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Help4HD Second Annual Symposium

HOPESters Natty and Caitlin headed down to Southern California on August 22nd for Help4HD’s 2nd annual symposium in Riverside, California. The event was hosted at The Mission Inn and featured an array of guest speakers and presenters representing research groups, caregiver organizations, pharmaceutical companies, and advocacy groups. Keynote speakers included Dr. Donald Cleveland of UC San Diego, Dr. Leslie Thompson of UC Irvine, and representatives of the Inland Caregiver Resource Center and Riverside Community Health Foundation. This symposium was a full day of education, resource sharing, and community building for those who attended.


Sponsors of the event included Auspex Pharamceuticals, Teva CNS, Lundbeck Pharmaceuticals, Raptor Pharmaceuticals, and the Griffin Foundation. Attending as a representative of HOPES was a wonderful opportunity to meet some of the dedicated individuals and organizations working to raise awareness and support for Huntington’s disease and those that it affects. The HD community is truly astounding in the amount of compassion and dedication individuals have for each other and I am grateful to have played even a small role in Help4HD’s goal to create a world “where everyone knows what HD and JHD is; a world in which compassion is a normal response to the devastation that this horrific disease [causes].”

Below is a brief summary of each presentation.

Terry Tempkin, NP-C, MSN— University of California, Davis HDSA Center of Excellence
“Preparing for a stem-cell based treatment for HD: Pre-Cell and Beyond”

Terry Tempkin presented current updates on UC Davis’s progress in its HD stem cell treatment clinical trial. The proposed treatment uses mesenchymal stem cells engineered by Dr. Jan Nolta of UC Davis to overproduce BDNF as a therapeutic for HD. In HD, medium spinal neurons of the striatum die out, resulting in many of the symptoms seen in HD patients. Current research has identified lowered levels of BDNF as a key cause of this cell death as the mutant Huntingtin protein blocks production of BDNF at the RNA level and reduces axonal transport from cortical cells to the striatum. Mesenchymal stem cells have been developed as a viable candidate for delivery of BDNF into the striatum due to their reliable safety profile and ease to engineer. Mouse models of HD treated with implantation of these engineered mesenchymal stem cells have showed success in decreasing behavioral symptoms such as anxiety and reduced striatal atrophy. The group has completed the first phase of their project plan, “Pre-Cell”, and are now seeking FDA approval for the first in-human trial of gene therapy engineered mesenchymal stem cells implanted into the brains of patients with Huntington’s disease.

Dr. Don Cleveland — University of California, San Diego
“Therapeutic strategies in HD: developing a gene silencing therapy for neurodegenerative disease”

Dr. Cleveland presented on a potential treatment for HD that is currently in mouse models and was initially designed for Amyotrophic Lateral Sclerosis (ALS). The treatment uses antisense oligonuceltides (ASOs), which are chemically similar to DNA and mRNA and are able to base pair with the mutant huntingtin mRNA and signal the cell to degrade it, preventing the production of huntingtin protein. In partnership with Isis Pharmaceuticals, Dr. Cleveland’s work builds on this technology with a designer DNA infusion into the spinal cord targeted against the Huntingtin gene. Success in mouse models shows reduced Huntingtin expression for more than 3 months and partial disease reversal. Trials for safety in human patients have begun and consist of four monthly doses. Efficacy trials are expected to begin in 2017.

Heather Hare, Director of Communications and Outreach at Huntington Study Group (HSG)

Heather Hare discussed the role that the Huntington Study Group (HSG) is playing in current HD research. HSG is a network of investigators, scientists, and HD experts who work to find viable HD treatments, expand the global HSG network, and design and facilitate clinical trials. As of August, they are enrolling in Legato-HD and Signal. HSG is also working to raise clinical trial participation by partnering with sponsors and research sites to cover travel expenses and make sites more accessible. They have also created a Future Contact Database, which notifies subscribers when a new trial is open for enrollment. They hope to streamline the relationship between sponsors, trial participants, and research groups to improve the success and accessibility of clinical trials.

Contact info:

Sonia Slevinski: University of Iowa Department of Psychiatry, Napolis Lab
Kids HD + Kids JHD Studies

Sonia Slevenski attended as a research group representative from Iowa. Her group is working on two studies for kids affected by Huntington’s disease (HD) and Juvenile Huntington’s disease (JHD). The first is an ‘at-risk’ study, which follows children who are at-risk for HD in order to track their brain structure and function with MRI and computer analysis. They also test thinking, memory, movement, balance, self-awareness using quizzes, brain tests, and behavior questionnaires. The intent is to identify how early changes begin to occur for those who eventually develop HD. Researchers also use genetic analysis to aid in this research and match early changes with gene status. However, due to the ethical implications of research studies with minors, all information is deidentified out of respect for allowing those in the study to decide whether they want to know their gene status once they become of legal age. Preliminary results have found some evidence for brain changes happening as far as 30 years from expected onset, including reduced putamen and increased thalamus volumes.
The other study is for those affected by JHD. The research is attempting to identify the brain changes that occur in JHD in contrast to adult-onset as well as what potential biomarkers can be identified. The JHD protocol is similar to the at-risk protocol, and researchers are hopeful that this study will result in a better understanding of JHD in order to make progress on potential treatments. This is one of the first studies to look at exclusively JHD and, in combination with the at-risk trial, is trying to understand how HTT plays a role in the developing brain. 

Carmen Estrada, Executive Director of Inland Caregiver Resource Center
Note: Carmen was not able to attend and another representative from the organization spoke in her stead.

The final presentation was from a representative of the Inland Caregiver Resource Center. HD and JHD affects not just those with the diagnosis but also those who care for them. These caregivers are typically under a lot of stress, trying to balance work and caring for their loved one. Caregivers face many challenges including a lack of preparation, lack of support, lack of self-care, and loss of identity. The ICRC works to provide services for caregivers not limited to HD, such as information and referrals to other agencies, family consultation, vouchered services like respite care and supplemental services, and short-term counseling. They also run support groups, educational conferences, and support and bereavement programs. A particular concern of the ICRC is a lack of self-care that caregivers often suffer from. Of the population that they serve, about 2/3 have identified having symptoms of depression. In order to alleviate some of this stress, ICRC helps caregivers develop a care plan, both for the patient and caregiver, provides short term counseling, respite care, and recommends a variety of strategies and services to help caregivers. Caregivers do not lack in resilience and love, but providing support for them is critical to prevent burnout.


Conferences and Conventions: Table of Contents






11th Annual Huntington Disease Research Symposium


On September 13th, the UCSF Memory and Aging Center hosted the 11th Annual Huntington Disease Research Symposium. The symposium featured scientists discussing their work in basic science and clinical HD research. It was a great opportunity for HD patients and families to meet local researchers, become more informed about progress in HD research, and learn about ways get involved.

Stem cells figured heavily in the basic science portion of the symposium. Steve Finkbeiner[1] from the Gladstone Institute of UCSF kicked off the conference by discussing among other things, the use of skin or blood samples from HD patients to make stem cells, which then can then be differentiated into brain cells. This process preserves the patient’s genetics and may help more directly test the efficacy of prospective therapies. These stem cells are called induced pluripotent stem cells and induced neuronal stem cells, respectively. Scientist Vikki Wheelock[2] discussed a different kind of stem cell, mesenchymal stem cells, and the potential ability to engineer non-HD mesenchymal stem cells to deliver drug treatments. These stem cells come from adult bone marrow.

Many of the researchers rely on bioinformatics and the use of new research methods like optogenetics to make advancements in understanding HD. For example, Alexandra Nelson[3] discussed her efforts to understand HD’s effects on the brain using optogenetics, a technique that a lab at Stanford pioneered. Optogenetics takes advantage of light sensitive proteins in algae. The genes for these proteins can be packaged inside of a virus and injected into an animal’s brain to make nearby neurons light-sensitive. Through this technique, Alexandra Nelson hopes to understand how the living cells that survive HD can be harnessed to deal with the symptoms.

Three researchers from the Memory and Aging Center at UCSF, Michael Geschwind[4], Natasha Boissier[5], and Erica Pitsch[6], discussed the clinical side of HD research. Overall, despite the acknowledgement of the scientists that many of these treatments and advancements are in preliminary stages, and that clinical research may be halted if it is determined to be ineffective or unsafe, hope was in the air at the symposium.

More Information about the Scientists Involved

[1] Steve Finkbeiner
[2] Vicki Wheelock
[3] Alexandra Nelson
[4] Michael Geschwind
[5] Natasha Boissier
[6] Erica Pitsch


Help 4 HD International Symposium 2014

On Friday, July 19, HOPESters Natty, Preston and Kristen made the trip down to Santa Maria, California to attend the first ever Help4HD International Symposium. The mission of Help4HD International is to facilitate conversations in the research community by providing vital information regarding research and clinical trials to the Huntington’s disease community.  For more information on the organization visit:

Below are the summaries of all the keynote speeches with attached video archives of the presentations:

Congresswoman Lois Capps, Representative, Santa Barbara County^

Congresswoman Lois Capps, the US Representative, Santa Barbara County, made the opening address at the event. She commended the Huntington’s disease community for its resilience in the face of adversity and called for the community to continue to advance on three fronts: supporting caregivers, caring for the sick and bolstering research efforts. Rep. Capps also highlighted the policy advances in assisting Huntington’s disease afflicted individuals and their family such as the HD Parity Act which aims to waive the 24-month waiting period for Medicare eligibility for Huntington’s disease patients. In addition, as a member of the Rare Diseases Caucus, Rep. Capps pledged to push for the study of rare diseases and is positive that the research on rare diseases will produce a ripple effect that will benefit patients of other illnesses like Huntington’s disease.

Dr. Ira Shoulson, Founder HSF (Huntington Study Group) and PSG (Parkinson Study Group)^

Dr. Ira Shoulson, the founder of the Huntington Study Group and Professor of Pharmacology, Neurology and Human Sciences in Georgetown University, was the first keynote speaker at the symposium. Dr. Shoulson focused on the different organizations involved in research, current state of clinical research, and explored the future of Huntington’s disease treatments. He highlights the concern of patients who register for clinical trials, as they are often worried that they might be assigned to receive the placebo treatment; he addresses this concern by emphasizing the documented benefits of the placebo effect. Furthermore, Dr. Shoulson talks about the measures put in place to protect patients undergoing clinical trials, such as informed consent measures and the regulatory processes of the FDA. He then concludes his presentation by discussing the current and future direction that Huntington’s disease research will move in. Dr. Shoulson mentions that current research can be divided into several areas: environmental factors, movement treatment, cognitive-enhancement, and gene expression modification. In the future, he believes that clinical trials may explore treating individuals possessing the dominant Huntington’s disease gene but have yet to develop the symptoms.

Ray Dorsey, MD, MBA, Professor of Neurology and Co-director, Center for Human Experimental Therapeutics ^

Dr. Ray Dorsey, who joined the symposium via a Skype Call, investigates new treatments for movement disorders. Using web-based conferencing, his work seeks to provide care to those with Parkinson’s disease and other diseases, regardless of their geographic location.

Dr. Dorsey began his talk by asking the community to consider what they could do to help the HD community advance research and what clinicians can do to relieve the burden of those affected by the disease.

He stated that the greatest accomplishment in recent medicine was the transformation of HIV/AIDS from a fatal disease to a chronic, manageable one in the past 30 years. Despite a lack of information about retroviruses and the immune system, researchers were able to develop and obtain FDA approval for an effective drug. Now, over the last generation, about ten drugs have been discovered to treat HIV. People can now live healthy, productive lives for decades.

He asks the audience if scientists can do something similar for Huntington’s disease. For example, Nancy Wexler came from a family affected by HD and was able to identify the gene that caused Huntington’s disease. This occurred at a time where genes were thought to cause these diseases, but it was unheard of to determine their location.

Dr. Dorsey then transitioned to how he is advancing the state of Huntington’s disease care through his work with the study, Connect. Huntington. Due to the lack of resources available to individuals in remote or rural regions, telemedicine has become increasingly important as a mechanism to provide these individuals with the care they need. These resources include consultations with neurologists and other doctors on various issues. Individuals should not be denied treatment due to their location.

The aim of the Connect.HD is to provide care to those affected by HD directly in the individual’s home via internet-connected devices like smartphones or computers. There are five states participating in this study, including California. Requirements include the presence of Huntington’s disease in the home as well as access to an internet-connected device. If you are interested in participating in this study, contact Ray Dorsey at

Dr. Suzanne Pontow, Co-director, Umbilical Cord Blood Collection Program^

Dr. Suzanne Pontow, Co-Director of the California Umbilical Cord Blood Collection Program at the UC Davis Health System and a Stem Cell Research Program Supervisor at the Institute for Regenerative Cures, discussed both research and clinical applications, specifically for HD patients, for neonatal stem cells and the California Umbilical Cord Blood Public Bank.

She explained that a major research tool for the Institute is the use of neonatal stem cells both in research and clinical applications. The neonatal stem cells are collected from placental tissues and cord blood. The stem cells are made up of mesenchymal and hematopoietic cells, which are multipotent cells. Multipotent cells can differentiate into many but not all types of cells. For instance, hematopoietic stem cells can differentiate into several types of blood cells and mesenchymal cells can differentiate into bone cells, cartilage cells or fat cells, but they are limited to differentiation into these areas. However, both hematopoietic and mesenchymal cells can be induced into a pluripotent state from which they can become any type of cell in the human body.

Dr. Pontow described one example, in which researchers worked with a group of at-risk newborns for autism spectrum disorders. Researchers isolated hematopoietic stem cells from the cord blood of newborns at risk for Huntington’s disease shortly after birth. The cells were cultured, induced into a pluripotent state and were differentiated into neurons. By studying these neurons, they could see if the neurons were developing normally and examine how the neurons responded to various drugs as a way to look for cures or to slow progression of the disease. This “disease in a dish” model is applicable across a wide range of disease types and allows researchers to conduct extensive research about a disease without invasive patient procedures.

Neonatal cell studies are of great importance when it comes to finding treatments for disease. These cells are readily available, easy to harvest and are “youthful”, which according to Dr. Pontow, means that they “last longer in culture and go through more successful divisions than adult derived stem cells.” These advantages allow easier assessment of immune system development and function, making neonatal cells an attractive research and therapeutic tool. With the creation of The California Umbilical Cord Blood Collection Program, there should be more of these cells available for different applications.

Dr. Peg Nopoulos, Professor of Psychiatry, Neurology, UI HD, Kids HD/Kids JHD^

Dr. Peg Nopoulos, Professor of Psychiatry, Neurology and Pediatrics in the University of Iowa, focused her discussion on juvenile Huntington’s disease (JHD).  Dr. Nopoulos explained the genetics behind JHD and the differences between the symptoms of adult onset HD and juvenile onset HD. She talked about the Kids-HD program, which is a specialized program where HD experts research on reducing the length of time for diagnosis of potential patients. Dr. Nopoulos explained there are difficulties diagnosing a non-specific symptom because current diagnostic tools cannot distinguish between children with and without the disease due to behavioral cues. Instead, she recommended the use of quantitative MRI as a more accurate tool, which measures the caudate volume of the brain.

Dr. Jan Nolta, Director UC Davis Stem Cell Program, Institute for Regenerative Medicine^

Jan A. Nolta, director of the UC Davis stem cell program and the UC Davis Institute for Regenerative Cures, is moving forward with groundbreaking plans to use mesenchymal stem cells (MSCs) as delivery agents for two potential treatments for Huntington’s disease, BDNF (brain derived neurotrophic factor) and RNA interference. Her research goal is to slow down the striatal (responsible for movement control and communication) degeneration and coax new striatal neurons to be formed in HD patients. Her approach is to use MSC adult stem cells from the bone marrow to repair damaged tissues by responding to the scene of injury and producing healing factors.

A few years ago, she received a grant from the California Institute of Regenerative Medicine to prepare for a clinical trial, where they would implant into the brains of Huntington’s disease victims mesenchymal stem cells that have been engineered to secrete the BDNF needed to protect neurons and keep them healthy. She also has a separate multi-million dollar grant from the state stem cell agency to develop an RNAi delivery system using mesenchymal stem cells. If the trial of MSCs with BDNF is successful, it will provide proof of principle for MSCs as a delivery system for RNAi. “These grants are extremely important to California and to the field of regenerative medicine,” said Nolta. “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.”

Patients with HD have much lower levels of BDNF than usual in their brain tissues and mutant protein blocks production of BDNF at RNA level. Nolta’s safe and effective strategy is to use mouse models to produce BDNF from MSCs transplanted into the striatum as a way to delay progression and potentially recruit new neurons. Her initial data, in conjunction with previous reports, indicate that instriatal BDNF delivery, via MSCs, can prevent motor dysfunction and neuropathological abnormalities in rodent models of HD

Mr. Kevin McCormack, Communications Director, the California Institute for Regenerative Medicine^

Mr. Kevin McCormack, Communications Director of the California Institute for Regenerative Medicine, emphasized the importance of the role of patient advocacy in making a difference for other Huntington’s disease patients and their families. Mr. McCormack explained that he and many others were working to connect patient advocates for Huntington’s disease to form a collective voice to impact policy decisions. He concluded his address by reinforcing the California Institute for Regenerative Medicine’s commitment to improve the lives of patients.

Kayla Horton, Graduate student, CIRM Bridges to Stem Cell Research^

Kayla Horton is from a family both affected by Huntington’s disease and cystic fibrosis. Her familial connections motivated her to study medicine. Horton is studying the use of human fat tissue as a source of stem cells as she is trying to discover the difference between studying adipose cells versus bone marrow in the context of stem cell research.

Mesenchymal stem cells (MSCs) have many advantages. They are easily accessible, hypo-immunogenic, anti-inflammatory, capabilities for neurogenesis and angiogenesis.

However, there are some delivery disadvantages. This study is looking for non-invasive delivery of this treatment through intravenous administration. Currently, direct implementation means brain or spinal surgery, which implants the paramedic cells.

Horton is attempting to develop a safe, non-invasive method of delivering hMSCs overexpressing neurotropic factors in order to provide neurodegenerative and protective effects to a CNS injury. Her hypothesis is to use intranasal administration of genetically modified and preconditioned hMSCs that will efficiently migrate to cell injury.

A non-invasive chemotaxic model exploits the MSCs’ innate migratory ability. They move towards the chemicals released by an injury. The goal is to deliver it through the nose, which would be non-invasive and easily repeatable as the MSCs die off.

In a recent study, the team did observe migration of cells in mice from nasal injection to the striatum, which means that Kayla Horton’s research could maybe one day provide a mechanism through which MSCs can be safely delivered to the brain without invasive surgery.

Ms. Teresa Tempkin, RNC, MSN, ANP, UC Davis HDSA Center of Excellence^

Ms. Tempkin’s primary focus is to be a part of the effort to find meaningful treatment for HD and to help families navigate their HD journey. She works with Dr. Jan Nolta and their objective is to obtain FDA approval in order to successfully complete a 2 year phase I trial of cellular therapy in patients with early stage HD. The gene therapy development candidate is donor-derived human MSCs that have been engineered to secrete brain derived neurotrophic factor (MSC/BDNF). Via recruitment from the  membership of the Huntington Study Group, her team has enrolled over 325 patients in more than 14 observational studies and clinical trials since 1997. Despite extensive knowledge of the genetics and neuropathology of HD, only palliative treatments exist.

She explained that the study has two phases: Pre-cell and HD-cell. Pre-cell study is a longitudinal observational study to enroll a cohort of early stage HD patients who are potential candidates for planned cellular therapy trial. HD cell phase is the phase 1 clinical trial of MSC/BDNF neurosurgical implanted into striatum using techniques similar to deep brain simulator implantation. In conclusion, she stated that managing expectations and burden of study for participants and caregivers is paramount and that the biggest obstacle in clinical research is time, money and FDA approval.

Dr. Ellen Feigal, Senior Vice President, Research and Development, California Institute for Regenerative Medicine^

Dr. Ellen Feigal, Senior Vice President, Research and Development, California Institute for Regenerative Medicine (CIRM), focused on the CIRM’s experience and future developments. Dr. Feigal explained the research development model used by the CIRM in managing the research projects under its charge. She also highlighted the challenges faced by research organizations in obtaining funding for conducting research.

Lavonne Goodman, MD^

Dr. Goodman began with a question: How do we reach people and get them to see the importance of clinical trials and find the energy to participate when their families are struggling with the disease? There are plenty of families that are passionate about research, but how can they garner that passion to help buoy others into participating?

It’s very hard to find treatment resources that are evidence-based. There isn’t a lot of research that has been done in this respect so the challenge for clinicians is to figure out how to manage Huntington’s disease in a way that is safe and effective.

Goodman facilitated a panel of expert physicians worldwide to figure out best practices for caring for a patient with HD. They discussed drug treatment and approached it pharmalogically, but realized the need to educate family members about the disease and teach them how to promote the health and well being of Huntington’s disease patients. One can print out the documents and take them to one’s physician in order to provide a resource of care.

Goodman studied chorea, obsessive compulsion, behavior issues and is now presently looking at psychosis, apathy, anxiety, agitation and sleep disorder. There is currently no evidence-based treatment for these symptoms. The goal is to give some guidance to patients, families, generalists on how to properly manage these specific symptoms.

For more information on the algorithm and Dr. Goodman’s work, visit

Dr. Nathan Goodman, PhD, Systems for HD^

Dr. Nathan Goodman is a senior scientist at The Institute for Systems Biology in Seattle. A PhD computer scientist, he has expertise and extensive history in the building and management of large databases in biologic systems. He, with support from the Hereditary Disease Foundation, is the primary author of HDBase, a web site which assembles datasets of interest to HD researchers, including reported drug studies in HD mouse models. He is in charge of web-based data acquisition and storage. His presentation was on technology-driven research for HD treatments.  To find drugs, he stated that we should start at the start and fix the “bad gene”. The second idea is to shut down the “bad gene” via ISIS RNA drugs. The third idea is to find earliest effects via human observation trials or study of HD mice. He talked about methods to find genetic modifies to slow down HD. One method he mentioned is the ISB method, which is a whole genome sequencing of HD families and individuals.

The first ever Help4HD Symposium ended with two powerful advocate stories by Francis Saldaña and Margaret Gallardo.

KP, PL & NJ 2014


World Congress 2013- Premanifest HD

In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.

The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.

HD is a unique disease because it is one of few diseases where patients who choose to test and do test positive for the mHTT gene will almost inevitably develop symptoms, making cohorts of premanifest HD subjects a valuable group for scientists to study, because the age of disease onset, severity of symptoms, and progression of the disease varies substantially. While it is valuable to study this population, studies of premanifest HD patients are complicated by the fact the line between pre-symptomatic HD and diagnosed HD is difficult to distinguish at times. So the need for biomarkers and a better description of premanifest and early stage HD needs to be outlined and to reach a consensus among physicians and researchers because the first treatment of HD will likely lie in delaying the onset and reducing the severity of HD rather than finding a cure.

Table of Contents:

1.Premanifest HD (Karl Kieburtz, United States)
2.Motor Assessment Reviewed (Ralph Reilmann, Germany)
3.Neuropsychology in Premanifest HD (Julie Stout, Australia)
4.MRI biomarkers in Premanifest HD (Rachael Scahill, United Kingdom)
5.Overview of pridopidine DRF Study design (Karl Kieburtz, United States and Anna Wickenburg, Sweden)

Premanifest HD (Karl Kieburtz, United States)

One of the first speakers at the Congress began his discussion of the success of other diseases and their associated biomarkers to confirm a diagnosis. One example, autosomal dominant Alzheimer’s disease (ADAD), common in a small population in Colombia has specific biomarkers: amyloid protein aggregation and hippocampal volume. ADAD is similar to HD, since it is a neurodegenerative disease in which the patient’s children have a 50% chance to inherit the disease because the disease is caused by the genes on one of the alleles that the patient possesses. For more on the genetics of HD click here. The amyloid protein aggregates and decreased hippocampal volume indicates the neurodegenerative effects of ADAD. ADAD has biomarkers that serve as diagnostic criteria that are parallel to biomarkers in HD patients that could potentially be used for diagnostic criteria for HD. The measure of hippocampal volume in ADAD corresponds to the decreased striatal and white matter volume measured by MRI in HD and premanifest HD patients. The functional test and imaging tests for ADAD in a 2- year randomized study of 210 ADAD patients in a Colombian population confirmed the diagnostic viability of these two tests. Kieburtz ended his discussion with a suggestion of what the HD community needs to find similar diagnostic criteria to ADAD. He called for a consensus and definition for both premanifest and active HD. He suggested the community needs a test that measures cognition, but also has an imbedded functional component. Finally he said that biomarkers of clinical features such as MRI images need discussion, definition, and universal acceptance.

Motor Assessment Reviewed (Ralph Reilmann, Germany)

Following up Dr. Kieburtz discussion, Dr. Reilmann elaborated on the disadvantages of the standard HD evaluative test, the UHDRS-TMS, and described specific tests that could potentially be useful in the diagnosis of HD. The UHDRS-TMS is useful but does not catch sudden changes in HD progression and ultimately has a profound placebo effect because it focuses primarily on motor symptoms. Still motor symptoms studies are useful because they are common to the phenotype of the disease and are not influenced by a language barrier like cognitive and behavioral tests. The Track-HD study uses the Tapping Force Assessment (TFA), which encompasses two tests, having patients both tap as fast as they can and tapping in a metronomic pattern, meaning they try to keep a specific pace that is first set by a beeping in their ear. The patient then has to keep the same pace of the tap with their index finger after the beeping stops. Dr. Reilmann suggested that TFA was more sensitive to changes of HD progression than the UHDRS-TMS test.

Neuropsychology in Premanifest HD (Julie Stout, Australia)

Dr. Julie Stout discussed the evidence of small but significant cognitive and behavioral deficits in premanifest HD, as well as profound structural effects in the brain. Classical cognitive symptoms of HD include slowed thinking, forgetfulness, apathy, and problems with decision-making.  Stout found that these symptoms existed in patients well before they were diagnosed with HD but only at a minor level. These results are picked up by very specific cognitive tests and Stout claims that an average patient’s life would not be significantly changed by such small decreases in cognition. However, these cognitive impairments accelerate quickly before diagnosis and thereafter, according to the Hopkins Verbal Learning test, visual spatial, transformation, motor, visual working memory, attention, and spoken reading speed tests. These deficits can be detected 10 to 15 years before the onset of HD. Unlike cognitive deficits; Stout says that MRI scans reveal profound structural changes in brain volume which can be detected up to 20 years in premanifest HD patients. However, Stout says that neural activity increases in some areas of the brain in premanifest HD patients, perhaps compensating for neurodegenerative effects that have already taken a toll on white matter and striatal volume. So while decreased brain volume is correlated with decreased cognitive and motor effects, the latter takes a longer time to manifest because of brain elasticity and compensatory activity.

MRI biomarkers in Premanifest HD (Rachael Scahill, United Kingdom)

Dr. Scahill discussed structural MRI as a leading option for biomarkers in HD. The usefulness of MRI is that is a common machine in most hospital and clinic setting. It is relatively inexpensive compared to other imaging options such as PET, fMRI, and diffusion metrics. MRI imaging of decreases in striatal volume is highly correlated with symptom progression. However due to individual variation in initial amount of grey and white matter it is difficult to make MRI a definite clinical feature. Ultimately Rachael suggests that MRI images have to taken into account along with functional and behavioral tests of HD patients. However it is still an essential measure of disease progression. Meanwhile other imaging techniques are getting better, more common, and less expensive.

Overview of pridopidine DRF Study design (Karl Kieburtz, United States and Anna Wickenburg, Sweden)

Kieburtz and Wickenburg end the discussion of premanifest HD by discussing the ongoing study of pridopidine in HD. Pridopidine is a drug that stabilizes dopamine levels in the nervous system. The MermaiHD and HART studies suggest that pridopidine reduces inflammation in the brain in HD patients and improves motor symptoms overall. While the drug is well tolerated in patients and moving on in development, there is a small concern about dangers with anthemia and seizures, so the next study is testing higher doses of pridopidine in the hopes that higher doses will create greater clinical results.

W. St. Amant


World Congress 2013 – Coping Skills Session

In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.

The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.

Coping Skills Session

One of the most difficult ideas to accept about Huntington’s Disease is that (currently) there is no cure or treatment: it is fatal and devastating. Given this harsh reality, some of the most important skills for patients and their loved ones to acquire involve those associated with coping. On the second day of the HD World Congress in Rio de Janeiro, three lecturers shared their research and personal experiences about how to cope in a world with HD.

Suicidality in Huntington’s Disease^

The first lecture entitled “Suicidality in Huntington’s Disease” was given by the researcher Aam Hubers from the Netherlands. Hubers explained that HD patients are between two and eight times more likely to commit suicide, amount to 5.7% of HD deaths coming from suicide. Five to ten percent of HD patients attempt to commit suicide, and on average at least 11% of patients admit to having had suicidal ideation within the most recent month. Suicidal ideation occurs most when patients begin having possible symptoms of HD, meaning that 20% of newly premotor symptomatic patients and newly motor symptomatic begin having suicidal ideation. These patients are more likely to use antidepressants, have a depressed mood, and tend to be more aggressive and anxious. Given these disturbing statistics, Hubers explained how her future research was aimed at discovering how HD patients who experienced suicidal ideation coped and resisted making a suicide attempt. Her data collection revealed the pressing necessity for a deeper exploration of how HD specifically can cause psychological problems and how those problems can be addressed with and without medication.

Gene Veritas^

The second lecture, “Gene Veritas”, was presented by Kenneth Serbin from the United States. Serbin explained that his mother and himself had both tested positive for the HD gene, and after her death he began to search for ways to cope with what seemed like a death sentence. Serbin mentioned twelve of the coping strategies that he had written about on his blog so far at These included:

-Learning about the disease

-Gaining discipline from exercise

-Having a healthy diet

-Studying available supplements (creatine, CoQ, Omega 3, blueberry concentrate, etc)

-Taking psychiatric medications, as they have been show to have a neuroprotective effect

-Going to support groups and psychotherapy


-Finding a passion in life

-Doing “neurobics” (mental aerobics) to increase BDNF in the brain

-Going public about having HD to overcome denial and stigma

– Becoming an advocate to connect with people

-Assisting with research studies

Serbin uses these coping skills and more, he explained, to be proactive in his own health and the HD community. With the current state of scientific research, Serbin genuinely believes that testing positive for HD is no longer a death sentence if one takes control of their HD diagnosis now.

Living with HD^

The third and final lecture in this session was entitled “Living with HD – Then and Now” and was given by Charles Sabine from the United Kingdom. Structured mostly as a motivational presentation, Sabine told his story about HD in his family. His father was diagnosed with HD in 1984, and surrounding that diagnosis were fear, shame, and ignorance. In 2005, Sabine and his brother both tested positive for the gene, but Sabine used his own diagnosis as a platform to emphasize the power of patient organizations in the HD community. He utilized his position as a public figure to support the passage of the Genetic Information Nondiscrimination Act (GINA) in 2008 in the United States, which protects Americans from discrimination against employers and insurance companies based on genetic information, and gave media coverage in Britain of HD organizations, events, and bills, which he continues to do today. Sabine closed his lecture noting that testing positive for HD in the present is a much less negative experience than in the past specifically because of amazing outreach done by patients and their families.

These three lectures shared one common, inspiring theme: though there is not currently a cure for HD, there is still hope! Whether it is hope for a treatment, for personal longevity of life, or even just hope for support from the HD community, there are always ways to maintain a positive outlook on living with HD if one manages to realize the exciting possibilities the future holds for curing this disease.

C. Bartlett 2013


World Congress 2013 – Therapies

In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.


The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.


The last day of the conference focused on various therapies, life habits, and treatment options. Each talk was presented by a different scientist.

Management of Behavioral Problems in HD (David Craufurd, United Kingdom)^

Behavioral problems have a large effect on the quality of life for an HD patient. They may include depression, suicide, anxiety, agitation, irritability, impulsive aggressive, apathy, perseveration, psychotic symptoms, disturbed sleep patterns, and OCD; the most common symptoms are fatigue and lack of initiative or perseverance. Often, these symptoms can become more distressing than the cognitive and motor symptoms. While cognitive and psychological symptoms have a far greater impact on Functional Capacity, both sets of symptoms respond to treatments and medications available now.

Dr. Craufurd explained that depression and irritability remain at relatively equal levels throughout different stages, but anxiety is often more prevalent in late-stage HD. Treatments vary from person to person. Depression in HD patients often responds well to conventional antidepressant medication. Selective serotonin reuptake inhibitors, at higher doses, can be helpful for irritability. Physicians and other medical professionals must be aware that relapse often occurs when treatment stops. In addition to medication, general psychiatric support is needed, making a great argument for beginning cognitive behavioral therapy during early stages of the disease.

Treatment of apathy is not always pharmological, but rather, it requires psychoeducation within structured environments such as adult day care and exercise programs. Physicians should avoid the use of dopamine blocking or depleting drugs in excess as neuroleptics and tetrabenazine might worsen apathy.

One should always consult their medical professional before beginning any course of medical treatment.

Deep Brain Stimulation in HD (Binit Shah, USA)^

Many HD patients experience a symptom set known as chorea, a random, involuntary arrhythmic set of movements of the face, trunk, and limbs. Chorea is thought to be a loss of striatal GABAergic inhibitory projections to the Globus pallidus externa. While pharmalogical treatments such as tetrabenazine exist, surgical treatment for chorea has become available in recent years.

Surgery to treat chorea often involves making legions in the pallidum of the brain, known as a pallidotomy. During this procedure, an electrode is inserted into the brain, heated up, and then used to target specific nuclei. The other form of brains surgery, deep brain stimulation, uses electrical fields to attack its targets. Results essentially decrease inhibition of indirect pathways, which lead to the trademark excessive moments.

Deep Brain Stimulation (DBS) is a surgical implantation of electrodes into deep brain structures while patent is awake. Connection and implementation of a pulse generator occur under general anesthesia.

As with any brain surgery, there are certainly risks, as well as candidacy factors. While DBS and pallidotomies can have immediate results, a “honeymoon effect” can occur, in which results are not long lasting. To be a candidate for this type of surgery, one must express appropriate motor symptoms that are less prominent than ataxia or dystonia. The patient cannot have severe impairments to cognitive or physiological functions as the patient must be actively engaged in the operating room and programming period. It is unclear whether these procedures are associated with adverse cognitive effects. While DBS and pallidotomy can provide some relief, it has no impact on the slowing or stopping of the progression of Huntington’s disease. Other motor features will still express and cognitive/psychological symptoms can predominate. Unfortunately, it is costly as well and is not covered by many insurance plans.

Swallowing and Nutrition (Francis Walker,US)^

Huntington’s disease creates a metabolic inefficiency within an individual’s body. While appetite, food consumption and energy consumption increase in HD, weight loss is often present. Weight loss, especially in late stages, is often due to swallowing and increased movements. As for earlier stages, the causes are unclear. However, increased CAG length is associated with lower weight in HD patients.

Many problems arise with swallowing. Mylohyoid and geniohyoid muscle contractions within the throat are erratic and uncontrollable. This can lead to a delay in swallowing, retention of food in the mouth, incomplete or repeated swallows, and a lack of coordination between speaking, swallowing, and breathing. Additionally, impulsivity and eating too fast cause choking hazards. Chorea and impersistence of the tongue and pharynx result in a spillage of food.

Signs of trouble swallowing include repeated throat clearing, coughing, “wet mouth” speaking tones, progressive slowing of feeding, regurgitation, and congestion.

There are certain methodologies that can be used to ease difficulties associated with eating. In the early stages of the disease, avoid excessive eating. If weight loss is prominent, physicians should look for signs of gastritis or depression. During mid-stages, develop strategies to slow down and create smaller portions. Increased calories within meals as well as regular meal routines can help. In late stages, high-fat meals are essential for calories.

Below is a list of other tips and hints for caregivers responsible for HD patients’ meals:
• Use gravy sauces or condiments with dry foods.
• Crush medications in apple sauce.
• Avoid distractions and talking while eating.
• Learn the Heimlich maneuver.
• Place food on the back of the molars if the patient has trouble maneuvering food within the mouth.
• Use thickened liquids.
• If gurgling or wet sounds occur, ask the patient to cough.
• Make sure food is swallowed. Try swallowing twice, if needed.

Late stage treatment options and wishes in relation to quality of life (Raymund Roos, Netherlands)^

End-of-life treatments and plans can be difficult for families to think about, let alone plan. HD patients face a variety of dilemmas such as pneumonia, the decision to insert a feeding tube, use of deep sedation, and even, at times, physician assisted suicide or euthanasia.

The most common causes of death for HD patients include pneumonia, choking, suicide and euthanasia. It is important for medical professionals to understand the challenges their patients face and, if applicable, in their state or country, know the options and procedures if the patient requests death with dignity. The criteria for ending life include 1) voluntary participation, 2) suffering unbearably without relief, 3) a physician must have informed knowledge of the situation, 4) no reasonable or alternative solution exists, and 5) the procedure is performed professionally and carefully.

Dr. Raymund Ross conducted a survey study in the Netherlands, where the Termination of Life and Request and Assisted Suicide Act legalizes euthanasia under strict conditions. The aim of the study was to determine whether there were any end-of-life wishes present in Dutch HD patients. Furthermore, he attempted to understand if certain disease characteristics contributed to these wishes.

75% of survey participants indicated that they had thoughts about end-of-life alternatives due to the loss of their personal dignity. Often these patients had been exposed to family members who had suffered an earlier fate, which influences the patient’s decision as he/she understands the disease progression.

Dr. Raymund Ross explored the results of discussion of euthanasia with patients, which often decreased the amount of follow-through from the patient. He also encouraged physicians to take initiative to talk to patients about end-of-life matters early on, as to not complicate matters for their caregivers when the patient can no longer make decisions for his or herself.

Further Reading^

1. “Hereditary Disease Foundation – Predictive Test Guidelines.” Hereditary Disease Foundation. N.p., n.d. Web. 17 Jan. 2014. .
2. Semaka, A., L. Balneaves, and M. Hayden. “”Grasping the Grey”: Patient Understanding and Interpretation of an Intermediate Allele Predictive Test Result for Huntington Disease.” Journal of Genetic Testing (2013): 200-17. Print.
3. HSG Pharos Investigators. “At Risk for Huntington Disease: The PHAROS (Prospective Huntington At Risk Observational Study) Cohort Enrolled.” JAMA Neurology63.7 (2006): 991-96. Print.
4. Tabrizi Et Al. “Potential Endpoints for Clinical Trials in Premanifest and Early Huntington’s Disease in the TRACK-HD Study: Analysis of 24 Month Observational Data.” The Lancet 11.1 (2012): 42-53. Print.

KP 2014


World Congress 2013 – Basic Science Session

In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.

The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.

On the first day of the HD World Congress in Rio de Janeiro, four speakers each gave a lecture on the basic science behind current research on the search for a treatment and cure for Huntington’s disease. The speakers were Elena Cattaneo from Italy, Tiago Fleming Outeiro from Germany, Marcy E. MacDonald from the United States, and Ignacio Munoz-SanJuan from the United States.

The lecture given by Elena Cattaneo was entitled “What Do We Really Know About Huntington Function in HD?” She explained that huntingtin is an important protein during embryonic development, such as during gastrulation, and has key functions in the living brain. The number of CAG repeats has grown in a linear progression in animals, beginning with just one repeat in sea urchins 800,000,000 years ago and increasing as multi-cellular organisms evolved into more complex beings. One example of the importance of CAG repeats is in the formation of rosettes, a special kind of grouping of cells that give structural support to neurons, during neural tube creation in the nervous system. If there are too many or too few CAG repeats in the huntingtin protein in the nervous system, rosettes will not form. Cattaneo also gave a similar example about ADAM10, which is critically important for use in the brain but is overproduced in the caudate of HD brains. Her overarching message emphasized the dynamic nature of huntingtin, a subtle point often lost in studies of the mutated version of the protein.

The next lecture by Taigo Fleming Outeiro was entitled “Molecular Chaperones in HD.” Molecular chaperones are quality-control mechanisms that monitor and regulate protein folding and degradation. Outeiro’s talk focused on the big research questions concerning the involvement of these molecular chaperones in what causes proteins to misfold, as well as when and why neurons become dysfunctional and die as a result of this misfolding. The example chaperone discussed was DJ-1, which is associated with familial Parkinson’s disease and has an increased presence in the cortex and cerebellum of HD brains. Some of its roles as a chaperone include preventing apoptosis (or breakdown) of misfolded proteins that still function and sensing oxidative stress in cells. In mouse, fruit fly, and yeast models, DJ-1 and other similar molecular chaperones (also known as orthologues) have been shown to alleviate mutant HD toxicity by refolding or rescuing misfolded proteins. Outeiro concluded that because of this research, there is hope that molecular chaperones could be used to regulate protein-misfolding disorders in the future.

Marcy MacDonald gave the next lecture, which was entitled “Is HD also a prion disease?” She immediately clarified that HD is NOT a prion disease because it does not involve Prion Proteins (or PRNPs) and it is much more common than prion diseases, such as Creutzfeldt-Jakob disease. Given that context, MacDonald emphasized that there is much more hope for finding a cure for HD than for various prion diseases because the research could take so many more routes. For example, MacDonald noted that while HD is predominantly known for being a neurodegenerative disorder that attacks medium spiny neurons in the striatum in the brain, the mutant protein is indeed in all cells and tissues of the body. She suggested that perhaps this means that the HD protein triggers an effect in all cells and tissues instead of just in the brain. For instance, the amount of energy being produced in lymphoblastoid and neuronal progenitor cells decreases as the amount of HD repeats increase in an organism. This could impact the affected organism throughout the entire span of its existence, not just after symptoms have begun. MacDonald hoped that key insights into new ways of looking at HD, such as how the entire HD process works from beginning to end in the whole body, could stimulate a variety of fresh ideas for research.

The final lecture, given by Ignacio Munoz-San Juan, was about “Synaptic Mechanisms in Huntington’s disease – Understanding the HD Brain to Develop Novel Therapeutics.” Typical therapeutic approaches include attempting to modulate mutant HD expression, modulating chemicals that decrease toxicity in the brain, and modulating mechanisms such as energy-production and protein death, which affect the organism overall. To find new therapeutic approaches, studies are being conducted observe HD as it progresses in people, in various animal models, and in specific cell-types in the body. For example, PDE10 is a powerful activator of striatal transcription and it enriches medium spiny neurons in the striatum. After observing that PDE10 is expressed more in HD brains, researchers have started testing to see how PDE10 can be used to rescue dysfunctional medium spiny neurons in HD brains and are hoping to be Phase 2 of clinical trials with PDE10. This is just one example of how observational studies have led to new research in the lab to treat or cure HD.

These four lecturers each gave a fantastic overview of the basics of current research in the search for a treatment and cure for HD, especially given their variety of backgrounds in science. There is indeed hope out there.


HDSA 20th Anniversary of Gene Discovery Symposium

The Huntington’s Disease Society of America hosted the “20th Anniversary of HD Gene Discovery: Lessons Learned” celebration symposium in the Hart Senate Building in Washington D.C. on Wednesday, April 3, 2013. HOPES was able to send a representative to the event. This is a summary of the representative’s experiences.


The Huntington’s Disease Society of America (HDSA) hosted an educational, free symposium to celebrate the discoveries and accomplishments made in the twenty years since Nancy Wexler and teams of “gene hunters” discovered the location of the gene that causes Huntington’s disease (HD) on chromosome 4 (More on the huntingtin gene here). A panel of speakers – all former members of the gene hunter teams – spoke about the past, present, and future of HD research.

Dr. Francis Collins, MD, PhD, Director of the National Institutes of Health (NIH)^


The day started off with a presentation by Dr. Francis Collins, director of the National Institutes of Health (NIH). While at the University of Michigan, Dr. Collins was an instrumental member of one of the teams invested in finding the location of the HD gene.

Dr. Collins declared the month of April to be one of many celebrations. Sixty years ago, in 1953, the paper describing the structure of the double helix in DNA was published. Thirty years ago, in 1983, scientists successfully mapped chromosome 4. (Mapping means the scientists were successfully able to determine the location of the genes on that chromosome.)Twenty years ago, the location of the HD gene on chromosome 4 was discovered. Finally, only ten years ago, under the direction and leadership of Dr. Collins as director of the NIH, the human genome was finally sequenced.

The NIH is a part of the U.S. Department of Health and Human Services and is the “nation’s medical research agency making important discoveries that improve health and save lives” ( The NIH is the largest supporter of biomedical research in the world. Their goals for improving the lives of millions are ambitious, but necessary. Dr. Collins stated that the NIH is working on re-engineering the drug discovery pipeline while removing bottlenecks in the process. The National Health Service formed the National Center for Advancing Translational Sciences (NCATS) whose work is to advance projects that will remove bottlenecks in the drug discovery process, such as a chip that screens for the toxicity of certain drugs using induced pluripotent stem cells. The chip will assist in determining whether or not a drug will pass the blood-brain barrier prior to beginning clinical trials. The NIH is also a major funder of various areas of Huntington’s disease research, such as mitochondrial DNA maintenance, huntingtin protein biology, translational therapeutics, and Sirt 1/BDNF metabolism.

The BRAIN Initiative, recently announced by President Obama, will invest $100 million into mapping the systems of the brain beginning in fiscal year 2014. Essentially, mapping means scientists will have a better understanding of how and why the brain is connected. This will theoretically help researchers develop better treatments and cures based off of this information.

Tracing Our Roots: Nancy Wexler, PhD^


Dr. Nancy Wexler is an iconic figure in the world of HD research. After watching her mother suffer from the disease, Nancy’s entire family invested their lives into the search for a cure. Nancy Wexler’s father met with Marjorie Guthrie, Woody Guthrie’s widow, and decided to create the Hereditary Disease Foundation. The mission of the Hereditary Disease Foundation, at the time, was to seek out and create collaborations amongst the world’s brightest scientists dedicated to curing HD. There were many complex challenges. At the time, it was believed that humans didn’t have biological markers, or indicators of a biological state that highlights certain genetic abnormalities, which would make it nearly impossible to discover what was causing genetic disease. However this did not stop the scientists.

Dr. Wexler first ventured to Venezuela in July of 1979. Venezuela contains one of the largest HD families in the entire world. Wexler and her team made the treacherous journey to Lake Maracaibo where they studied over 18,000 people. After collecting blood samples and family lineages, Dr. Wexler discovered that HD was first brought to this region by a woman in the 1800’s, potentially a slave or mistress of a European.

With a combination of the information collected from this Venezuelan family, as well as that of the American family that Dr. Collin’s lab studied, many new developments followed. The Venezuelan information led to the discovery that the CAG repeat length corresponds to age of onset of disease symptoms and indicated that environmental and other genetic factors can affect the age of onset. The combination of research findings led the scientists to chromosome 4, and more specifically, the mutation responsible for HD in 1993.

Dr. Wexler described not only her scientific efforts, but her humanitarian ones as well. The Venezuelan family members affected by HD were extremely poor. Many lived in huts and slept on dirt floors. There was no Western medical care whatsoever. When Dr. Wexler returned to the United States, the Hereditary Disease Foundation donated funds to create Casa Hogar, a home for families affected by the disease. Since 1979, the Hereditary Disease Foundation has donated over $17 million to bettering the quality of life of Venezuelans afflicted by this disease.

Dr. Nancy Wexler finished her talk by stating her belief that the cure lies in tackling the disease progression via the silencing of the mutant gene.


Current Affairs: James F. Gusella, PhD^

Dr. Jim Gusella was another gene hunter who was instrumental in finding the location of the gene. He concentrated his talk on various HD basics.  With the discovery of the HD mutation in 1993, scientists were able to determine the genetic difference between a normal person and HD person at any age. While we may take this achievement for granted twenty years later, at the time the development was a huge boost to understanding the underpinnings of HD. The “trigger of this entire process of genetics is now known.”

Huntington’s disease affects compounds that control the manifestation of the disease. Symptoms can be determined before genetic diagnosis as specialized doctors now have enough information to understand the cognitive, psychological, and physical features of the disease.

Dr. Gusella finished his talk with the same message as Dr. Wexler. He said that it is best to think of this disease as a process that must be stopped before any damage is done. Preventing disease progression before it starts is a guiding mission of his research group.


The Promise of the Future: Marcy MacDonald, PhD^


The last gene hunter to speak was Dr. Marcy MacDonald. Dr. MacDonald began her talk with what was becoming the theme of the symposium: Interventions must be made during, but ultimately before, a life-long disease progression.

The “big goal” of researchers is to discover a way to cut or reduce the number of CAG repeats to a normal count (individuals with 35 repeats or higher will almost assuredly have symptoms of HD in a normal lifespan). Every human being needs the huntingtin protein to function, so reducing the total levels of the huntingtin protein is likely to be detrimental. We each have two copies of the HD gene (just like all of the other genes in our bodies). For most HD patients, one copy produces a version – or allele – of huntingtin that has a normal CAG length, while the other produces the mutant version of the protein with the expanded CAG region. It is crucial to control the mutant expression and not touch the normal huntingtin protein.

Dr. MacDonald advocates that scientific research needs to shift to discovering the earliest features of disease progression, as current methods primarily analyze only symptomatic individuals. Understanding how the earliest effects of the HD mutation differ or concur in various HD populations would allow scientists to make great strides in targeting the mutant protein expression.

HD is systemic. The brain is the most important organ affected, but many more types of cells throughout the body are impacted as well. This concept has been confirmed by a study of induced pluripotent stem cells (iPS) in HD patients. This study allowed scientists to use multiple lines of iPS cells (which function similar to embryonic stem cells) to re-create and study various cell types. Dr. MacDonald stressed the need to move away from research approaches aimed at a single target in the brain, as these methods have been ineffective and cost a large amount of money. Instead, it is important to discover various cell networks and functions affected in patients at the earliest age possible and research how environmental factors can affect disease progression.

Dr. MacDonald ended by discussing how HD is a “pioneering vanguard disease.” The research produced in the last 20 years has changed the way other neurological disease and therapeutic approaches are viewed by the scientific community. Emphasizing the need to find cures not just for HD, but all neurological illnesses, creates a collaborative paradigm that allows for a successful exchange of information and research.

Question & Answer^

The day finished with a question and answer session in which attendees could inquire about certain points the scientists had made during their talk. Many of the people in the audience were personally affected by HD, whether they were caregivers, loved ones, or living with the disease. One of the overarching questions involved the fear that scientists are only realizing how much more complex this disease is, making it even harder to find the cure. Many of the attendees wondered if this meant discoveries were further down the road than previously thought. All of the scientists responded with the idea that “complexity is an opportunity” (Gusella). The more complexity, the “more possibility for solutions” (MacDonald). What was stressed to the audience, especially by Dr. Wexler, was the idea that the silencing of the mutant gene and early intervention along with potential therapies are the greatest opportunities we have for a cure.




Huntington Study Group’s Huntington’s Disease Clinical Research Symposium 2012

Saturday, November 10, 2012, marked the sixth annual Huntington’s Disease Clinical Research Symposium in Seattle, Washington. This event, organized by the Huntington Study Group, was open to the public and provided an opportunity for attendees to learn about the latest in clinical research and trials.

Below are several keynote summaries and their findings:

Ashwini Rao (Columbia University) on the Role of occupational and physical therapy in improving function in Huntington’s disease^


Dr. Ashwini Rao of Columbia University began his presentation by outlining the definition of occupational and physical therapy. Occupational therapists are professionals who aim to improve the health of clients in their daily activities through engagement in their occupation. Health care professionals who aim to promote movement, pain reduction, and health in their clients, on the other hand, conduct physical therapy.  After overviewing the development of clinical guidelines for the therapies, Dr. Rao explained that there is an underutilization of physical therapy at all stages of Huntington’s disease (HD), particularly in the early stages.

There are several problem clusters that arise in HD patients: balance and gait, posture and balance, and hand control. The following cluster symptoms were determined from a study conducted by Dr. Rao’s lab that examined gait and balance performance. In the pre-manifest stage of HD, symptoms may be observable as slower speed, shorter stride, more variable steps, and diminished hand function. In the manifest stage, symptoms are apparent as decreased speed, shorter and more variable steps, decreased step frequency, variable timing, and difficulty with eating, writing, and household or work-related tasks. For more information on the study, please click here.

In addition to identifying problem clusters, Dr. Rao also introduced an intervention framework. He recommended that patients diagnosed with HD engage in fall prevention exercises, gait and balance training, and appropriate regular physical exercise, regardless of their stage of symptoms. Dr. Rao noted that a study published by the New England Journal of Medicine showed that 48 regular sessions of tai chi, as well as tango lessons, improved postural balance in patients with Parkinson’s disease. (For more information on this study, click here) This exercise regimen may translate to HD patients as well, with a larger number of sessions being more effective.

Dr. Rao recommended that all HD patients begin an interdisciplinary model of care, with therapy tailored to their specific stage of the disease. Dr. Rao believes that those who have been recently diagnosed and are in early stages should seek out a therapist as soon as possible. In his opinion, developing a relationship with this therapist would allow an early assessment of motor markers and the creation of an exercise program that includes strength, balance, and cardiovascular capacity components. It is extremely important to make exercising habitual, as well as involve family and close ones in a daily regimen.

As patients progress into middle disease stages, they should continue with their exercise programs, as well as transition to therapeutic exercises in order to discover markers that might indicate risks. A home assessment should be conducted to determine the need for shower chairs, safety bars, scatter rugs, and any other items that might make the home friendlier and safer. Patients should also consider assistive devices such as a walker. Dr. Rao stated, “similar to cars, four wheel drive is the best” as it improves speed, stride length, and reduces variability in motion. Footwear should contain a supportive light cushioned sole, as well as flexible upper foot and heel support.

In terms of postural control during eating, patients should consider a sturdy chair with a high back. They should also throw out all the traditional mealtime rules such as having one’s elbows on the table (a necessary strategy). It is important to remove distractions during mealtime as well.

As for financial concerns, Dr. Rao mentioned a New York Times article on the topic of a recent settlement clarifying Medicare will pay for services needed to maintain a patient’s current condition in order to prevent or slow deterioration. This includes the necessary therapies outlined in Dr. Rao’s talk.

To learn more about Dr. Rao’s research, click here.

Dr. Steve Hersch (Mass General Hospital) on the Secondary Prevention of Huntington’s disease ^

Dr. Steve Hersch of Massachusetts General Hospital described the necessity of devising clinical trial designs that include at-risk individuals that do not want to undergo genetic testing. By allowing at-risk individuals to participate without learning their CAG count, researchers can enable greater participation while preventing coercion of unwanted genetic testing. Candidates would be anonymously tested for pre-manifest HD via cognitive and blood markers, as well as neuroimaging. (For more information on neuroimaging, click here.)

Dr. Hersch then transitioned into describing the research his lab has been conducting on the safety, tolerability, and potential efficacy signals for high-dose creatine to treat HD. (For more on creatine, click here). Creatine increases brain energy and has shown to be safe and tolerable. Creatine additionally slows brain atrophy and is actually modifying the effects of HD in patients that are pre-symptomatic. However, it is not yet clear if it can delay the onset of symptoms.

In addition, Dr. Hersch stressed that the creatine used in these studies is medical grade and not the creatine often found in health stores. One should not test high doses of creatine unless done so under medical supervision. As for clinical trials, Phase III of the CREST-E study will be a more rigorous study of the efficacy of creatine. Recruitment for the trial is ongoing. (For more on the CREST-E study, click here)

Dr. Blair Leavitt (University of British Columbia) on the Changing demographics at its prevalence on HD^

Dr. Blair Leavitt of the Centre for Molecular Medicine and Therapeutics (University of British Columbia) began his presentation by describing the prevalence of HD: 5 in 100,000 globally have the disease. In British Columbia, the location of his research, HD affects at least 1 in 1000. However, there has recently been a rise in the prevalence of the disease. Dr. Leavitt mentioned that new mutations have been occurring in families where HD had previously been absent.

As life expectancy increases in the United States, Dr. Leavitt believes that HD will soon become a disease of older people as life expectancy increases, similar to how Alzheimer’s is known today. Currently, many people might have HD, but will not live long enough to express symptoms. However, as technology and medicine improves, more individuals are expected to live long enough to the point where they are symptomatic.

Lavonne Goodman M.D. on Clinical Trials: Why Isn’t Everyone Doing It?

Dr. Lavonne Goodman, HD patient advocate, cited informal surveys conducted recently aimed at understanding why more people aren’t participating in clinical trials (For more on clinical trials, click here). Their findings suggested that a lack of awareness has prevented many people from participating. Often, there is a desire to participate, but many of those affected by HD are not aware of when or where trials are happening, and why these clinical trials are being conducted. Participation rates in clinical trials increased locally when trial advocates visited HD support groups and informed the group of local trials. In addition, advocates provided information packets about these trials, and addressed members’ questions and concerns. Many of the members of these support groups asked the following questions:  What studies and trials are currently ongoing? What is available in my geographic area? Are any open for enrollment? Why are these studies being done? What is the enrollment process?

Many other barriers must be overcome to increase HD clinical trial participation. These barriers include a fear of drug risks and side effects and stress. The stress of dealing with HD is often hard enough; adding a clinical trial to one’s to-do list can seem too overwhelming. The logistics are also difficult, as one must consider time lost at work, travel expenses, and potential loss of income. And again, lack of knowledge can be a deterrent as people might not want to participate if they think they are getting the placebo, or have to stop taking drugs that currently work for them. In addition, people are afraid that confidentiality will be breached and discrimination will ensue from medical providers or insurance.

Currently, and are two resources where individuals can learn about trials occurring in their areas. However, these two websites are not always up-to-date. The Huntington’s Disease Society of America is working on improving information about clinical trials on their website in the next few months.

KP 12/17/2012


University of California at San Francisco 2012 HD Research Symposium

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.

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 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, 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 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.


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