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University of California at San Francisco 2010 HD Research Symposium

HOPES summary of the talks from scientists and clinicians

Note: This article includes references to Dimebon, which is no longer being considered as a potential treatment for HD after the HORIZON clinical trial showed that Dimebon was not better than a placebo. For more information, click here

Lisa Ellerby, PhD, Buck Institute for Age Research^

Target Validation in Huntington’s Disease

Dr. Ellerby’s talk focused on the question: “What are possible biological targets for drugs designed to treat HD?” Therapeutic drugs work by targeting specific processes in the human body that have gone awry in disease. For example, the common symptom chorea in HD is thought to be a result of the increased activity of the neurotransmitter dopamine. Tetrabenazine is used to treat chorea because the drug reduces the amount of dopamine in the brain.

At present, the pharmaceutical industry is focused on developing therapeutics for approximately 200 to 300 different targets in the human body that may be related to HD. However, those few hundred targets represent a very small subset of all possible biological targets and it is possible that drugs that have been created for other diseases could have therapeutic benefits for individuals with HD. One example of this is Dimebon, a drug that was originally used as an anti-histamine and is now being studied in clinical trials for HD because of its neuroprotective effects.

Dr. Ellerby is interested in identifying targets that play specific roles in the death of neurons in HD. While it is well known that the mutated Huntingtin protein (Htt) results in the neurodegeneration characteristic of HD, Dr. Ellerby’s research is important because it can provide insight into how this neuronal death occurs. Her lab used small interfering RNA (siRNA) to block the production of different proteins and then assessed the effects of these knockdowns on neuronal death. If shutting off a particular target results in decreased neuronal death, it is possible that this target plays a role in neurodegeneration due to mutant Htt. These experiments found that blocking the activity of proteases, enzymes that break down other proteins, reduces the death of neurons in a cellular model of HD. Specifically, Dr. Ellerby mentioned that decreasing the level of a family of proteases known as matrix metalloproteases (MMP) reduces the toxicity of mutant Htt. By using siRNA to identify targets that play a role in HD, Dr. Ellerby’s research is laying a foundation for the discovery and development of drugs that can prevent, treat, and reverse the devastating effects of HD.

Jill Larimore, BSc, 4th year graduate student in neurobiology at UCSF^

Immune System Dysfunction in Huntington’s Disease

Ms. Larimore, as a member of Dr. Muchowski’s lab, researches the effect of HD on immune system function. Using yeast and animal models, her lab explores the HD on the molecular level in order to find new therapeutic targets. Ms. Larimore began her talk by explaining the immune system of the brain and the role of microglia cells. These specialized cells differ from those found in the peripheral immune system (i.e. the immune system which operates in all parts of the body besides the brain and spinal cord). Although the blood-brain barrier normally keeps these immune systems apart, Larimore’s research interestingly showed that there was peripheral immune system activation in HD patients. This indicates that the neurological symptoms of HD are either paralleled in the peripheral immune system or communication between cells traverses the blood-brain barrier to connect the two immune systems.

The Muchowski lab’s research also showed that HD increased inflammatory response in both the neural and peripheral immune system, even before manifestations of HD symptoms. Inflammation is an acute immune response that counters tissue injury by releasing chemical signals in the area of injury. Physical inflammation acts as a barrier against the spread of infection while immune cells repair the damaged tissue. Although normally beneficial, inflammation can be harmful when it becomes chronic and remains after healing. In HD patients, a key immune protein, interleukin-6 (IL-6) was found at higher concentrations both in the brain and body. IL-6 helps activate and regulate inflammatory response in the immune system, and indicates immune activity when found in heightened concentrations. In the brain, microglia activation increased as well, indicating microglia were responding to tissue damage in the brain. While immune activation could potentially be a natural healing response, Muchowski’s lab hypothesized that it was chronic inflammation that contributes to HD progression.

Similar inflammatory symptoms found in other neurodegenerative diseases have been extensively researched. Treatments have been found to regulate the heightened inflammatory response that occurs when certain immune proteins are activated. In mouse models of Alzheimer’s disease, the cannabinoid type 2 receptor (CB2) in the brain was found to decrease IL-6 and other proteins involved in the immune response in both the peripheral and neural immune systems. Inhibition of the CB2 receptor in a mouse model of HD worsened symptoms, as shown in behavioral assays (testing the mouse for motor functions and balance). Activating the CB2 receptor resulted in improved coordination and motor function, and slowed the onset of HD symptoms. Because CB2 therapeutics are already in clinical trials for autoimmune diseases, if CB2 is found to be beneficial in HD models by decreasing inflammation in the brain and the peripheral immune system these drugs could potentially be clinically tested as a therapy for HD.

Jan Nolta, PhD, Stem Cell Program, UC Davis^

Working toward mesenchymal stem cell-based therapies for HD

Dr. Jan Nolta, director of stem cell research at UC Davis, presented on recent developments in her work on therapies for HD using mesenchymal stem cells (MSCs).  MSCs have been found to deliver protein products throughout tissue for 18 months at a time. MSCs can potentially be engineered to deliver proteins that help prevent neurodegeneration to the brain. MSCs themselves exhibit neuroprotective activities. They restore synaptic connections, decrease inflammation, decrease neuron death and increase vascularization. Using vessels in the brain as train tracks, they are able to travel throughout the brain to assist other cells. Videos taken under a microscope show that MSCs are “social cells,” meaning they are constantly communicating with other cells around them. By interacting with another cell, an MSC can sense the needs of that particular cell and initiate a flow of appropriate nutrients directly into the other cell. In this way, MSCs act as cellular “paramedics” of the body.

One possibility for an HD therapy involves injecting MSCs into the brain where the cells could help reduce neurodegeneration by saving damaged neurons. Scientists at UC Davis conducted tests on non-human primates to ensure that injecting MSCs into the brain is safe for humans. Safety testing was recently completed with MSCs being injected through the skull into the brains of fetal non-human primates. Fortunately, results showed that after 5 months, the MSCs were still present. This means MSCs will be able to stay in the brain for a good length of time, theoretically assisting neurons and preventing additional cell death. Also, no tumors or tissue abnormalities were detected, indicating that MSC injection is largely safe. More studies about the intracranial transplantation and long-term MSC safety are needed.

Research on MSCs in Dr. Nolta’s lab currently involves three main goals: test bone marrow-derived MSCs to see if they restore neurons in non-human primates, test MSCs for the ability to secrete factors like brain-derived neurotrophic factor (BDNF) that help brain cell function, and to investigate MSC production of siRNA. Dr. Nolta was happy to announce that the FDA recently approved injection of MSCs into the central nervous system of individuals with another disease called amyotrophic lateral sclerosis. This sets an important precedent that will increase the likelihood that Dr. Nolta’s eventual therapy will work in other diseases.

Michael Geschwind, MD PhD, UC San Francisco Memory and Aging Center^

Update on Clinical Studies and Trials in Huntington’s Disease

Dr. Michael Geschwind, a neurologist at the UCSF Memory and Aging Center, provided updates about clinical trials in HD. First, he reviewed the two types of clinical research: observational and clinical trials. An observational study is a type of study in which individuals are observed and certain outcomes are measured (such as motor control or mental function) but no attempt is made to affect the outcome in the form of treatment or therapy. In contrast, a randomized double-blind clinical trial is a study in which each individual is assigned randomly to a treatment group (experimental therapy) or a control group (placebo or standard therapy) and the outcomes are compared. Currently, there is important and promising HD-related clinical research being conducted both within and outside of the United States. The following paragraphs summarize the significant points regarding recent or ongoing studies in the HD field.

The PREDICT-HD study is an observational study that began in 2001, was expanded in 2008, and is still underway. The ultimate goal of the PREDICT-HD study is to define the earliest biological and clinical features of HD before at-risk individuals have diagnosable symptoms of the disease. While the current approach is to treat HD at the beginning of the onset of symptoms, this study aims to help design future studies of experimental drugs aimed at slowing or postponing the onset of HD in the at-risk population prior to observable symptoms. The PREDICT-HD study has identified markers that were shown to appear long before an individual would expect to be diagnosed. One marker is CAG repeat length: CAG stands for the nucleotides (DNA building blocks), cytosine, adenine, and guanine. The HD mutation consists of multiple repeats of CAG in the DNA.  This study validated the CAG repeat length-age formula, in which the CAG repeat length for an individual could estimate the average age of HD onset.  In general, fewer than 30 repeats is considered normal, whereas more than 39 repeats means the person will likely develop HD in a normal lifespan. To read more about CAG repeat lengths click here. Other markers such as the size of ventricles in the brain and the volume of other specific brain areas (i.e. striatum) were also found.  In short, the PREDICT study has validated models for predicting motor onset of HD, which will ultimately increase the likelihood of treating HD before patients become symptomatic.

The DIMOND-HD study was a phase II clinical trial investigating the efficacy of the drug Dimebon, which is a small molecule that inhibits nerve cell death. This drug has been shown to decrease cognitive impairment in Alzheimer’s patients, and has been shown to improve cognition and memory in rats. Dimebon is often referred to as latrepirdine. The DIMOND-HD study evaluated the safety of administering Dimebon for 3 months and the efficacy of Dimebon in improving cognitive, motor, and overall function in subjects with Huntington’s Disease. The study was completed in the summer of 2008, and showed that Dimebon is a well-tolerated drug that generally improves cognition in HD. The researchers concluded that the drug should be tested in phase III clinical trials, which has resulted in the HORIZON trial described below. To read more about Dimebon click here.

The HORIZON study is a randomized, double-blind, placebo-controlled study that is ongoing at 37 sites, spanning 7 countries. The study is in phase III of clinical trials, and also aims to expand upon the results of the DIMOND-HD study and determine if Dimebon (latrepiridine) safely improves cognition in patients with Huntington’s disease.

The HART study is also a randomized, double-blind, placebo controlled study that is ongoing in both Europe and North America. The purpose of the study is to determine if ACR-16, also known as pridopidine and Huntexil, is effective and safe in the symptomatic treatment of HD. ACR-16 is a dopamine stabilizer, which means that it works to help regulate the many functions of dopamine in the striatum and other areas of the brain. ACR-16 has passed phase II of the clinical trials in Europe, and has been allowed to be tested in stage III in North America (US and Canada). Initial results of the clinical trials are promising, and have shown that ACR-16 can improve motor control and may translate to 0.5-1.5 years of disease improvement in voluntary and involuntary movements. To read more about ACR-16, click

The following table outlines the types of characteristics researchers are looking for in each of the ongoing HD Clinical Trials described above. For more information, click on the links provided.

Inclusion Criteria for HD Clinical Trials

PREDICT-HD StudyFor more information on the PREDICT-HD study click here Gene negative and gene positive individuals: specifically, men and women at risk for HD, who have been tested for the HD gene mutation, and who have not been diagnosed with symptoms of HD (CAG > or equal to 36 for CAG-expanded group or CAG < 36 for CAG-norm group).
• 18 years of age or older
• Able to commit to a minimum of 5 yearly evaluations
• Commitment of a companion to attend visits or complete surveys via mail
• Able to undergo a MRI
HORIZON StudyFor more information on the HORIZON study click here • Have clinical features of HD and a CAG polyglutamine repeat expansion ≥ 36• Have cognitive impairment as noted by the following:

1. A screening MMSE and a baseline (pre-dose) MMSE score between 10 and 26 (inclusive); and

2. A subjective assessment of cognitive impairment with decline from pre-HD levels by the Investigator after interviewing the subject and caregiver;

•  Are willing and able to give informed consent

•  Aged 30 years or older

• Have a caregiver who assists/spends time with the subject at least five days per week for at least three hours per day and has intimate knowledge of the subject’s cognitive, functional, and emotional states, and of the subject’s personal care.

HART StudyFor more information on the HART study click here • Able to provide written Informed Consent prior to any study related procedure, including consent to genotyping of the CYP2D6 gene.• Clinical features of HD, and a positive family history and/or the presence of ≥ 36 CAG repeats in the Huntington gene.

• Male or female age ≥ 30 years.

• Willing and able to take oral medication and to comply with the study specific procedures.

• Ambulatory, being able to travel to the assessment center, and judged by the Investigator as likely to be able to continue to travel for the duration of the study.

• Availability of a caregiver or family member to accompany the subject to two visits.

• A sum of ≥ 10 points on the mMS at the screening visit.

• For subjects taking allowed antidepressants or other psychotropic medication, the dosing of medication must have been kept constant for at least 6 weeks before enrollment.

Works Cited

F. Clum, C. Garnett, T. Wang and A, Lanctot, 2010