As the 25th anniversary of the identification of the genetic expansion responsible for HD approaches, a new generation of HD researchers is emerging. Scientists, investigators, and clinicians from diverse professional backgrounds have come together to apply their expertise to the study of HD biology and therapeutic development. HD Insights interviewed six of these next-generation HD researchers who have been invited by the Huntington Study Group (HSG) to attend the 2015 HSG annual meeting. We bring you their backgrounds, their current work, and their vision for the future of HD research in this edition.
They come from all over the world, bringing experience in nursing, engineering, mathematics, and the biological sciences. Their research has been recognized as particularly promising by the HD research community. Three of them represent the inaugural group of HSG Shoulson Scholars, recognized as outstanding junior investigators with promising futures in HD research. The others are among those recognized by the Huntington’s Disease Society of America (HDSA) as HD Human Biology Project Fellows. The HDSA HD Human Biology Project was launched in 2013 to fund research that advances understanding of the biology of HD in human patients.
Together with the winners of the second annual HD Insights of the Year competition, these individuals represent the promise of future HD research and therapeutic development. We hope that the brief profiles presented here will be the first of many opportunities they will have to share their excellent work and their service to the HD research community.
Next Generation Scholars at HSG 2015
2015 Shoulson Scholars
Kelly Andrzejewski, DO, PhD, Nancy Downing, PhD, RN, SANE-A George McNally, BMedSci 2013
HDSA HD Human Biology Project Fellows
Helen Budworth, DPhil Tanya Garcia, PhD Jun Hua, PhD
NAME: Kelly L. Andrzejewski, DO, PhD
EDUCATION: BS, Biology, Canisius College, Buffalo, NY; DO, Michigan State University College of Osteopathic Medicine, East Lansing, MI; PhD, Michigan State University, East Lansing, MI
CURRENT POSITION: Experimental Therapeutics in Movement Disorders Fellow, University of Rochester Medical Center, Rochester, NY
HOBBIES: Spending time with family and friends
RESEARCH INTERESTS: Dr. Andrzejewski conducted her PhD research on a mouse model of Parkinson disease, which sparked her interest in pursuing training as a movement disorders specialist. She completed her neurology residency at University Hospitals Case Medical Center in Cleveland, OH, and then joined the Experimental Therapeutics fellowship program at the University of Rochester. Her clinical experience with HD patients during her fellowship led her to focus her research on assessing the feasibility of measuring HD motor symptoms using wearable sensors and smartphone technologies. After completing her movement disorders fellowship in June 2016, she plans to practice as a movement disorders specialist and HD clinical trial investigator. She is also interested in further investigating the role of the cannabinoid system in HD pathophysiology and exploring other potential therapies for HD.
HOPES FOR THE FUTURE: Dr. Andrzejewski hopes that the next ten years will bring new treatments to slow or halt the progression of HD. She told HD Insights, “We all know that research takes a long time, and that we need groups of investigators such as those that make up the Huntington Study Group to help develop new treatments for HD.”
PUBLICATION HIGHLIGHT: Andrzejewski K, Gwin J, Harris DA et al. Sensor-based remote measurement of the motor symptoms of Huntington’s disease. [abstract] To be presented during the Ninth Annual Huntington Disease Clinical Research Symposium, October 24, 2015, Tampa, FL.
NAME: Nancy R. Downing, PhD, RN, SANE-A
EDUCATION: BSN, RN, and PhD, College of Nursing, University of Iowa, Iowa City, IA; postdoctoral research with Janet Williams, PhD, RN, FAAN, and Jane Paulsen, PhD
CURRENT POSITION: Assistant Professor, College of Nursing, Carver College of Medicine
Department of Psychiatry, University of Iowa
HOBBIES: Bicycling, including the 15,000-person RAGBRAI Ride across Iowa
RESEARCH INTERESTS: Dr. Downing’s research focuses on improving quality of life and caregiver experiences for individuals with HD, those at-risk for HD, and their families. She describes these measures as “palliative,” emphasizing that despite the tendency to conflate this with end-of-life care, these measures are aimed at improving quality of life and functioning throughout the disease course.
She is currently developing patient-reported outcome measures that can better measure quality of life for HD patients and their caregivers, as well as investigating the ways in which HD gene carriers and their families conceptualize and cope with the gradual loss of function in HD. Through her work identifying lifestyle-based interventions, Dr. Downing hopes to elucidate low-risk ways for individuals at risk for HD, and those living with the disease, to improve their functioning. As a geneticist, she is interested in the effects of these interventions on epigenetic modifications that may affect HD progression.
HOPES FOR THE FUTURE: Dr. Downing hopes that the next ten years will bring the development of gene-based therapeutics that can modify disease course. She hopes that lifestyle-based adjuvants to biological therapies identified through large-scale studies, such as diet changes, physical exercise, and mental exercises, will become mainstream and help to improve patients’ and families’ quality of life.
PUBLICATION HIGHLIGHT: Downing NR, Kim JI, Williams JK, et al. WHODAS 2.0 in prodromal Huntington disease: measures of functioning in neuropsychiatric disease. Eur J Hum Genet. 2014 Aug;22(8):958-63.
NAME: George McNally, BMedSci
EDUCATION: BMedSci, Psychological Medicine, University of Birmingham, Birmingham, England
CURRENT POSITION: Final-year medical student, University of Birmingham
HOBBIES: Playing sports, including field hockey, skiing, golf, and tennis
RESEARCH INTERESTS: Mr. McNally became interested in neuropsychiatric rating scales used in HD through his research mentor, Dr. Hugh Rickards. His work has focused on exploring the validity of the Problem Behaviors Assessment (PBA), developed by Dr. David Craufurd, using novel analytical methods. His research has led to a collaboration with Dr. Craufurd to further develop seven apathy items into a potential PBA subscale. This is Mr. McNally’s first foray into research, and he plans to continue his work in HD research when he finishes his medical training and moves into clinical practice.
HOPES FOR THE FUTURE: Mr. McNally hopes that efforts to modernize and refine rating scales and other assessment tools will help improve the detection of important symptom changes in HD clinical trials, and especially inform trials of novel disease-modifying therapies.
NAME: Helen Budworth, DPhil
EDUCATION: BS, Genetics and Microbiology, University of Liverpool, Liverpool, England; DPhil in Biochemistry, Wolfson College, University of Oxford, Oxford, England; post-doctoral research at the Lawrence Berkeley National Laboratory, Berkeley, CA
CURRENT POSITION: Biochemist Research Scientist, Lawrence Berkeley National Laboratory
HOBBIES: Surfing and enjoying the beautiful beaches of California
RESEARCH INTERESTS: Dr. Budworth has devoted her career to studying mechanisms of DNA repair in human disease and exposure to harmful agents. She joined Dr. Cynthia McMurray’s lab in 2011, applying her knowledge of DNA repair mechanisms to the study of HD. In 2013, Dr. Budworth was awarded an HDSA HD Human Biology Award to study transcriptomic and metabolomic biomarkers of HD progression in humans. Her work has led to a collaboration with Dr. Christopher Ross at Johns Hopkins University, in which blood samples from individuals with HD and control patients are analyzed for their transcript and metabolite patterns. They then correlate the metabolite profiles of plasma from patients with the gene expression differences observed in genes that control metabolic processing. The work holds promise for producing robust biomarkers of HD progression.
HOPES FOR THE FUTURE: Dr. Budworth told HD Insights, “We are on the cusp of breakthroughs for much more effective treatments for HD. Gene therapy, and the evolution of more gene editing tools, will hopefully be of great benefit to HD patients, in whom the monallelic single gene mutation is a very good target for gene therapy. Our lab has identified the role of somatic expansion in the onset of disease, that is, further expansion of the polyglutamine repeat in patients, in addition to what they inherit. This opens the door for new therapeutic options − by slowing down or blocking somatic expansion, we can delay the onset of disease. This is a very exciting avenue for therapeutics.”
PUBLICATION HIGHLIGHT: Budworth H, Harris FR, Williams P, et al. Suppression of somatic expansion delays the onset of pathophysiology in a mouse model of Huntington’s disease. PLoS Genet. 2015 Aug 6;11(8):e1005267. doi: 10.1371/journal.pgen.1005267. eCollection 2015.
NAME: Tanya Garcia, PhD
EDUCATION: BS, Mathematics, University of California, Irvine, CA; MS, Industrial Engineering and Operations Research, University of California, Berkeley, CA; MSc, Statistics, University of Western Ontario, London, ON, Canada; PhD, Statistics, Texas A&M University, College Station, TX
CURRENT POSITION: Assistant Professor of Biostatistics, School of Public Health, Texas A&M University
HOBBIES: Traveling, hiking, and exploring the outdoors with her husband and two rescued dogs
RESEARCH INTERESTS: Dr. Garcia’s work focuses on the development of statistical models to predict HD progression. Using data from previous observational studies such as PREDICT and COHORT, she and her colleagues are developing an advanced statistical model of patient-specific features of HD progression. The model aims to be able to predict not only when events occur in the progression of the disease, but also how long it takes those events to occur in time. The applications of the model could be far-reaching. In particular, Dr. Garcia and colleagues hope to be able to better predict and design clinical trials by using the model to inform power calculations and effect sizes needed in trial design of the trials.
HOPES FOR THE FUTURE: “We are close to finding out which different biomarkers are really associated with disease onset,” Dr. Garcia told HD Insights. “We hope we will have very reliable, targetable biomarkers in 10 years, and that our developing statistical methods will help with this process.”
PUBLICATION HIGHLIGHT: Wang Y, Garcia TP, Ma Y. Nonparametric estimation for censored mixture data with application to the cooperative Huntington’s observational research trial. J Am Stat Assoc. 2012;107(500):1324-1338.
NAME: Jun Hua, PhD
EDUCATION: BS, Electrical Engineering, University of Shanghai for Science and Technology, Shanghai, People’s Republic of China; MS, Precision Instruments, Shanghai Jiao Tong University,
Shanghai, People’s Republic of China; MSE, Biomedical Engineering, and PhD, Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD
CURRENT POSITION: Assistant Professor and Research Scientist, F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD; Assistant Professor, Russell H. Morgan Department of Radiology, Johns Hopkins University
HOBBIES: Spending time with his two young children, skiing and snowboarding, playing various sports and traveling with family
RESEARCH INTERESTS: Dr. Hua specializes in the development and application of advanced MRI technologies to the study of human neurological diseases. Dr. Hua’s research collaboration with Dr. Christopher Ross has revealed increased blood volume in small arteries and arterioles in the brains of prodromal HD patients, before brain atrophy can be observed. His current research is focused on the use of novel functional and physiological MRI techniques to develop early functional biomarkers of HD progression based on neurovascular and metabolic changes in the brain. He emphasizes the importance of HD as a model disease that can shed light on the mechanisms of other neurodegenerative diseases.
HOPES FOR THE FUTURE: Dr. Hua hopes to see improvements in functional biomarkers, which have historically been difficult to develop due to the small effect sizes and difficulty in detecting these biomarkers with current methods. He is particularly interested in new technological developments that will enable more accurate and specific biomarker detection.
PUBLICATION HIGHLIGHT: Hua J, Unschuld PG, Margolis RL, et al. Elevated arteriolar cerebral blood volume in prodromal Huntington’s disease patients. Mov Disord. 2014 Mar;29(3):396-401. doi: 10.1002/mds.25591. Epub 2013 Jul 11.
This year’s MDS International Congress took place in San Diego, California
By: Meredith A. Achey, BM
The 2015 International Congress of Parkinson’s Disease and Movement Disorders took place on June 14−18 in San Diego, California. Despite some less-than-sunny weather, the congress offered some bright glimpses into the next decade of HD research and therapeutic development.
This year marked the 25th anniversary of the MDS International Congress. In a therapeutic plenary session on the first day of the meeting, Dr. Ira Shoulson (see HD Insights, Vol. 9) discussed the great increase in attention paid to HD, demonstrated by the number of sessions and posters presented at this meeting compared with the first Congress 25 years ago. Highlights of these sessions included a video course titled “What if it’s not Huntington’s disease?”, a session on “What’s new in Huntington’s disease?”, and a guided poster tour focused on “HD and other choreiform disorders.”
In their video session “What if it’s not Huntington’s disease?” Drs. Anne-Catherine Bachoud-Lévi and Joaquim Ferreira guided attendees through an impressive series of video clips demonstrating common and uncommon presentations of HD, as well as other movement disorders often confused with HD. The presenters emphasized the importance of distinguishing generalized chorea from other movements, along with the necessity of recognizing less common presentations of HD. As a reminder that clinicians may see movement disorders where there are none, the presenters also threw in a video of a normal patient, asking the audience first to identify her diagnosis and the “abnormalities” observable in her facial movements. This fast-paced but enjoyable session reinforced the necessity of not jumping too quickly to a diagnosis for the practicing movement disorders clinician.
The “What’s new in Huntington’s disease?” session covered the most recent developments in HD biomarkers, basic science, and clinical research. Dr. Ralf Reilmann discussed the current array of biomarkers in pre-manifest and manifest HD and whether these are ready for use in clinical trials. Dr. Michael Levine followed with a discussion of the latest findings in laboratory and animal-model research and their influence on the development of novel therapies. The session concluded with an update from Dr. Cristina Sampaio of CHDI on the latest in disease-modifying and symptomatic treatments currently in development.
The HD-themed Guided Poster Tour highlighted some particularly compelling posters on HD clinical and basic science, as well as the continuing exploration of biomarkers, imaging changes, and their clinical correlates. Poster presenters ranged from well-known clinicians and investigators to PhD candidates, and hailed from Australia, Europe, and North America. Dr. Sam Frank presented the results of the First-HD study, emphasizing in particular the participant reports of improved global impression throughout the trial (see HD Insights, Vol. 10). Also presenting on clinical trials, Dr. Bernhard Landwehrmeyer discussed a recent analysis of data from MermaiHD and HART suggesting that there was no significant increase in adverse events in participants taking anti-depressants or anti-psychotics and pridopidine. Two posters described novel objective measures of HD symptoms, including a shoe-worn inertial sensor tested at Oregon Health and Sciences University, and the use of a Wii balance board to assess HD progression evaluated at UC San Diego. In addition, Dr. Ashwini Rao described his lab’s work evaluating gait modulation as a marker of HD progression. Two Australian researchers each described novel physiological measures of HD − Ms. Lauren Turner presented her discovery of abnormal electrophysiological responses in pre-manifest HD patients, and suggested that these may represent compensation, while Dr. Fiona Wilkes presented a compelling new analysis of IMAGE-HD imaging data showing callosal thinning with HD disease progression.
The 19th MDS Congress provided many opportunities for HD experts and those new to the field to learn about the latest in clinical and scientific understanding of the disease and its treatment.
Abstracts from the meeting can be accessed at www.mdsabstracts.com.
BY: Meredith A. Achey, BM
MANUFACTURER: Vaccinex Inc.
MOLECULAR FORMULA: Anti-semaphorin 4D (SEMA4D) monoclonal antibody
MECHANISM OF ACTION: VX15/2503 may slow or prevent neurodegeneration in HD by inhibiting SEMA4D, a signaling protein shown to be important in neuroinflammatory processes.1
Animal models of HD and human individuals with HD both exhibit immune dysregulation and increased inflammation in addition to the characteristic neuronal atrophy observed in the disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling protein implicated in several processes that may increase neuroinflammation, including glial cell activation, inhibition of oligodendrocyte and astrocyte migration, inhibition of neurodevelopment, and inducement of apoptosis.2 Given the increased inflammatory response and chronic immune activation observed in HD, SEMA4D inhibition may slow the progression of neurodegenerative processes.
SEMA4D has also been implicated in assisting in the abnormal growth of cancer cells because its high expression at the margins of invasive growths inhibits anti-tumor immune cells from entering the tumor. Strikingly, in metastatic processes, SEMA4D inhibition promotes inflammation and immune activity to encourage rejection of invasive growths,3 in contrast to the inhibitory effect VX15/2503 exhibits on neuroinflammation in mouse models of HD. VX15/2503 was also recently evaluated by Vaccinex in a phase I study in adults with solid tumors.
Vaccinex has developed the anti-SEMA4D monoclonal antibody VX15/2503 using their novel vaccinia virus − based platform for screening human antibodies as therapeutic targets. According to the company’s website, other similar processes that use yeast and bacteriophages to express candidate proteins are limited because the proteins do not undergo the post-translational modifications typical of a mammalian cell, and therefore may be less consistent in their quality and biophysical properties.4,5
In collaboration with the Huntington Study Group, Vaccinex is currently conducting a Phase II clinical trial of VX15/2503 in HD patients, called SIGNAL (NCT02481674), which is designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of this novel monoclonal antibody in late prodromal and early manifest HD. Secondary endpoints include a number of imaging and biomarker studies, including MRI and PET imaging, as well as measurements of SEMA4D activity in T-cells and in the circulation. Clinical features of HD will be measured using components of the UHDRS, as well as the quantitative motor (Qmotor) assessment system (see HD Insights, Vol. 6), HD-CAB (Cognitive Assessment Battery), and the Problem Behaviors Assessment.6
VX15/2503 showed promise for neuropathology and cognitive symptoms of HD in the YAC12B mouse model, but did not demonstrate motor improvements.2 The SIGNAL trial may help to determine whether SEMA4D inhibition in the early stages of human HD might have similar effects.
1 Smith ES, Jonason A, Reilly C, et al. SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease. Neurobiol. Dis.2015;73:254-268.
2 Southwell AL, Franciosi S, Villanueva EB, et al. Antisemaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease. Neurobiol. Dis. 2015;76:46-56.
3 Evans EE, Jonason AS, Bussler H, et al. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies. Cancer Immunol. Res. 2015;3(6):689-701.
4 Vaccinex Inc. Vaccinia Technology. [Web page]. 2015;vaccinex.com/activmab/vaccinia-technology/
5 Smith ES, Zauderer M. Antibody library display on a mammalian virus vector: combining the advantages of both phage and yeast display into one technology. Curr Drug Discov Technol. 2014;11(1):48-55.
6 Kingma EM, van Duijn E, Timman R, van der Mast RC, Roos RA. Behavioural problems in Huntington’s disease using the Problem Behaviours Assessment. Gen Hosp Psychiatry. 2008;30(2): 155-161.
NAME: Maurice Zauderer, PhD
CURRENT POSITION: President and CEO, Vaccinex Inc.
EDUCATION: BS, Physics, Yeshiva University, New York, NY; PhD, Cell Biology,
Massachusetts Institute of Technology, Cambridge, MA
HOBBIES: Listening to music (particularly Mozart), and golf
Dr. Maurice Zauderer is the founder, president, and CEO of the privately held biotechnology company Vaccinex Inc., headquartered in Rochester, NY. Vaccinex focuses on the development of new human antibodies to combat a variety of conditions, including multiple sclerosis, cancer, and more recently, HD. Vaccinex’s VX15/2503 monoclonal antibody has recently been evaluated in Phase I trials for safety in multiple sclerosis and solid tumors, and the company has initiated a Phase II study to evaluate the safety, tolerability, and efficacy of VX15/2503 in HD. Dr. Zauderer recently shared his thoughts with HD Insights on VX15/2503 and its potential use in HD. The following is an edited transcript of the conversation.
HD INSIGHTS: Dr. Zauderer, can you describe the mechanism of action of VX15/2503 in HD?
ZAUDERER: VX15/2503 is a monoclonal antibody to semaphorin 4D, which is a member of the semaphorin family of proteins. Semaphorins direct the movement of cells in the body. They play a very important role during embryonic development, where cells move to shape different tissues and organs, and they continue to be important in the adult, because the adult continues to generate a variety of cells that are required to migrate to different locations in the body. For example, immune cells are generated in one location, but they must migrate to the site of an infection. Semaphorins play an important role in guiding that migration, and we have shown that semaphorin 4D plays a particularly important role in guiding the migration of cells that are relevant to neuroinflammatory and neurodegenerative diseases.
Microglia and astrocytes are two important inflammatory cells in the central nervous system that are activated by semaphoring 4D. They are beneficial in an acute situation, but they can both contribute to neurodegenerative processes if they are chronically activated. They produce biological modifier molecules such as cytokines that can cause damage to neural tissue. It is important to be able to regulate their activation and to minimize their effect on these neuroinflammatory and neurodegenerative processes. Vaccinex’s new therapy, VX15/2503, is a humanized antibody that is specific for semaphorin 4D, which it neutralizes, and thereby inhibits chronic activation of microglia and astrocytes and prevents some of the deleterious consequences that are associated with neuroinflammatory and neurodegenerative disease.
HD INSIGHTS: You have studied VX15/2503 for use in multiple sclerosis (MS) and in solid tumors with Phase I trials. Why have you proposed it for use in HD?
ZAUDERER: In both progressive MS and HD, microglia and astrocytes contribute to the slow, but progressive, neurodegenerative process.
HD INSIGHTS: You recently collaborated with Dr. Amber Southwell and colleagues on a study of VX15/2503 in the YAC128 mouse model of HD.1 Can you tell us about that study?
ZAUDERER: That was a very exciting collaboration. The YAC128 mouse model expresses a fully human mutant huntingtin gene that leads to neuroinflammation and neurodegeneration. The mice typically develop HD-like symptoms between six and 12 months of age with a variety of cognitive and behavioral deficits, and with neuropathology such as decreased brain volume. Our goal was to see whether VX15/2503 could prevent the development of these deficits. We tested it as a preventive therapy, by treating YAC128 mice starting at around six weeks of age. It was very gratifying to see that at least in some areas, we saw a marked amelioration of the disease process.
HD INSIGHTS: You also saw some changes on imaging.
ZAUDERER: Yes: for example, we observed reduced loss of brain volume. One characteristic feature of HD is loss of about 10 percent of both white matter and grey matter volume. Incidentally, this is also true in progressive MS. We demonstrated that use of VX15/2503 significantly reduced the loss of brain volume in YAC128 HD transgenic mice.
HD INSIGHTS: You recently launched a Phase II clinical trial of VX15/2503 in HD called SIGNAL. What do you hope to learn from this study?
ZAUDERER: We are enrolling patients who are in the prodromal and early manifest stages of HD. Our goal is to see whether treating patients with VX15/2503 delays or prevents the onset of disease. We actually just enrolled our first patient about a week ago, so it is too early to know. However, we have tested VX15/2503 in about 40 patients at various stages of MS, and it has had a good safety profile to date. We are hopeful that we will continue to have a good safety profile and be able the judge the efficacy of the drug as well in this study. The neuropathology and the behavioral and cognitive symptoms of HD continue to progress after clinical diagnosis. About one-third of the patients we will be working with will be in the early manifest stage of HD, because we want to see whether our VX15/2503 continues to have an impact on disease progression.
HD INSIGHTS: Changing gears, Vaccinex recently announced an agreement with Five Prime Therapeutics. Are there any implications for HD?
ZAUDERER: That was an antibody development agreement. Vaccinex has a novel human antibody selection technology that has been of interest to a number of other companies, including Five Prime Therapeutics, and Janssen Pharmaceuticals. In those relationships we select fully human antibodies against targets of interest to those companies. It is a technology collaboration.
HD INSIGHTS: Before you founded Vaccinex, you were a highly successful academic. Can you describe what motivated the change from academia to private enterprise?
ZAUDERER: I very much enjoyed my academic research career. I was on the faculty at Columbia University, then at the University of Rochester Cancer Center for a total of 25 years before founding Vaccinex. It was a very enjoyable time in my life. As it happened, my laboratory developed some novel technologies that were of commercial interest. I was approached by a group of investors who were very interested in founding a biotechnology company based on those technologies, and I thought this would be an interesting challenge, and indeed it has been. It was an opportunity to do something different in my life.
HD INSIGHTS: Any regrets?
ZAUDERER: No, none at all. On the contrary, it has been a very enriching experience. The qualities you need and that you cultivate as an academic scientist are different from the qualities that you need and cultivate as an entrepreneur. I really feel this has been a growth opportunity for me.
HD INSIGHTS: Can you elaborate on those qualities?
ZAUDERER: In academic life, the most important value is innovation on an individual level; it is the basis for publication, the basis for promotion, and for grants. When you are at a biopharmaceutical company, the process of bringing a product from the laboratory to the clinic is so complicated that you very quickly realize that you cannot possibly do it without a lot of cooperation with other people. So, although innovation continues to be important, cooperation is equally important, and that involves a whole different set of relationships and skills. I feel fortunate to have been put in a situation where I have had to develop and cultivate those skills.
HD INSIGHTS: Do you have any advice for academics who are thinking of making the transition to industry?
ZAUDERER: It is much more challenging than I realized when I first jumped into this. There are numerous organizational, financial, and development challenges. You need a very strong group of supporters in order to be able to do this successfully.
HD INSIGHTS: Dr. Zauderer, thank you very much for your time and good luck with your efforts in HD.
Welcome to the twelfth edition of HD Insights, released at the 2015 Huntington Study Group Annual Meeting and Ninth Annual HD Clinical Research Symposium. We are pleased to continue our mission to promote, disseminate, and facilitate research in HD. We thank our subscribers, our Editorial Board, our newest sponsors, Teva Pharmaceuticals and Raptor Pharmaceuticals, and our founding and longtime supporter, Lundbeck Inc., for their generous support of the periodical.
This edition highlights exciting current research and up-and-coming HD researchers. In our new “Meet the Next Generation” feature, we profile early- to mid-career investigators who have been recognized by the Huntington’s Disease Society of America and the HSG as investigators with promising futures in HD research. All six have been invited to attend the 2015 HSG Annual Meeting to present their work. With the second year of the Insights of the Year competition, we bring you nine of the most influential publications in HD from July 2014 to July 2015, identified by the winners of last year’s competition. Authors of the four most influential papers, selected by our Editorial Board and other researchers, will present their work in a special panel session at the HSG meeting. Dr. Maurice Zauderer, founder, president, and CEO of Vaccinex Inc., discusses his company and their monoclonal antibody VX15/2503, which has just entered Phase II trials in HD. For those who were unable to attend the 19th International Congress of Parkinson’s Disease and Movement Disorders in San Diego, CA this year, we summarize the HD-related highlights of that meeting. Finally, we continue to provide an up-to-date status report on HD clinical trials.
HD Insights strives to provide relevant, interesting, and useful information to the global HD research community in academia and industry. We will continue to introduce new features and new explorations in the coming year, and welcome your suggestions and submissions. If you would like to become a supporter, or submit an article, comment, or suggestion, please send us an email at email@example.com. For a free electronic subscription, please send an email to firstname.lastname@example.org. Thank you for your continued support.
– – RAY DORSEY, EDITOR I N CHIEF
Editorial Board Members
Ray Dorsey, MD — Editor, University of Rochester
Donald Kennedy, PhD — Stanford University
Nobuyuki Nukina, MD, PhD — Riken Brain Science Institute
Rodrigo Osorio — Agrupación Chilena de Huntington
Bernard Ravina, MD — Voyager Therapeutics
Ralf Reilmann, MD, PhD — George Huntington Institute
Sarah Tabrizi, MBChB, PhD — University College London
Leslie Thompson, PhD — University of California Irvine
Meredith A. Achey, BM
Chen Chang, PhD
Yijuang Chern, PhD
Janelle Drouin-Ouellet, PhD
Marta Fernández-Nogales, PhD
Chien-Hsiang Huang, PhD
Joshua L. Plotkin, PhD
Steven G. Potkin, MD
Amber L. Southwell, PhD
Zhiqun Tan, PhD
Romina Vuono, PhD
Edward J. Wild, PhD
X. William Yang, PhD
Meredith A. Achey — Deputy Editor
Robin Taylor — Production Editor
Martin Holmes — Technical Editor
David Kolko — Distribution Specialist
Huntington Study Group
Shari Kinel, JD — HSG Executive Director
Liz McCarthy, BA — HSG Director, Special Programs
Heather Hare, BA — HSG Director, Communications & Outreach
Stevan Ramirez, MBA — HSG Director, Finance & Operations
Kristin Strazdins — HSG Accounting and Office Manager
HD INSIGHTS (TM)
DISCLOSURES: DR . DORSEY RECEIVES GRANT SUPPORT FROM PRANA BIOTECHNOLOGY, TEVA, AND THE HUNTINGTON STUDY GROUP.
In our final issue of 2015, HD Insights highlights influential HD research in the 2014-2015 academic year. The winners of last year’s Insights of the Year competition nominated nine papers in lab, clinical, and imaging and biomarkers research. The Editorial Board and other researchers voted for the most influential papers, selecting one each in basic and clinical science and two in imaging and biomarkers as most influential. Authors of the most influential papers will present their research in a special panel discussion at the 2015 HSG annual meeting. Congratulations to all the nominees and winners!
In the lab…
Most influential paper
Targeting ATM ameliorates mutant huntingtin toxicity in cell and animal models of HD
By: Lu XH, Mattis VB, Wang N, Al-Ramahi I, van den Berg N4, Fratantoni SA, Waldvogel H, Greiner E, Osmand A, Elzein K, Xiao J, Dijkstra S, de Pril R, Vinters HV, Faull R, Signer E, Kwak S, Marugan JJ, Botas J, Fischer DF, Svendsen CN, Munoz-Sanjuan I, Yang XW
(Summary by X. William Yang, MD, PhD)
Emerging evidence suggests that DNA damage and repair pathways can contribute to the pathogenesis of a number of neurodegenerative disorders. We investigated the pathogenic role in HD of ataxia-telangiectasia mutated (ATM), a protein kinase involved in DNA damage response, apoptosis, and cellular homeostasis. Loss-of-function mutations in both alleles of ATM cause ataxia-telangiectasia in children, but heterozygous mutation carriers are disease-free. Persistently elevated ATM signaling has been observed in Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), and in polyglutamine disorders such as HD and spinocerebellar ataxia type 3 (SCA3). We showed that ATM signaling was consistently elevated in cells derived from the BACHD mouse model and in disease-vulnerable brain tissues from BACHD mice and HD patients (Figure).
ATM reduction mitigated toxicities induced by mutant Huntingtin (mHTT) fragments in mammalian cells and in transgenic Drosophila models. By crossing the murine Atm heterozygous null allele onto BACHD mice expressing full-length human mHTT, we showed that genetic reduction of one copy of the Atm gene ameliorated multiple behavioral deficits, and partially improved neuropathology. Small-molecule ATM inhibitors, originally developed for radiosensitization in cancer therapy, reduced mHTT-induced cell death in a rat cortico-striatal neuronal co-culture assay and in induced pluripotent stem cells (iPSCs) derived from HD patients. Our study provides converging genetic and pharmacological evidence that partial reduction of ATM signaling could ameliorate mHTT toxicity in a number of cellular and animal models of HD, suggesting that ATM maybe a useful therapeutic target for HD.
Aberrant astrocytes impair vascular reactivity in Huntington’s disease
By: Hsiao HY, Chen YC, Huang CH, Chen CC, Hsu YH, Chen HM, Chiu FL, Kuo HC, Chang C, Chern Y
(Summary by Chien-Hsiang Huang, PhD, Chen Chang, PhD, and Yijuang Chern, PhD)
Increased blood vessel density has been recognized in animals and patients with HD. Our study further reveals that a fraction of the cortical blood vessels in the brains of HD mice (R6/2) is nonreactive (Figure). Such impaired blood vessels in HD brains result from aberrant astrocytes that release too much vascular endothelial growth factor and inflammatory mediators. The impaired vascular reactivity causes abnormal regulation of cerebral blood flow and may be responsible for brain atrophy in R6/2 mice. Whether the formation of the nonreactive vessels is detrimental or beneficial to HD remains to be elucidated. The nonreactive vessels warrant future investigation in clinical settings, and the integrity of vascular reactivity may be used as a new biomarker to evaluate the progression of HD.
Impaired TrkB receptor signaling underlies corticostriatal dysfunction in Huntington’s disease
By: Plotkin JL, Day M, Peterson JD, Xie Z, Kress GJ, Rafalovich I, Kondapalli J, Gertler TS, Flajolet M, Greengard P, Stavarache M, Kaplitt MG, Rosinski, J, Chan CS, Surmeier DJ
(Summary by Joshua L. Plotkin, PhD)
Reduced trophic support of striatal projection neurons (SPNs) is thought to play a key role in the progression of HD. This has been widely attributed to diminished levels of brain-derived neurotrophic factor (BDNF). In a recent study, we showed that BDNF signaling through tyrosine-related kinase B receptors (TrkBRs) was indeed attenuated in the striatum of early symptomatic BACHD and Q175 mouse models of HD, but without changes in BDNF expression or delivery to the striatum. This attenuation led to a synapse-specific loss of corticostriatal long-term potentiation, and progressive weakening of cortical synapses to indirect pathway SPNs (iSPNs), a circuit pathology consistent with the early choreic symptoms of HD.
Although TrkBRs were activated normally, their signaling was blunted by engagement of another target of BDNF: p75 neurotrophin receptors (p75NTRs). Elevated p75NTR signaling occurred due to increased expression of its downstream target: phosphatase and tensin homolog deleted on chromosome 10 (PTEN). PTEN is an inhibitor of TrkBR signaling, and was specifically up-regulated in iSPNs (Figure). Synaptic potentiation could be rescued in HD iSPNs by inhibiting 75NTRs, PTEN, or intermediate signaling partners. This study suggests that targeting postsynaptic p75NTR signaling, rather than presynaptic BDNF delivery, offers a promising therapeutic strategy for HD.
In the clinic…
Most influential paper
Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients
By: Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, Zetterberg H, Leavitt BR, Kuhn R, Tabrizi SJ, Macdonald D, Weiss A
(Summary by Edward J. Wild, PhD)
The genetic cause of HD – mHTT, encoded by the CAG-expanded mHTT gene – has been known since 1993. Clinical trials of “gene silencing” drugs that aim to reduce the production of mHTT in the brain are now underway in HD patients.
Quantifying mHTT in the central nervous system (CNS) would be helpful for understanding whether these therapies are having the desired effect, and would aid in studying the biology of mHTT in HD. However, mHTT accumulates inside cells, and its concentration in cerebrospinal fluid (CSF) is very low. Until now, mHTT could not be detected in the CNS.
We have developed a new, ultra-sensitive, “single molecule counting” immunoassay to detect and measure the concentration of mHTT in CSF. The immunoassay uses an antibody pair specific to mHTT over wild-type huntingtin. Fluorescence events corresponding to single molecules of antibody-bound protein are counted, enabling precise quantification at femtomolar concentrations.
We analyzed CSF from volunteers from two cohorts and for the first time, successfully quantified mHTT in mHTT carriers. We showed that mHTT levels in premanifest HD were intermediate between control and manifest HD levels (Figure). Moreover, the concentration of mHTT independently predicted disease burden as well as motor and cognitive scores. Associations with known neuronal proteins suggest the mHTT detectable in CSF is derived from dying neurons. We now plan to use this new assay to determine whether the level of mHTT in CSF can predict HD onset or rate of progression, and to study the first “gene silencing” drugs in clinical trials.
The role of tau in the pathological process and clinical expression of Huntington’s disease
By: Vuono R, Winder-Rhodes S, de Silva R, Cisbani G, Drouin-Ouellet J; REGISTRY Investigators of the European Huntington’s Disease Network,
Spillantini MG, Cicchetti F, Barker RA
(Summary by Romina Vuono, PhD)
More than twenty years after the discovery of the genetic defect responsible for HD, there are still many unanswered questions. For example, why do HD patients differ dramatically in their age at onset of manifest disease and disease progression, despite similar CAG repeat lengths? Recent studies have suggested that other genetic influences may play a role. So far, more than 24 genes have been linked to HD, but their relevance remains unclear as to whether, and how, they may drive the HD pathogenic cascade and resultant clinical features.
We have recently shown that the microtubule-associated protein tau gene (MAPT), known to be associated with many neurodegenerative diseases, can give rise to pathology in the brains of HD patients. We have reported pathological tau aggregates, as well as tau oligomers (thought to be the most toxic form of tau), in postmortem HD brain tissues (Figure). These findings were common to young-onset as well as older HD patients, confirming that tau pathology was related to the disease process, rather than related to age. We highlighted the clinical significance of this pathology by demonstrating that a genetic variation of the MAPT gene (MAPT H2 haplotype) affected the rate of cognitive decline in a large cohort of HD patients. Our findings highlight a novel and important role for tau in the pathogenic process and clinical expression of HD, which in turn may open up new therapeutic approaches.
Huntington’s disease is a four-repeat tauopathy with tau nuclear rods
By: Fernández-Nogales M, Cabrera JR, Santos-Galindo M, Hoozemans JJ, Ferrer I, Rozemuller AJ, Hernández F, Avila J, Lucas JJ
(Summary by Marta Fernández-Nogales, PhD)
Intronic mutations that produce an alteration in exon 10 alternative splicing of the MAPT (Tau) gene in frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17) result in an increase of tau isoforms with four repeats of microtubule binding domains. This is sufficient to cause neurodegeneration, though the reason is not yet known. It is possible that these tau binding domains increase the binding energy of tau to the microtubules.
We discovered an increase in tau isoforms with four microtubule binding domains in the cortex of HD patients and a concomitant decrease in isoforms with three microtubule binding domains, as well as an increase in total tau levels, similar to that observed in other dementias. This change is accompanied by the appearance of a new tau-histopathological hallmark in the brains of HD patients, consisting of deposits of rod-shaped tau protein that fill previously reported invaginations of the nuclei of some striatal and cortical neurons (Figure). We have named these inclusions “tau nuclear rods.”
Furthermore, we were able to demonstrate that tau protein plays a role in the pathogenesis of HD by verifying that the partial or total reduction of tau in an HD mouse model produces a significant improvement in motor coordination. This discovery opens the possibility of using emergent pharmacological tools under development for the treatment of other tauopathies in HD patients.
In imaging and biomarkers…
Most influential paper
Cerebrovascular and blood-brain barrier impairments in Huntington’s disease: potential implications for its pathophysiology
By: Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagacé M, Kuan WL, Saint-Pierre M, Dury RJ, Alata W, St-Amour I, Mason SL, Calon F, Lacroix S, Gowland, PA, Francis ST, Barker RA, Cicchetti F
(Summary by Janelle Drouin-Ouellet, PhD)
We report here on our work using a combination of approaches to show that the cerebrovasculature is compromised at four different levels in the context of HD. We show that:
1) mHTT protein aggregates are found in all compartments of the neurovascular unit
2) blood vessels are more dense but smaller in size
3) this change in size and density is accompanied by an increased blood-brain barrier permeability that leads to
peripheral blood cell infiltration, and
4) there are mHTT aggregates in transcytotic vesicles.
These observations appeared on MRI and in postmortem tissue in both the R6/2 mouse model and HD patients (Figure).
These findings raise critical questions regarding the impact of vascular alterations on neuronal network activity and degeneration in HD, and could indicate a more significant crosstalk between elements of the blood and the CNS than originally thought. This could in turn create an increased inflammatory response as a result of immune cell infiltration to the brain and facilitate mHTT accumulation due to the leaky blood-brain barrier. We aim to further elucidate the contribution of blood-brain barrier compromise, and the resulting presence of inflammatory elements, to the pathophysiology and progression of HD.
Most influential paper
Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression
By: Southwell AL, Smith SE, Davis TR, Caron NS, Villanueva EB, Xie Y, Collins JA, Li Ye M, Sturrock A, Leavitt BR, Schrum AG, Hayden MR
(Summary by Amber L. Southwell, PhD)
The lack of quantitative, robust, and reliable biomarkers for use in early subclinical diagnosis is a major obstacle for development of disease-modifying therapies for HD. Such markers are needed to assist in monitoring disease Progression, patient stratification, and evaluating efficacy of therapeutics in the clinic.
The Hayden lab at the University of British Columbia (UBC) has collaborated with colleagues at UBC and the
Mayo Clinic to develop an ultrasensitive method of measuring mHTT in the cerebrospinal fluid (CSF) of HD patients and model mice, called microbead-based immunoprecipitation and flow cytometry (IP-FCM), that could meet these needs. See Figure for a schematic that summarizes the method.
Using IP-FCM, we have shown that mHTT in the CSF originates in the brain and is released by injured or dying brain cells. Levels of mHTT in the CSF increase with worsening HD symptoms, suggesting that this approach will be useful as a measure of disease progression.
Additionally, lowering mHTT in the brain using gene-silencing treatments results in a measurable reduction of mHTT in the CSF, indicating that this method could be used to verify and quantify changes in brain mHTT levels in response to experimental therapies. This advance is clinically relevant and will enable more rigorous assessment of important endpoints in evaluating therapies for HD.
Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin
By: Tan Z, Dai W, van Erp TG, Overman J, Demuro A, Digman MA, Hatami A, Albay R, Sontag EM, Potkin KT, Ling S, Macciardi F, Bunney WE, Long JD, Paulsen JS, Ringman JM, Parker I, Glabe C, Thompson LM, Chiu W, Potkin SG
(Summary by Zhiqun Tan, PhD, and Steven G. Potkin, MD)
The onset of symptoms in individuals who carry the mutant HD allele (mHTT) remains variable and unpredictable. To speed development of new therapies, biomarkers that reflect the development of the HD pathological process are quantitatively associated with the course of illness are needed. We reported that oligomeric peptides that contain the polyglutamine expansion coded by mHTT, and CSF fluid from individuals with HD, and BACHD transgenic rats, enhance seeded aggregation in a PC-12 cell model and its cell lysate. Oligomers derived from other proteins, including Aβ and α-synuclein, do not induce seeding. We demonstrate that seeding is mHTT template-specific and may reflect an underlying cell-to-cell mechanism of huntingtinopathy propagation.
Light and cryo-electron microscopy (cryo-EM) confirm that synthetic seeds nucleate and enhance mHTT aggregation in cell lysates. This seeding assay (Figure) distinguishes individuals with HD from healthy controls. Seeding measures in asymptomatic gene-positive individuals fall between HD patients and controls. This quantifiable seeding property in the CSF of individuals with HD may serve as a molecular biomarker assay to monitor HD progression, and to evaluate therapies that target mHTT. The automation of the assay is in process.