocking proteins that play a key role in more than two dozen degenerative and often fatal diseases.

“By studying the structures of two key proteins that form amyloids, we were able to identify the small chain of amino acids responsible for amyloid fiber formation and engineer a ‘molecular cap’ that attaches to the end of the fibers to inhibit their growth,” said research leader David Eisenberg, director of the UCLA-Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator.

The study was published online June 15 in the journal Nature and will be available in an upcoming print edition.

“This research is an important first step toward the development of structure-based drugs designed against amyloid diseases,” said Eisenberg, who is a UCLA professor of chemistry, biochemistry and biological chemistry and a member of the California NanoSystems Institute at UCLA. “Our results have opened up an avenue so that universities and industry can start creating therapeutics that could not have been produced 10 years ago.”

Amyloid fibers are elongated, water-tight structures formed from two linked protein sheets. Proteins from each sheet contribute side chains, causing them to interlock like the teeth of a zipper, Eisenberg said.

The fibers are found not only in Alzheimer’s disease but in a variety of conditions, including Lou Gehrig’s disease, Parkinson’s disease, type 2 diabetes and a family of disorders related to mad cow disease, among others. In Alzheimer’s and other neurodegenerative diseases, the tau protein forms amyloid fibers inside brain cells, destroying them through a mechanism that is still being investigated.

Though many serious diseases are characterized by amyloid fibers, Alzheimer’s is the most prevalent, Eisenberg said. Today there are 5 million patients in the U.S. who suffer from Alzheimer’s, with 500,000 new cases every year. Alzheimer’s health care cost this year alone have been estimated at $178 billion, including the value of unpaid care for Alzheimer’s patients provided by nearly 10 million family members and friends.

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