Saturday, February 11, 2012, marked the ninth-annual HD research symposium at the University of California at San Francisco. The UCSF Memory and Aging Center and the HDSA Center of Excellence at UC Davis Medical Center partnered to present this free public conference where attendees could learn the latest in HD research.
Several HOPES members appeared at the event. This page gives a summary of the presentations they heard.
Table of Contents
- Dr. Steve Finkbeiner on the Translation Gap
- Dr. Paul Muchowski on the Immune System and HD
- Dr. Lisa Ellerby on Drug-Target Validation
- Dr. Jan Nolta on Mesenchymal Stem Cells
- Teresa Tempkin on Clinical Studies
- The UCSF Memory and Aging Center on Clinical Studies, Behavioral Strategies, and New Research Discoveries
Dr. Steve Finkbeiner on the Translation Gap^
In the first presentation, Dr. Steve Finkbeiner addressed some of the major challenges in turning basic science research into clinical therapies, a hurdle that he referred to as the “translation gap” (or more piquantly, “the Valley of Death”). To give some perspective, Dr. Finkbeiner estimated that it requires the evaluation of some 5,000-10,000 compounds to develop just one FDA-approved drug, a process that takes an average of 11.8 years and costs up to $802 million. Because of the huge investments needed to bring a drug to market, many compounds that show positive results in animal models of disease are never investigated in humans. This gap is especially pronounced for diseases affecting the brain (such as HD), because their animal models are perceived to be unreliable and their drugs are notoriously expensive to test in clinical trials. To address this issue, Dr. Finkbeiner argued that new collaborations are needed between academic institutions, which provide much of the initial research into promising therapeutics, and industry partners, who can usher these findings into clinical trials. Despite the many difficulties in moving a promising new treatment across the translation gap, Dr. Finkbeiner was optimistic. Innovative partnerships like the ones he described could one day pave the way for a drug that effectively treats HD.
Dr. Steve Finkbeiner is the Associate Director of the Gladstone Institute of Neurological Disease, Director of the Taube-Koret Center for Huntington’s Disease Research, and the Director of the Hellman Family Foundation Program in Alzheimer’s Disease Research.
Dr. Paul Muchowski on the Immune System and HD^
The second presentation of the day was delivered by Dr. Paul Muchowski, who discussed his work in linking the immune system and HD. His work was originally inspired by the observation that HD affects more than just neurons, since mutant huntingtin is expressed everywhere in the body. It was recently discovered that the immune system actually gets activated before the onset of symptoms in HD patients. This led Dr. Muchowski to wonder whether immune activation contributes to neurodegeneration in HD. In other words, is the brain sending “danger signals” to immune cells, which then harmfully attack brain tissue and cause the symptoms experienced by HD patients?
To answer this question, Dr. Muchowski’s lab looked at microglia, immune cells that act as the brain’s surveillance tools. When there is tissue damage in the brain, microglia cluster together to signal the body to react and rescue the damage. The more microglial activation there is in the brain, the fewer neurons that are lost. So, the researchers wondered: does mutant huntingtin protein impair the function of microglia? After performing some staining and assays in cells, Dr. Muchowski and his colleagues discovered that the migration of microglia is impaired in HD patients. Thus, the immune system’s response to damage of brain tissue is less efficient, because the microglia are not able to quickly and accurately signal the site of injury. To confirm this theory, they added mutant huntingtin protein to “normal” microglia in mice, and found that these microglia became impaired, and exhibited activity akin to that of the microglia in mouse models of HD.
Because of these findings and others, transplants of bone marrow in humans (to provide “normal” microglia and other immune cells to HD patients) have been conducted. Early trials have been promising: patients exhibited slowed development of behavioral symptoms as well as decreased synaptic loss. There is now a great deal of research being done to determine which FDA-approved anti-inflammatory drugs can provide similar benefits in HD patients. Researchers are also studying mice to investigate other methods of targeting the immune system, and to establish how these different therapies might affect response to regular infections. Dr. Muchowski’s lab is one of the many that are eagerly pursuing this exciting avenue of research, and the researcher expressed hopes of having more good news to report soon.
Dr. Paul Muchowski is a researcher at the Gladstone Institute of Neurological Disease and UCSF.
Dr. Lisa Ellerby on Drug-Target Validation^
Dr. Lisa Ellerby’s presentation focused on her work in drug-target validation with the goal of developing HD therapeutics. Research has demonstrated that the huntingtin protein is large and contains many distinct structural motifs and regions, which confer on it numerous functions, such as intracellular transport. Since the one driving trigger of Huntington’s disease is the abnormal conformation of mutated huntingtin and, thus, the disruption of its functions, understanding the pathways by which huntingtin acts will give insight into the process of identifying targets for therapeutic consideration and drug development in HD. In the short run, however, the ideal therapeutic target for Huntington’s disease is an already FDA-approved and marketed drug, which, once identified, can subsequently be validated in its mechanism of modulating the effects of HD. In a small study that Dr. Ellerby’s research group conducted, a library of 1,150 FDA-approved compounds was screened with a simple in vitro HD model. In other words, each of these compounds was tested for beneficial effects in striatal cells that roughly mimic HD pathology and behavior. Ultimately, six similarly structured compounds stood out, but more notably, many of these compounds were already drugs marketed as antihistamines or anti-migraine medications; for example, one of the compounds identified was Claritin®, a well-known allergy medicine.
For subsequent therapeutic trials, the group decided to study in depth a compound known as pizotifen, an anti-migraine drug which can cross the blood-brain barrier. Initial experiments in vitro revealed that pizotifen treatment in striatal cells activated the ERK pathway, the same mechanism by which some growth factors exert their neuroprotective effects. Dr. Ellerby’s group proceeded to perform a drug therapeutic trial for various dosages of pizotifen in HD mouse models. Despite a lack of improvement in mouse weight, pizotifen not only significantly improved mouse performance on the rotarod, a revolving rod used to assess motor coordination, but also demonstrated beneficial effects in terms of increased striatal size and DAARP-32 levels, a marker of neuroprotection. Other compounds known as polyphenols have already been shown to extend lifespan and improve rotarod performance in mice via ERK activation, but the fact that pizotifen is already a tested and approved drug in Europe renders it an ideal target for further study. Though more testing and experiments must be done to study the signalling behavior of pizotifen and to improve its function in vivo, Dr. Ellerby’s work presents an effective method for the discovery and characterization of HD therapeutics.
Dr. Lisa Ellerby is an Associate Professor at the Buck Institute for Research on Aging.
Dr. Jan Nolta on Mesenchymal Stem Cells^
The fourth and final talk of the morning was presented by Dr. Jan Nolta, who updated us on her work using mesenchymal stem cells (MSCs) in HD research (for more on MSCs, see https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2011/07/mesenchymal-stem-cells-2/). Dr. Nolta is exploring the potential of MSCs to deliver brain-derived neurotrophic factor (BDNF) to the brain. BDNF and other neurotrophic factors have been shown to have beneficial effects in HD brains (see https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/neurotrophic-factors-and-huntingtons-disease/), and Dr. Nolta hopes that engineered MSCs which secrete these factors may become a viable clinical therapy for HD. She has also shown that MSCs themselves, as adult stem cells that can repair damaged tissue, are beneficial in HD mouse models. The injected cells use a bystander mechanism of tissue regeneration — rather than replacing hurt cells, they repair them by traveling to the site of injury and producing healing factors. MSCs have further been shown to have a strong safety profile in mouse and primate models, indicating that they may be safe for clinical use and continue to circulate in the body many months after injection. Because of their proliferative abilities, MSCs can be produced indefinitely in good manufacturing practice clean-room facilities, and so are appealing as potential treatments for HD.
Besides preparing for a phase I clinical trial of MSC injection and performing pre-clinical research on the potential for MSCs to deliver BDNF to the brain in HD patients, Dr. Nolta is investigating the possibility of MSC delivery of siRNA molecules that knock down the mutant hutingtin protein. siRNA is a method by which a gene is prevented from being translated*into a protein by causing its mRNA sequence to bind to a complementary sequence that removes it from the body (for more information on siRNA, see https://www.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/rna-interference-rnai/). By removing mutant huntingtin, Dr. Nolta hopes to mitigate some of its harmful effects on brain and body functions. Although still grappling with some drawbacks to MSC delivery and the treatment of HD, such as the difficulty of crossing the blood-brain barrier to target the MSCs into the brain, Dr. Nolta ended her talk confidently. She noted that these areas of research hold a lot of potential for clinical applications.
Dr. Jan Nolta is the director of the Stem Cell Program and Institute for Regenerative Cures at UC Davis School of Medicine.
Teresa Tempkin on Clinical Studies^
Teresa (Terry) Tempkin, RMC, MSN, ANP began the afternoon panel on clinical research by providing an update on HSG (Huntington’s Study Group) clinical studies. To provide some background, she reviewed the purpose of research studies and the type of studies that currently exist. Tempkin states that the goal of a research study is “to study information collected about the people enrolled in order to learn about manifestations of disease or to test the safety/benefit, side effects, and risks of an intervention designed to help people affected by a disease.” The biggest difficulty in clinical research, aside from funding, is getting eligible people to participate in the studies. To illustrate this point, Tempkin explained five practical reasons to participate in clinical trial studies, including having a desire to help; contributing to the efforts for a cure and effective treatments for HD; having spare time; caring about HD research for future generations; and feeling a need to actively respond to HD.
A lot of research, time, and effort goes into the creation of clinical trials, and so they have strict guidelines and protocols that researchers and participants must follow during the pathway to new drugs and therapies. All trials are double-blind, which means that the participant and researchers are unaware of who receives the active drug and who receives the placebo. The trial proceeds in three unique phases. After the pre-clinical mode, phase I begins, and the drug is tested in healthy humans for safety. During phase II, the drug is tested in a small population with the disease to establish safety and dosing. This is followed by phase III, in which the drug is tested in a larger population for efficacy, after which FDA approval is sought. More than 3,000 people are enrolled in HSD observational studies and nearly 1,000 people are enrolled in HD clinical treatment trials. Worldwide, there are 210 clinical sites in 28 countries. Despite the often long process of both observation and clinical trials, Tempkin stressed their importance in increasing the body of knowledge in the HD community and providing an avenue for further advances and developments.
Teresa (Terry) Tempkin, RN, MSN, ANP is a registered nurse at the UC Davis Medical Center. She is a representative of the HDSA Center of Excellence at UC Davis, where she is actively involved with clinical trial research.
The UCSF Memory and Aging Center on Clinical Studies, Behavioral Strategies, and New Research Discoveries^
In the second half of the afternoon session, representatives from the UCSF Memory and Aging Center multidisciplinary team presented a series of talks with topics ranging from how to manage the behavioral traits of HD to promising findings from recent HD research.
Dr. Michael Geschwind commenced the series with updates from recent clinical studies in PREDICT-HD. As an observational study of healthy individuals (who can be gene-positive or gene-negative) from HD families, PREDICT-HD aims to find the earliest detectable changes in thinking, emotions, and motor skills caused by HD. Synthesizing 18 published papers from the study, Dr. Geschwind validated the possibility of diagnosing people with HD several years before motor onset of the disease. Existing research has confirmed that volume changes in certain areas of the brain — like the striatum, putamen, and white matter — can be used as markers for HD more than 15 years before motor onset. By allowing people with HD to be diagnosed before the diagnostic threshold, these early markers can be employed to identify gene-positive participants for trials of drugs that slow the progression of the disease. Because the striatum and the putamen play an important role in regulating movements, learning, and the communication of different brain regions, their shrinkage is responsible for a diverse set of cognitive disorders experienced by people with HD.
In the next presentation, Dr. Katherine Possin reviewed and offered caregivers many strategies for managing the most commonly impacted cognitive functions, including circadian rhythms, implicit memory for skills and habits, spatial perception, self-awareness, planning and organizational ability, and verbal skills. Reminding listeners that these symptoms do not originate from psychological disorders, Dr. Possin encouraged caregivers to remain patient, consoling, and attentive. To assist people with HD in planning, organizing, and reducing frustration and irritability, caregivers can help their loved ones by establishing daily routines, structuring conversations around limited subjects, and straying away from open-ended questions.
In the closing talk, Dr. Gail Kang and Dr. Sharon Sha took turns sharing some promising findings published on HDBuzz, a news website for HD research, in 2011. Some highlights from the presentation:
• A recent demographic survey conducted by The Huntington’s Disease Association in England indicated that HD might be twice as common as we previously thought. As both governmental agencies and biopharmaceutical companies use prevalence figures extensively in allocating funds, this finding foreshadows a significant future increase in HD funding.
• HD protein affects cilia, tiny hair structures found on every cell. In mice with HD protein, researchers have found cells with abnormally long cilia, and an overlap between the location of the HD protein and the location of the cilia. Future research on the relationship between the HD protein and cilia might yield important information about the function of the huntingtin gene.
• Melatonin, a compound produced by the pineal gland to regulate our sleep/wake cycle, has been proven effective in delaying the onset and extending the survival of HD mice. Mice receiving melatonin treatments maintain longer motor control, live longer lives, and have less brain atrophy.
• Prana Biotech’s new trial of using PBT2 to reduce copper binding has produced positive results on mice with HD. The compound not only improves the motor control of the mice, but also extends their lives by 40%. Researchers are carrying out Phase 2 of the trial in the United States and Australia.
• Giving TSA (Trichostatin A), a histone deacetylase inhibitor (HDAC), to mice with age-related long-term memory problems has been shown to improve their memory. Researchers are further exploring the possibility of using HDAC inhibitors in treating the various cognitive disorders caused by HD.
• Researchers at UCSD are looking at Memantine, an existing medication for Alzheimer’s disease whichhas been shown to slow the progression of HD in mice. Although an effective dosage for the drug has yet to be determined, a low dosage has proven effective in improving the movements of the mice, and early administration has proven effective in reversing their problems with motor learning.
• According to a questionnaire sent out to many individuals with HD, lifestyle matters. The study reports that, on average, the onset of HD occurs about five years earlier for passive participants, regardless of the numbers of GAG repeats in their genes. However, it should be noted that neither the scale of the study nor its methodology was thoroughly discussed.
Dr. Michael Geschwind is the Michael J. Homer Chair of Neurology at the UCSF School of Medicine. Dr. Katherine Possin is an Assistant Professor of Neurology at the UCSF Memory and Aging Center. Dr. Gail Kang is an Assistant Clinical Professor at the UCSF School of Medicine. Dr. Sharon Sha is a Neurology Fellow at the UCSF Memory and Aging Center.