By: Emily Fisher and Alicia Semaka
There are two ways to answer the question “how many people have Huntington disease (HD)?” The first is by determining the prevalence (i.e., the proportion of a population that has a given condition at a particular point in time), and the second is by determining the incidence (i.e., the number of people who will develop a condition over a defined period of time) of HD. Prevalence answers the question of “how many people currently have HD?” and incidence answers the question of “how frequently are people being diagnosed with HD?” Research suggests that the answers to both of these questions are changing and perhaps increasing. These changes will have important biological, economic, and social implications for the future.
The prevalence of HD has been reported to vary with ethnicity and geographical location, confirming that demographic differences influence the number and composition of individuals with HD. Since HD is believed to have major origins in Northern Europe, 2 it is not surprising that populations of Northern European descent are recorded as having the highest prevalence of HD in theworld.3 In the 1970‘s and 1980’s, a number of studies around the globe examined the prevalence of HD. In Europe it was estimated that an average of 4-7 persons per 100,000 were affected with the disease.4,5,6,7 Canadian studies suggested 2.4-8.4 persons per 100,000 had HD.8,9 In the United States, it was estimated that 4.1 – 5.2 persons per 100,000 were living with thedisorder.10,11 Figure 1 reviews additional global prevalence estimates for HD. While a number of studies have examined the prevalence of HD, very few studies have investigated the disease’s incidence. Findings from Minnesota, USA suggested that 3 individuals per million were diagnosed with HD each year between 1950-1989.12 In British Columbia, Canada, 6.9 individuals per million were diagnosed each year between 1987-1999.13
In recent years, the accuracy of published prevalence estimates for HD has been called into question. The majority of prevalence estimates for HD were conducted prior to the identification of the genetic mutation underlying the disease; with a genetic test now available, diagnosing HD has become more precise. Patients with atypical symptoms, late disease onset, and negative family histories are more likely to be diagnosed, reflecting a likely increase in the number of persons living with the disease. However, fear of experiencing genetic discrimination from health insurers, among family members, or in social settings14 may prevent some individuals from disclosing that they are either at-risk or premanifest for HD, thus making it difficult to accurately identify every patient in a given population.
A brief review of the number of patients cared for by the Huntington Disease Association in the United Kingdom (UK) indicated that approximately 6,700 individuals in the UK are currently living with HD. This means that 12.4 per 100,000 persons or 1 out of every 8,065 individuals may be affected with HD15.Although these numbers at best provide a minimum prevalence estimate in the UK, since the Association does not care for all HD patients in England and Wales, the numbers do demonstrate that previous prevalence figures are likely underestimated. Fortunately, recent increases in HD awareness and access to information and support, developments of legislations dedicated to preventing genetic discrimination, and continuations of promising basic and clinical HD research have had impact on the willingness of individuals to involve themselves in the HD community. More patients and families are reaching out to medical service providers and becoming involved in HD research, and their increased involvement in the HD community provides an ideal opportunity to reassess the global prevalence of HD.
While the need to establish new baseline prevalence estimates for HD is apparent, these figures must be frequently revised to determine how the prevalence of HD changes over time. Factors such as the projected demographic shifts in median age and our increasing longevity will likely impact the prevalence of HD in the coming years. With an aging population that is expected to live longer, more individuals who have late onset HD will be diagnosed, thus increasing the number of affected individuals. Accurate prevalence estimates are vital to ensuring that there is appropriate access to clinical services and support for patients and families. Additionally, since medical and research funding is often allocated on the basis of the disease burden on society, it is imperative to know the true prevalence of the disease in order to secure proportional financial support for HD research and care. With a combined global effort from HD patients, families, researchers, and caregivers, we will finally be able to accurately answer the question: “How many people have Huntington disease?”
1 Hayden, MR. Huntington’s Chorea. New York: Springer, 1981.
2 Warby, SC et al. Expansion in the Huntington Disease Gene Is Associated with a Specific and Targetable Predisposing Haplogroup, American Journal of Human Genetics 2009; 84:351–366.
3 Caro AJ. Huntington’s Chorea; a clinical problem in East Anglia. PhD thesis, University of East Anglia.
4 Quarrell OWJ, Tyler A, Jones MP, et al. Population Studies of Huntington’s disease in Wales. Clin Genet 1988;33(3):189-95.
5 Simpson A, Johnston AW. The prevalence and patterns of care of Huntington’s disease in Grampian. Br J Psychiatry 1989; 155:799-804.
6 Harper, PS. The epidemiology of Huntington’s disease. Human Gen 1992; 89:365-376.
7 Barbeau A, Coiteux C, Trudeau JC, Fullum G. La Choree de Huntingdon chez le Canadiens Francais, Union Medicale de Canada 1964;93:1178.
8 Shokeir MHK. Investigations on Huntington’s disease in the Canadian Prairies I. Prevalence. Clin Genet 1975; 7(4):345-8.
9 Reed TE and Chandler JH. Huntington’s chorea in Michigan. I. Demography and genetics. Am J Hum Genet. 1958; 10(2):201-25.
10 Folstein SE, Chase GA, Wahl WE, et al. Huntington Disease in Marlyland: Clinical Aspects of Racial Variation. Am J Hum Genet 1987;41(2):168-79.
11 Kokmen E, Ozekmekpi S, Beard M, et al. Incidence and prevalence of Huntington’s disease in Olmsted County, Minnesota (1950 through 1989). Arch Neurol 1994; 51(7): 696-8.
12 Almqvist E, Elterman D, MacLeod P, Hayden MR. High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin Genet 2001;60(3):198-205.
13 Bombard Y, Veenstra G, Friedman JM, et al. Perceptions of genetic discrimination among people at risk for Huntington’s disease: a cross sectional survey. BMJ 2009; 338:b2175.
By: Mahmoud Pouladi, PhD
The 2011 World Congress on Huntington’s Disease in Melbourne, Australia, brought together HD clinicians, basic scientists, patients, families, and support groups. Peter Harper and Sarah Tabrizi gave the opening addresses.
Peter Harper presented historical highlights of HD, emphasizing the uniqueness of the HD community among other neurodegenerative disease communities. He said the HD community should take pride in the closeness that exists between HD scientists, clinicians, patients and patient families. He ended his presentation with the idea that HD should no longer be regarded as untreatable, given the current state of research and understanding in the HD community.
Sarah Tabrizi spoke about HD disease pathways and mechanisms that are currently the subject of therapeutic efforts. She said that many pharmacological candidates targeting these pathways will be entering clinical trials over the next two years. She presented findings from the TRACK-HD study, in which various measures, particularly those of brain atrophy, showed significant deterioration over a 1-2 year period. The results indicate that therapeutic interventions in early HD may be possible. Professor Tabrizi also announced the launch of a new study, TrackOn-HD, which aims to investigate neural compensatory mechanisms that may delay cognitive decline in HD gene carriers.
Colin Masters revealed Prana Biotechnology’s plans to conduct clinical trials of their metal chelator PBT2 as a treatment for HD. Abnormal interactions between copper and/or iron and mutant huntingtin in the brain of HD patients have long been suspected, and treatment with PBT2 may benefit these patients. Clinical trials of PBT2 are scheduled to commence in late 2011 in Australia and the USA.
Three scientists presented their efforts to reduce levels of mutant huntingtin in HD gene carriers and clinical patients. Frank Bennett from Isis Pharmaceuticals presented an update on the company’s efforts to silence the mutant huntingtin allele, using antisense oligonucleotides (ASOs). Don Cleveland presented data that indicate that short-term silencing of expression of mutant huntingtin using ASOs is sufficient to improve phenotypes in a mouse model of HD. Beverly Davidson presented her findings on shRNA and miRNA – mediated approaches to silencing the expression of mutant huntingtin in mice and rhesus monkeys. In the monkeys, the reduction of endogenous huntingtin levels in the posterior putamen had no adverse effect on measures of motor function and learning.
Anthony Hannan discussed the influence of environmental factors on HD disease progression. Dr. Hannan and his colleagues have used mouse models of HD to demonstrate that environmental enrichment stimulates hippocampal neurogenesis, and enhances synaptic function in HD. He suggested that environmental or pharmacological interventions that strengthen synaptic function should be pursued as potential HD treatments.
Paul Muchowski spoke about the peripheral effects of mutant huntingtin on central HD pathology. He presented data suggesting that pharmacological modulation of molecular targets (i.e. antagonism of kynurenine 3-monooxygenase or agonism of cannabinoid receptor type 2) in the periphery could be beneficial in HD.
Robert Pacifici presented CHDI’s vision for a target-based, hypothesis-driven approach to drug discovery in HD. He pointed out that different animal models of HD may be useful for modeling different aspects of HD, and that there is no such thing as a ‘good’ or ‘bad’ animal model. He also talked about the value of exploratory studies and observations made in HD patients, echoing the call for participation of HD gene carriers and patients in clinical research.
Michael Hayden discussed the changing prevalence of HD. He said that the increase in the proportion of elderly people in the global population is likely to increase the prevalence of HD and its associated burden.
The Congress also featured perspectives on international models of HD care from Daniela Rae (Europe), Andrew Churchyard (Australia), Amanda Krause (South Africa), Francisco Cardoso (South America), Darshana Sirisena (Sri Lanka).
Robi Blumenstein gave the Congress closing presentation, and outlined the three elements he believes will be essential for a successful HD trial: an effective treatment; methods to measure the positive effects of treatment; and the active participation of HD gene carriers in clinical research.
NAME: Prana Biotechnology
HEADQUARTERS: Parkville, Victoria, Australia
STOCK PRICE AS OF 10/05/11: $1.59
52 WEEK RANGE: $1.13-4.50
MARKET CAPITALIZATION AS OF 10/05/11: $42.4 million
EMPLOYEES: Approximately 10
Prana Biotechnology’s research is driven by the hypothesis that metal protein attenuating compounds bind transition metals and prevent oligomerization of amyloid proteins in Alzheimer disease and of the huntingtin protein in Huntington disease. Prana Biotechnology CEO Geoffrey Kempler sat down with HD InsightsTM at the World Congress on Huntington’s Disease to discuss Prana’s research in neurological disease modification. Excerpts from the discussion are below.
INSIGHTS: Could you tell us a little bit about Prana?
KEMPLER: Prana began in 1997 as a private company through some seed capital financing that came in from myself and a friend of mine, Barry Lieberman. We became interested in some work that was happening at Harvard Mass General. The work was on the amyloid protein and the role of metals in facilitating the aggregation of this protein into oligomers and plaques. What we were doing was considered heretical because we were really the first group to start to understand the metal binding sites on these proteins, and that these metals were driving the aggregation of the proteins. We supported our research very privately. We had a peripheral concept growing that was already available in the market and matched our scientific theory. There, we could do that concept work. By us understanding the mechanism that’s behind protein aggregation, we’ve been able to drive an enormous amount of academic publications through our support laboratories at Harvard, here in Melbourne at the Mental Health Research Institute and the University of Melbourne, and at some other collaborations we’ve had in various parts of the world.
INSIGHTS: It makes a lot of sense that a company like yours might be interested in Alzheimer disease, which has a very large market. Tell us why you are interested in Huntington disease.
KEMPLER: You imagine that companies always look at market size and market opportunity, and that’s true. I don’t want in any way diminish that as a focus. We know that cognition is one of the key areas of deficit in Huntington disease patients. We know that it’s a major aspect of Alzheimer disease, but we also know that there’s some normal cognitive decline that comes just with the aging process even if you don’t have either of these diseases. In the animal experiments that we’ve done, we’ve demonstrated that our drug PBT2 actually had profound effects on a memory test that we gave to old mice that were not transgenically modified to have either Alzheimer disease nor Huntington disease. These mice were able to effectively complete the task post-treatment with the drug as effectively as young healthy mice. It told us that the drug would be useful wherever there is a cognitive deficit, particularly where that cognitive deficit emphasizes executive function deficit, such as early in the disease process.
INSIGHTS: So among the disorders that affect cognition, what attracted you specifically to Huntington disease?
KEMPLER: I think it was the advocacy of the Huntington disease researches. We have been approached by different researchers and different diseases, and we’re a little company so we can’t take on everything. But the people in Huntington disease were able to instill their confidence of our own drug in this indication. From a pragmatic perspective we saw that it was a disease where we could come along, present our case, get some attention, and actually see if we can bring benefit to patients.
INSIGHTS: Where there any researchers in particular who were especially strong advocates?
KEMPLER: I think I would have to certainly begin with Professor Ira Shoulson from Georgetown University, who had a lot of influence in our thinking, as well as Steve Hersch from Massachusetts General Hospital in Boston.
INSIGHTS: What did they do to persuade you?
KEMPLER: They were able to look at our data, explain the relevance of it to Huntington disease patients, and work with our scientists to generate new data. They were able to prepare feedback on what we’d produced and what others had produced, and really helped us understand that we might have a unique position with our drug.
INSIGHTS: There’s only one FDA approved treatment for HD right now. You are also aware that the Dimebon study failed to show benefit on cognition relative to placebo. How did that affect your thinking about coming into with a new compound to look at cognition in Huntington disease?
KEMPLER: We’ve spent so long on the outside of the accepted paradigms that we’re quite comfortable living in that little space. We feel that we’re likely to be in a pretty small group if not a bit unique amongst the drugs that actually have some promise.
INSIGHTS: Looking forward, what are your hopes for Prana and for Huntington disease?
KEMPLER: My big hope for Prana is that the many, many years of dedicated effort by outsiders, our staff, the investors, and by the community patient groups that have cooperated in our clinical trials and in our advocacy will be rewarded by PBT2 in the first instance. Getting approval for a drug that could bring cognitive benefit to patients with Huntington disease will parallel our ongoing important work in Alzheimer disease. We actually have an entire strategy that’s probably gone for the very high bar, and that’s to deal with the actual underlying disease process that’s behind each of these diseases. My hope for Prana in the very short-term is that we’ll be seen by the Huntington disease community as the drug in Phase II that appeared out of nowhere because it was from an Alzheimer universe.
By: Lise Munsie
In the lab. . .
Basic research into the biochemical pathways underlying the pathogenesis of HD continues, with the aim of targeting these pathways for drug delivery. PGC1α, which controls many aspects of oxidative metabolism, has been a focus of recent efforts. Martin and colleagues showed that an upstream activator of PGC1α may be involved in the characteristic downregulation of PGC1α in HD patient brain and muscle samples.2 They also used a transcriptional readout of an HD rat model to show that MSK1, a nuclear protein kinase with low striatal levels in HD patients, is responsible for PGC1α activation. When overexpressed, MSK1 can activate PGC1α, possibly through histone H3 phosphorylation, and lead to positive outcomes in the HD rat model. Taherzadeh-Fard and colleagues looked at genetic modifiers via single nucleotide polymorphisms (SNPs) in HD patients, and showed that downstream PGC1α transcription factors NRF-1 and TFAM are genetic modifiers of the age of clinical onset of HD.3 These data strongly support modulation of PGC1α activity as a potential therapeutic approach in HD. Labbadia and colleagues investigated the therapeutic potential of activating chaperones for HD.4 They used HSP990, a brain-penetrating HSP90 inhibitor that can be administered orally, and showed that while activating chaperones via the heat shock response is initially therapeutic, the heat shock response is gradually attenuated as disease progresses. The shut-down of the heat shock response seems to be linked to epigenetic modifications, and indicates that this approach, although potentially beneficial, may be more complicated than originally hoped.
In the scanner. . .
Basic research and clinical research are bringing us closer to disease modifying treatments for Huntington disease, but sensitive biomarkers are needed to assess disease progression and the efficacy of new treatments. Neuroimaging has now come into the spotlight to assist with this task, and large-scale, multi-site longitudinal studies such as TRACK-HD and PREDICTHD have recently released neuroimaging study results. The TRACK-HD team led by Dr. Sarah Tabrizi in London used magnetic resonance imaging (MRI) data to investigate clinical, cognitive, oculomotor and neuropsychiatric indicators of HD.2 They saw progression in prodromal HD over a 12-month period, and found that brain imaging measurements were the strongest and most consistent measures when tracking disease progression. TRACK-HD’s data has established an association between MRI neuroimages and clinically meaningful measures of disease progression. Furthermore, the study provides baseline data to estimate the sample sizes required to detect meaningful treatment-mediated improvements in a clinical trial. The PREDICT-HD team led by Dr. Jane Paulsen reported that their MRI data indicate that increased CAG length is associated with more rapid progression of striatal atrophy.3 Diana Rosas and colleagues used MRI to investigate the possible correlation between age of onset and rate of brain atrophy.4 The study showed that individuals whose motor symptoms appeared before the age of 40 years had an increased rate of brain atrophy. The study also found that topological distribution of cortical thinning was highly dependent on the age of onset and not necessarily on the length of CAG repeats.
In the clinic. . .
Recent efforts in drug discovery for HD have shifted to exploring different methods for silencing the allele that codes for mutant huntingtin. Allele-specific silencing using antisense oligonucleotides (ASOs) has been successful in non-brain-related disorders, and with recent advances in chemistry, pharmacology and drug delivery, the possibility of using ASOs to treat brain disorders is becoming more realistic. Recent clinical efforts have explored novel approaches to improve ASOs and have sought to develop ways to silence the allele that codes for mutant huntingtin, while sparing the normal allele. Gagnon and colleagues showed that ASOs with certain chemical modifications can specifically silence the allele that codes for mutant huntingtin, although the mechanism of this silencing remains unknown.2 Interestingly, these effects were protein and not transcript-dependent. Fiszer and colleagues used repeat-targeting RNA duplexes to discriminate between expanded and non-expanded alleles, and to mediate RNA-induced silencing complex (RISC) – dependent target silencing.3 They used a duplex of pure CUG/CAG repeat sequences to silence the allele that codes for mutant huntingtin, and they increased allele selectivity by introducing single or double C>U substitutions in an effort to modulate RISC activity. Chung and colleagues found that an overexpressed antisense strand at the HD locus (huntingtin antisense – HTTAS) has the ability to modulate huntingtin expression, its sense transcript counterpart.4 These results suggest that continued investigation of overexpressed antisense strands and their ability to decrease huntingtin expression should be pursued.
1 Martin E, Betuing S, Pagès C, et al. Mitogen and stress – activated protein kinase 1 – induced neuroprotection in Huntington’s disease: role on chromatin remodeling at the PGC-1-alpha promoter. Hum Mol Genet 2011;20(12):2422-34.
2 Taherzadeh-Fard E, Saft C, Akkad DA, et al. PGC1alpha downstream transcription factors NRF-1 and TFAM are genetic modifiers of Huntington disease. Mol Neurodegener 2011; 6(1):32.
3 Labbadia J, Cunliffe H, Weiss A, et al. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J Clin Invest 2011; 121(8):3306-19.
4 Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011;10(1): 31-42.
5 Aylward E, Mills J, Liu D, et al. Association between Age and Striatal Volume Stratified by CAG Repeat Length in Prodromal Huntington Disease. PLoS Curr 2011; 3:RRN1235.
6 Rosas HD, Reuter M, Doros G, et al. A tale of two factors: what determines the rate of progression in Huntington’s disease? A longitudinal MRI study. Mov Disord 2011; 26(9):1691-7.
7 Gagnon KT, Pendergraff HM, Deleavey GF, et. al. Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 2010; 49(47):10166-78.
8 Fiszer A, Mykowska A, Krzyzosiak WJ. Inhibition of mutant huntingtin expression by RNA duplex targeting expanded CAG repeats. Nucleic Acids Res 2011; 39(13):5578-85.
9 Chung DW, Rudnicki DD, Yu L, Margolis RL. A natural antisense transcript at the Huntington’s disease repeat locus regulates HTT expression. Hum Mol Genet 2011; 20(17):3467 77.
NAME: Sarah Tabrizi
CURRENT POSITION: Professor of Clinical Neurology at University College London
EDUCATION: PhD Biochemistry University College London, MBChB University of Edinburgh
CURRENT HD ACTIVITIES: Dr. Tabrizi is leading efforts in translational medicine. She is lead investigator of the TRACK-HD study that investigates the neurobiology of premanifest and early onset HD and has already been successful in identifying biomarkers that can be used to track the progression of neurodegeneration from its onset in HD patients. She is also researching immunobiology in HD, and cellular mechanisms of protein misfolding diseases.
HOBBIES: Spending time with family, reading, and running.
LAST BOOK READ: Herzog by Saul Bellow. It was great but heavy going!
Dr. Tabrizi established her own consulting clinic and specialist HD clinic in 2003. Since then, she has published more than 120 peer-reviewed articles, which have appeared in Molecular Cell, Lancet Neurology, Nature Communications, Journal of Experimental Medicine, EMBO Journal and PNAS. In addition to her ongoing projects in HD immunobiology, protein misfolding, and the TRACK-HD study, she serves on executive panels for the UK HD association, the European HD Network and NINDS. Dr. Tabrizi sat down with HD InsightsTM at the World Congress on Huntington’s Disease to discuss her HD research and hopes for the future of HD. Excerpts from the discussion are below.
INSIGHTS: What drew you to Huntington disease?
TABRIZI: My PhD supervisor Tony Schapira took me to a nursing home just outside London called Stagenhoe, where there were many patients with advanced Huntington disease. I was struck by the patients and how warm they were, how interested they were in the research. Then I met Gill Bates who had just published about her HD mouse. I followed up with the work Gill had done and also worked with her during my PhD. My PhD work cemented my interest in the disease. Once you start working in Huntington disease you get hooked.
INSIGHTS: You presented that a number of different biological markers that you’re helping develop track with HD. Can you tell us which of these biomarkers you view as the most promising?
TABRIZI: The markers that I’ve been most impressed with are the structural imaging markers –caudate volume, striatal volume, and whole brain atrophy. These are the markers that I think are the most promising and the most robust at this stage. However, a number of cognitive and quantitative motor markers are also important. We are developing these markers with our TRACK-HD team. The interesting part about the imaging is that we need to understand more about what these structural changes mean biologically. We need to understand what the pathological substrate is and the functional relevance of these imaging changes. That’s something through our ongoing work we’re seeking to do – to look at neural compensatory networks and functional plasticity.
INSIGHTS: You talked a little bit about your initial skepticism of structural imaging and how that’s been converted.
TABRIZI: My initial skepticism was that whether imaging would demonstrate convincing change, whether it would be robust enough, and whether you would be able to remove inter-scan variability to get good scan quality. Now I understand a great deal more about how the technologies. We have advanced ways of studying the brain, particularly with 3T MRI; we can very accurately and carefully map regions of the brain with very high sensitivity and low measurement error. Imaging gives us insight into regional changes. I’ve become converted in that imaging does appear to correlate very closely to functional and cognitive decline.
INSIGHTS: At the conference you also identified classes of experimental compounds that hold promise for Huntington disease. Can you discuss which of these you think holds the most promise?
TABRIZI: I wanted to give an overview of the compounds that were potentially neuroprotective or disease-modifying that would be going into clinical trials in the next 24 to 36 months. Phosphodiesterase inhibitors – phosphodiesterase 10 inhibitors, for example – are promising in pre-clinical data and have the potential to enhance synaptic function. Other compounds currently at or near clinic that have great potential are the KMO inhibitors that target peripheral immune cells. Also promising are those that use approaches such as ASOs and RNAi and aim to lower mutant huntingtin or enhance mutant Huntington clearance and/or correct gene transcriptional dysregulation, such as the SIRT1 inhibitor (Siena BioTech). In pre-clinical targets, the HDAC4 inhibitors are potentially exciting.
INSIGHTS: You mentioned phosphodiesterase 10 inhibitors had promising pre-clinical data. Can you tell us about that?
TABRIZI: There are two published recent papers in HD mouse models. In one, they use phosphodiesterase 10 inhibition treatment in primary striatal cultures, while in the other they have partly corrected synaptic dysfunction and transcriptional dysregulation. This is promising in that cAMP/cGMP downstream signaling has multiple beneficial effects on synaptic function and gene regulation.
INSIGHTS: How will those beneficial effects on synaptic function lessen the burden of Huntington disease?
TABRIZI: Huntington disease causes early synaptic functional defects and loss of the cortico striatal neural circuitry, as shown in numerous mouse model studies. Synaptic function is essential for memory, learning, and overall brain function, and very early neuronal loss and synaptic dysfunction occurs in Huntington disease. We know from TRACK-HD data that neuronal loss is also very likely to occur early in HD gene carriers. This is potentially reversible. If we can somehow promote synaptic function and promote synaptic plasticity, we can allow the brain to compensate for ongoing pathogenic effects of mutant huntingtin.
INSIGHTS: In the next few years what are the most promising avenues of research that we can expect to see coming out of the Tabrizi lab?
TABRIZI: I have a number of projects that are ongoing. I’m working on basic science and protein misfolding cell biology, particularly using prion cell biology as a model for protein misfolding biology. We’re looking at trying to understand how the misfolded prion proteins move around and use that as a model to take it forward to look at for example, mutant huntingtin trafficking. We’re also developing a number of human ex-vivo cell culture models to try and look at HD in a cell culture dish, as well as starting projects in which we probe the function of wild-type in peripheral human HD cells. On the more translational side, I have a big program looking at the role of the immune system and immune biology in modifying Huntington disease, while also investigating how wild-type and mutant huntingtin levels may vary between patients, how they may correlate with each other, and how they may link to disease progression. Finally, Track-On-HD is a new study aiming to explore neural compensatory networks and functional plasticity in the premanifest stage of Huntington disease. It’s essential to understand functional plasticity moving forward, especially in terms of future trials for pre-manifest individuals. Despite striking brain changes over time, our subjects are able to function at a high level. There must be remodeling and functional plasticity of synapses for this to occur. We’re using a number of novel methods to look and see if we can identify these neural compensatory networks. Clearly this will also give functional relevance to structural imaging. These are the main projects over the next two years and hopefully we’ll get some exciting and important data.
INSIGHTS: Thank you very much and your final thoughts?
TABRIZI: The meeting here in Melbourne has been really exciting. There’s a great feeling of positivity. The families that are here feel the progress has been made, and that we’re working together avidly to try and find potential treatment for Huntington disease. It is a great community.
Welcome to the first edition of HD InsightsTM! Our mission is to promote, disseminate, and facilitate research in Huntington disease by producing content that will be valuable and informative to the global community of HD researchers in academia and industry. To fulfill this mission, we have assembled a distinguished editorial board, outstanding writers, and a first rate production team. The editorial board represents four continents and has representatives of academia, industry, and the HD community. Our writers are some of the rising stars in HD research, and our production team has creative and dedicated individuals with diverse talents. In each issue, we will bring you insights from the leading scientists, innovators, and companies developing therapeutics for HD. In addition, we will keep you current on the emerging science, the proceedings from major HD meetings, and clinical trials in the field.
The genesis of HD InsightsTM came from the Huntington Study Group, which saw a need to disseminate research in the field, and from Lundbeck, which provided a generous unrestricted educational grant to help launch this periodical.
In our first year we plan on producing three issues timed to national and international meetings of HD researchers. To receive a free subscription to HD InsightsTM, simply email firstname.lastname@example.org with your name and organization. All of our content as well as bios and disclosures are available online at www.hdinsights.org.
As a new periodical aimed at meeting the needs of our readers, we are especially interested in your thoughts and suggestions for people to interview, events to cover, and ideas to explore. Also as a new periodical, we are eager to secure support to make HD InsightsTM an enduring periodical that informs and motivates over 1000 scientists, physicians, and drug developers specifically interested in HD. If you have ideas, want to contribute, or are eager to support, please contact me at email@example.com.
Together we can advance research and eventually therapeutics for Huntington disease.
Ray Dorsey, MD
Editor, HD InsightsTM
Editorial Board Members
Ray Dorsey, MD — Editor, Johns Hopkins University
Donald Kennedy, PhD — Stanford University
Nobuyuki Nukina, MD, PhD — Riken Brain Science Institute
Rodrigo Osorio — Agrupacion Chilena de Huntington
Bernard Ravina, MD — Biogen Idec
Ralf Reilmann, MD — University of Munster
Sarah Tabrizi, MBChB, PhD — University College London
Leslie Thompson, PhD — University of California Irvine
Huntington Study Group
Shari Kinel, JD — HSG Executive Director
Liz McCarthy, BA — HSG Administrative Manager
Jillian Lowell, BS — HSG Event Planner
Alicia Semaka, M.Sc.
Mahmoud Pouladi, PhD
Kristin Darwin, BS
Paige Nichols, BA
Robin Taylor — Production Editor
Martin Holmes — Technical Editor
Todd Bernhard — Copy Editor
Vinayak Venkataraman, BS — Website Designer
Dave Kolko — Distribution Specialist