Meet the Investigator

Meet the Scientist : Beverly Davidson


NAME: Beverly Davidson, PhD

TITLE: Chief Scientific Strategy Officer at the Children’s Hospital of Philadelphia (CHOP); Director of the Raymond G. Perelman Center for Cellular and Molecular Therapeutics; Arthur V. Meigs Chair in Pediatrics, CHOP; Professor of Pathology and Laboratory Medicine, University of Pennsylvania

EDUCATION: PhD and post-doctoral research fellowship, University of Michigan

HOBBIES: Cycling, running, water- and snow- skiing; visiting museums; spending time with her children

Dr. Beverly Davidson is a geneticist of the first rank, who has made groundbreaking advances in our genetic understanding of HD, and is working hard to develop new gene-based therapies for HD and other conditions. HD Insights recently spoke with Dr. Davidson about her ongoing research. The following is an edited transcript of the conversation.

HD INSIGHTS: You have been studying HD and its genetics for nearly 20 years. Can you tell us how you got into the field?

DAVIDSON: I recently woke up in the middle of the night thinking, “It has been 12 years since the publication of our knockdown studies.”1 I had no idea that it would take us this long to get to the clinic. How did I originally get into HD? I first started working in inborn errors of metabolism that affect the CNS. As a graduate student, I worked on Lesch-Nyhan syndrome. It always fascinated me how seemingly ambiguous mutations would induce such profound changes in the brain. I became fascinated by learning how mutations induce neuropathology, and developing ways to mitigate that neuropathology. I started early on in gene replacement strategies, always thinking in the back of my mind how we could apply some of the things we learn about getting genes into cells, and use this in some of the dominant neurodegenerative disorders.

We started working on RNA interference (RNAi) shortly after the seminal discovery by Fire and Mello in the late 1990s.2 We really did not have much success in achieving very selective knockdown until Tom Tuschl’s paper came out some time later, showing us that the best way to accomplish selective knockdown was by using very small RNA fragments that were complementary to the gene you were trying to knock down.

We started working on this with two collaborators at the time. We had developed the technology, but we needed an animal model, and in the laboratory next door to mine was Henry Paulson, who worked on spinocerebellar ataxia. Through close interactions with Dr. Paulson we came to know Dr. Harry Orr, Dr. Nancy Bonini, and others working in the polyglutamine repeat field. We collaborated with Drs. Orr and Paulson to test some of our ideas in cell and mouse models. That is how we came to work in polyglutamine repeat diseases. It was really by chance that we began to focus on these sorts of therapeutics for spinocerebellar ataxia, and then also HD, both of which are classical polyglutamine repeat disorders.

Actually, my interest in HD goes back a bit further. My very close friend’s father had HD, and I recall seeing her grandmother cross the street when I was a child. I was with my dad, who was the local physician in our small community in south central Nebraska. I asked dad what was wrong with Shelly’s grandmother – she acted as if she could not walk very well. I was too young to know what a drunk looked like, and dad had told me that she had HD, and of course that meant nothing to me. But now we have come full circle. Many of Shelly’s family have succumbed to HD, so maybe I was destined from a very young age to work on this disease.

HD INSIGHTS: That is a powerful story. You mentioned that when you first published your seminal paper looking at the knockdown of the HD gene 12 years ago, you did not think it would take so long to get new therapies to the clinic. Why has it taken so long?

DAVIDSON: As with any new technology, in 2004-2005 we were using state-of-the-art methods for the time. As we began to learn more and more about the biology of the system that we were co-opting to perform RNAi in cells, we learned that there were better and safer ways to accomplish this.

DAVIDSON: The next six to seven years were to perfect the system and understand the basic ingredients of what it was we were making, and understand the impact of what we were making on the cell. The reason for taking this stepwise, careful, methodical approach is that HD is already terrible, and the last thing I want to do is take something that is very debilitating and make it worse.

HD INSIGHTS: Can you tell us about what is most exciting to you currently in terms of RNAi or antisense oligonucleotides (ASOs)?

DAVIDSON: We focused early on gene-silencing strategies, the idea being that the delivery of the viral vector to the affected cell would provide a one-time treatment to the brain. Sometime after our studies were published, Frank Bennett, at what is now known as Ionis Pharmaceuticals, began a fantastic collaboration with Dr. Don Cleveland’s group. Initially, it was to study ASOs for an inherited form of amyotrophic lateral sclerosis. Then, they transitioned to testing the ASOs in animal models of HD. These were the same models that many of us were using to test therapies at the time. His data showed that just as in our RNAi experiments, he could positively impact the disease course with doses of the ASOs, and I think that really excited the community. Fortunately for Ionis, they have already been into the clinic with many of these molecules.

Ionis is a large company that was well set to do the basic pharm tox that needs to be done to advance these molecules into therapies. Ionis has already started early phase-testing in HD patients, which is exciting. So, while we still remained poised to do our studies, they were already doing some safety studies in HD patients. It is an exciting moment for the gene-silencing community.

HD INSIGHTS: Can you talk about the current status of your gene-silencing therapies and efforts?

DAVIDSON: All the work that was developed while I was at the University of Iowa was licensed to Spark Therapeutics, and remains right now in IND-enabling studies.

HD INSIGHTS: Tell us about the promise of these therapies for HD.

DAVIDSON: Animal data suggest that you need not rid every cell of the mutated huntingtin gene, but to provide benefit, you need to hit a sufficient number of cells. The viral-vector delivered RNAi approach that we are taking, initially, is set to target the striatal region of the brain. This is in contrast to ASO therapies, in which the targeting is best achieved in the cortical structures. You could think of these as two complementary approaches to achieve widespread gene-silencing in the brain, in which the ASO could provide benefit to cortical structures, and the RNAi approach could provide benefit to sub-cortical structures. Our hope is that we can extend the period that HD patients live productively with the disease, significantly delaying its progression.

HD INSIGHTS: In 2011, you published a paper showing the benefits of RNAi in a rhesus macaque model of HD.3 Can you tell us a little more about that study and what it suggests for humans?

DAVIDSON: That was a study that we felt was really important not only for the RNAi community focusing on HD, but also for the ASO community. The study asked the simple question, can you reduce normal huntingtin in normal monkeys without deleterious effect? These were normal rhesus monkeys, not an HD model, but being a nonhuman primate, their brain closely approximated that of humans.

Our data showed that you could partially reduce huntingtin expression, and it was not deleterious to the animal. That study, published by my group and Dr. Jodi McBride’s group at Oregon Health Sciences University, was the first to show that this approach was safe in a nonhuman primate. That was followed up by a longer-term study published by a group at Medtronic,4 in which they evaluated a very similar approach for six months, and came to the same conclusion as us.

That suggested to us all that this could work, and really propelled us to move forward with a non – allele-specific silencing strategy as a potential treatment for HD patients.

HD INSIGHTS: You mentioned the promise of RNA silencing treatments. Do you have any concerns about them?

DAVIDSON: I think the first question is, how much gene-silencing do we need? We will not definitively know that until we start human trials, but we think we know what we need to know from a lot of work done in animal models. There is always concern because this is a new and unknown therapy, but we are very hopeful that it is going to be as promising as the animal models predict.

HD INSIGHTS: Cures for neurological diseases are rare. Is it too soon to think that we could potentially cure HD?

DAVIDSON: This is not a cure. A cure would be where we would ablate the mutant gene product in every cell in the body, and that it would not manifest in any way in any tissue. Our hope is that these approaches will allow HD patients and premanifest individuals to live their lives to the fullest, and lengthen their time with no or minimal symptoms.

HD INSIGHTS: You have also done work in genetic conditions other than HD, and some of that work might even be ahead of where HD is. Could you tell us about some insights you have learned from other conditions?

DAVIDSON: The other condition we work on is spinocerebellar ataxia type 1, which, like HD, is a polyglutamine repeat disorder. We have also done some limited preclinical work in spinocerebellar ataxia type 7. Spinocerebellar ataxia type 1 was the first model in which we tested the RNAi approach, and spinocerebellar ataxia type 7, a second model. We have done more extensive dosing studies in spinocerebellar ataxia type 1 mouse models, and also tested some reversal studies in those models. I would not say that they are ahead of the HD program, I would say they are pretty close together.

We are also looking at the pathogenesis of HD and lysosomal storage diseases. We have some exciting data in HD, and this is really following close on the heels of some exciting work that has come out of Dr. Laura Ranum’s lab, where she has found that there are some funny transcripts that arise from the HD locus as a result of the CAG expansion.5 She sees transcripts in the nucleus that are not toxic in a normal-length allele, but in the setting of a disease-causing mutation, you can see these transcripts arising from that region, and if they are transported to the cytoplasm, they can be expressed as toxic proteins known as RAN translation products.

I think understanding how those products contribute to disease will be very interesting, as well as understanding other global changes that go on in the HD brain. I wonder whether we can take advantage of that information to develop small molecule therapies.

Will gene-silencing approaches be the be-all and end-all? I think the best approach might be a combination therapy where we tackle some of the downstream cellular impacts of mHTT and the mutant transcript, and in addition try to lower the insult through gene-silencing.

HD INSIGHTS: Thank you very much, Dr. Davidson. We greatly appreciate it.

DAVIDSON: I really thank HD Insights for the opportunity to let people know how we have reached where we are, and how excited we are to be so close to providing benefit to HD patients.

Selected recent publications:

  1. Monteys AM, Ebanks SA, Keiser MS, Davidson BL. CRISPR/Cas9 Editing of the Mutant Huntingtin Allele In Vitro and In Vivo. Mol Ther. 2017 Jan 4;25(1):12-23.
  2. Lin L, Park JW, Ramachandran S, et al. Transcriptome sequencing reveals aberrant alternative splicing in Huntington’s disease. Hum Mol Genet. 2016 Aug 15;25(16):3454-3466.
  3. Lee JH, Tecedor L, Chen YH, et al. Reinstating aberrant mTORC1 activity in Huntington’s disease mice improves disease phenotypes. Neuron. 2015 Jan 21;85(2):303-315.
  4. Katz ML, Tecedor L, Chen Y, et al. AAV gene transfer delays disease onset in a TPP1-deficient canine model of the late infantile form of Batten disease. Sci Transl Med. 2015 Nov 11;7(313):313ra180-313ra180.
  5. Lee JH, Sowada MJ, Boudreau RL, et al. Rhes suppression enhances disease phenotypes in Huntington’s disease mice. J Huntington’s Dis. 2014;3(1):65-71.


1Harper SQ, Staber PD, He X, et al. RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5820-5825.

2Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998 eb 19;391(6669):806-811.

3McBride JL, Pitzer MR, Boudreau RL, et al. Preclinical safety of RNAi-mediated HTT suppression in the Rhesus Macaque as a potential therapy for Huntington’s disease. Mol Ther. 2011 Dec;19(12):2152-2162.

4Grondin R, Kaytor MD, Ai Y, et al. Six-month partial suppression of Huntingtin is well tolerated in the adult rhesus striatum. Brain. 2012 Apr;135(4):1197-1209.

5Bañez-Coronel M, Ayhan F, Tarabochia Alex D, et al. RAN Translation in Huntington Disease. Neuron. 2015 Nov 18;88(4):667-677.

MEET THE SCIENTIST: Pavlina Konstantinova, MSc, PhD


NAME: Pavlina Konstantinova, MSc, PhD

TITLE: Director of Emerging Technologies and Huntington Disease Program Leader, uniQure

EDUCATION: MSc, Biochemistry and Microbiology, Sofia University, Bulgaria; PhD, Bulgaria Academy of Sciences, Sofia, Bulgaria; Post-doctoral research, RNAi-based gene therapy for HIV-1, Academic Medical Center, Amsterdam Netherlands; Post-doctoral research, Viral miRNA function, Duke University, Durham, NC

HOBBIES: Yoga and spending time with her family

Dr. Pavlina Konstantinova is a scientist whose research interests have centered on virology and RNA interference. She joined uniQure eight years ago to bring together these interests and develop gene therapy and delivery mechanisms. She initiated the company’s HD program several years later.

Meet the Investigator: Diana Rosas


NAME: H. Diana Rosas, MD

TITLE: Associate Professor, Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School.

EDUCATION: BS, Harvard College; MD, University of Chicago Pritzker School of Medicine

HOBBIES: Spending time with family, cooking, reading, spending time outdoors, and knitting

Dr. Rosas is an Associate Professor of Neurology and Radiology at Harvard Medical School and a committed HD researcher. She was involved in PRECREST, the first clinical trial to enroll prodromal and at-risk for HD individuals with a design that allowed trial participants to remain unaware of their genetic status. HD Insights spoke with Dr. Rosas about her story, her current research, and her hopes for the future of the field. The following is an edited transcript of the conversation.

HD INSIGHTS: Tell us how you first became interested in HD.

ROSAS: When I was a resident, I was fortunate to be invited to be part of the U.S.–Venezuela Collaborative Research Project directed by Dr. Nancy Wexler and sponsored by Dr. Anne Young, chairperson of Neurology at Massachusetts General Hospital at the time. That was a life-altering experience. I saw firsthand the ravages of HD. During my time there, I saw hundreds of patients and was exposed to the complex and incredibly variable manifestations of HD. I got a real sense of the impact that HD has on families, and also realized that there is much that we can do to help families in need. It was a life-altering experience, and one for which I am incredibly grateful. I have been involved in working with families and patients with HD ever since. I find that not a day goes by when I do not learn something new about the disease, some life lesson that teaches me about what is important. HD is such a complicated disease. It is a very humbling disease, and it is a very compelling disease. I feel very privileged to be able to care for patients with HD, to be involved in cutting-edge research, and to be able to participate in clinical therapeutic trials.  The advances in our knowledge about HD give me great hope that one day, we will be able to find a cure.

HD INSIGHTS: Now that 15 to 20 years have passed, you and others are positioning the field to conduct clinical trials in people who carry the genetic expansion but do not yet show clinical symptoms of HD. Can you tell us about those efforts?

ROSAS: We are at a really exciting time for emerging gene therapies and mutant huntingtin-lowering approaches. We want to target delaying the onset of clinical symptoms or slowing progression in patients that are already symptomatic. We also want to continue to explore new ways to treat the cognitive symptoms of the disease, which can be very functionally limiting, and to provide alternatives for treatments of the motor and psychiatric symptoms. The overall goal is to improve quality of life for our patients.

HD INSIGHTS: How early should we be targeting treatments?

ROSAS: I have been thinking a lot about this. Many of us think that we must intervene before people are symptomatic in order to make the biggest impact, to keep individuals from getting sick in the first place. Theoretically, you would want to start as early as possible, but there may be long-term side effects from chronic exposure that would need to be considered. For the moment, focusing on the period we’ve termed the “HD prodrome,” when very subtle clinical symptoms begin to surface but individuals are still fully independent, would be a very reasonable target. However, there is still considerable debate about how to determine this, and this is a critically important question.

HD INSIGHTS: You mentioned biological markers for prodromal HD. Which of those do you think are most promising?

ROSAS: Several large efforts have looked at developing biomarkers of preclinical progression, which must be sensitive, reliable, and clinically relevant. So far, the clinical markers that have been evaluated do not seem to have the necessary sensitivity to provide useful biomarkers for clinical trials. Several blood-based biomarkers are currently being evaluated. Some of those may provide us with important insights into HD pathology, as well as sensitive ways to determine the effects of drugs or to follow progression: pharmocodynamic markers. For example, some groups have developed assays to measure mutant huntingtin levels, which could be used to determine the efficacy of mutant huntingtin-lowering therapies. Several other groups are looking at neuroimaging, including structural, microstructural, functional, or chemical measures.  It will be incredibly important to develop meaningful markers of disease onset as well, but we must also spend more effort on preclinical studies that will inform us about the best time to intervene.

I think we must understand that we may need to conduct larger trials than we currently do, because of the variability in HD. There is a lot of variability in the rate of progression and phenotypic expression in symptomatic HD, which may be even greater in the premanifest population. We need to consider doing larger trials and incorporating biomarkers, which can then be validated for use in subsequent studies. We must also be cognizant that these individuals are otherwise healthy, living full lives and contributing to society, so determining the right time to start a treatment is critically important. 

HD INSIGHTS: You and your colleagues conducted one of the first-ever clinical trials in a prodromal HD population. Can you tell us about that clinical trial and what you learned?

ROSAS: You are referring to the PRECREST study, which was a placebo-controlled, blinded study of individuals who were either known gene carriers or at-risk for HD. One of the crucial challenges for using a genetic test or other markers to identify study participants is that, for most individuals, learning that they have a currently untreatable disease may not only be unwelcome but can be socially, economically, and psychologically detrimental. PRECREST solved this by enrolling participants from HD families without requiring personal genetic testing for entry, and by not disclosing the genetic test results needed later to analyze the data. This meant that participants at-risk for HD who wanted to participate without having to learn their genetic status could do so. This also meant that participants who did not have the genetic mutation could be healthy controls. PRECREST has great relevance to prevention trials being considered for other neurodegenerative diseases such as the forthcoming DIAN trials for AD (see Editor’s Desk, below).

We incorporated a number of biomarkers, including blood markers, imaging markers, and additional clinical cognitive assessments, into PRECREST. The study was designed in part to determine the kind of perspectives that individuals had about participating in the clinical trial, as well as to assess high-dose creatine, a nutritional supplement, for safety, tolerability and possible disease modification. There were studies that showed some potential benefit early in the course of HD, and we wanted to get a sense of how the treatment influenced these biomarkers.

PRECREST has great relevance to the ongoing debate in the neurogenetic community about equipoise between wanting to promote genetic testing, and also stringently respecting the desire of the 95% (at least in the USA) of at-risk people who wish to avoid genetic testing, while still helping find avenues for therapeutic progress. One of my current concerns is that the increasing focus on a shared electronic medical record may impede our ability to protect patients’ privacy, especially those at genetic risk of HD. Unfortunately, it is becoming increasingly difficult to fulfill our ethical and moral responsibility to keep our patients safe, and this includes safe from exposure of genetic status and risk of genetic discrimination.

I think that PRECREST established an important precedent in looking at incorporating individuals at genetic risk in a clinical trial, rather than only known gene carriers. It is worth considering this approach in future trials because there are limited numbers of individuals who choose to be tested. This would expand the size of the pool of individuals who would participate in a clinical trial. Most people at risk don’t want to know their genetic status and we have to ask if participating in a relatively short term Phase II study is worth the risk of knowing to those individuals.

One of the things that we learned from PRECREST was that our predictions about the potential behaviors of patients who knew their gene status were incorrect. I think most of us had a preconceived notion that gene-positive individuals would be the most enthusiastic, that they would stick it out no matter what. We thought that they would tolerate side effects. Our experience was otherwise. Individuals who knew their status were those who tolerated side effects less well, and appeared to have the hardest time coming in for visits. Some of their reasons were along the lines of, “When I come for the visits and I am being given the treatment, it reminds me about HD. It reminds me that one day I will be a patient. I was doing okay not having to think about it every day, but every day that I take a medicine, or every day that I have to think about HD, it makes it feel more tangible, and that is something that I am not ready to face just now, because I am healthy right now.”

ROSAS: I thought that was really instructive. We have to understand that these are people who have active lives and they want to stay active. Some want to get involved, others prefer to not think about HD until they have to. Everyone has different coping mechanisms.

HD INSIGHTS: Based on your experience in PRECREST, what, if anything, would you do differently for future prodromal trials?

ROSAS: We took great pains to protect the individuals’ genetic risks, so there were no inadvertent disclosures. The individuals who came actively participated in the trial, even those that could not tolerate drug came in for visits. Most found it a positive experience.

HD INSIGHTS: Looking into your crystal ball, what do you see as either the most promising therapies or interventions that will be evaluated for individuals with prodromal HD in the next five years?

ROSAS: Many in the field, and certainly families and patients, are excited about upstream gene-targeted therapies such as gene silencing, antisense oligonucleotides (ASOs), retroviral vectors, zinc finger nucleases, and CRISPR/Cas. I share that enthusiasm for those therapies, but we still have many challenges to think about. As we’ve been discussing, when would you start those therapies? Delivering those therapies is also a major challenge – the issue of the blood-brain barrier is a very real one. Will patients need to have invasive neurosurgery? Will they need to have implanted pumps? Will they need to undergo repeated lumbar punctures, as for ASOs (see HD Insights, Vol. 13)? We have to think more creatively about long-term administration and issues with delivery. It is likely that we will need to ensure that those treatments cover the entire brain. We may even have to consider systemic administration rather than CNS delivery, as we are becoming increasingly aware of the peripheral manifestations of the disease.

There are also some regulatory hurdles in terms of the outcomes that the FDA would accept for these treatments. Especially when you are talking about prodromal HD, you do not have a Total Functional Capacity to measure change in this population. There is still a lot of work that needs to be done to bring treatments to patients, including developing biomarkers to the point of being acceptable to the FDA as study outcomes.

HD INSIGHTS: Dr. Rosas, thank you very much for your time, and thank you for all your efforts on behalf of individuals affected by HD.

Editor’s Desk – Preventive Trials in Neurodegenerative Disease

cover image

Treatments that halt development of HD have gone from a distant dream to a promising avenue of exploration. In this edition, we examine some of the unique challenges and possibilities of future clinical trials in premanifest HD.

By: Meredith Achey, BM

While the PRECREST study broke new ground in HD research,1 preventive trials in other neurodegenerative diseases such as Alzheimer disease (AD) have increased dramatically in recent years.2 The Alzheimer’s Prevention Initiative3 and others have spearheaded preventative treatment trials in both genetically at-risk populations4-6 and those at-risk for AD based on biomarkers.7,8 A recent exploration of the ethical issues inherent in the choice of blinded or transparent enrollment in AD trials concluded that blinded enrollment was not required by traditional ethical considerations,9 but some feel that it helps to prevent coercion associated with requiring participants to learn their genetic status.1 As preventive trials in neurodegenerative disease become more common, these considerations will continue to be explored and confronted.

Randomized, Controlled Trials of Compounds for Prevention of Onset of Disease
Trial Name (Identifier) Disease Sponsor Compound Risk Status Revealed? Year Complete/Anticipated More Information
PRECREST HD Massachusetts General Hospital Creatine monohydrate No 2014 Rosas HD et al. 2014
DIAN-TU AD Washington University School of Medicine Gantenerumab; Solanezumab No 2019 Dominantly Inherited Alzheimer Network
TOMMORROW AD Takeda and Zinfandel Pharmaceuticals Pioglitazone No 2019 TOMMORROW Study
Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) Study AD Eli Lilly Solanezumab Yes 2020
NCT01998841 AD Genentech Crenezumab No 2020 Genentech Announcement
API-APOE4 AD Novartis CAD106; CNP250 Yes 2023 API-APOE4

1Rosas HD, Doros G, Gevorkian S, et al. PRECREST: A phase II prevention and biomarker trial of creatine in at-risk Huntington disease. Neurology. 2014;82(10):850-857.

2Friedrich MJ. Researchers test strategies to prevent Alzheimer disease. JAMA. 2014;311(16):1596-1598.

3Reiman EM, Langbaum J, Fleisher AS, et al. Alzheimer’s Prevention Initiative: a plan to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. 2011;26(s3):321-329.

4A Study of Crenezumab Versus Placebo in Preclinical PSEN1 E280A Mutation Carriers to Evaluate Efficacy and Safety in the Treatment of Autosomal-Dominant Alzheimer Disease (AD), Including a Placebo-Treated Noncarrier Cohort. Accessed May 10, 2016.

5A Study of CAD106 and CNP520 Versus Placebo in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer’s Disease (Generation). Accessed May 10, 2016.

6Dominantly Inherited Alzheimer Network Trial: An Opportunity to Prevent Dementia. A Study of Potential Disease Modifying Treatments in Individuals at Risk for or With a Type of Early Onset Alzheimer’s Disease Caused by a Genetic Mutation. (DIAN-TU). Accessed May 10, 2016.

7Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4). Accessed May 10,  2016.

8Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer’s Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset (TOMMORROW). Accessed May 10, 2016.

9Kim SYH, Karlawish J, Berkman BE. Ethics of genetic and biomarker test disclosures in neurodegenerative disease prevention trials. Neurology. 2015;84(14):1488-1494.

Meet the Investigator


Dr. Hoa Nguyen


NAME: Hoa Nguyen, M.D

CURRENT POSITION: Head of the Huntington Disease Working Group and Head of Cancer Genetics at the Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

EDUCATION: MD, Hannover Medical School, Hannover, Germany; research at Emory University, Atlanta, Georgia, USA, and McGill University, Montréal, Québec, Canada


Dr. Hoa Nguyen is a board-certified clinical geneticist who devotes his time to oncogenetics and predictive testing for HD. As a researcher, he leads the HD Working Group at the University of Tübingen. His team recently participated in the MitoTarget project, a three-year translational research program funded in part by the European Commission and led by Trophos, to study mitochondrial abnormalities in neurological diseases, and to test the company’s lead compound, olesoxime, in these diseases. He has also contributed to the development and description of the BACHD rat, a novel transgenic rat model of HD. Dr. Nguyen recently discussed his work with HD Insights. The following is an edited transcript of the conversation.

HD INSIGHTS: Dr. Nguyen, you are both a clinician and a researcher. Can you describe your clinical practice?

NGUYEN: I do most of the predictive testing and counseling here, including for HD patients and families. Currently I am working more with oncogenetics. As you may have heard, Angelina Jolie spoke publicly about her BRCA-1 mutation, and since then, a lot of requests have come in!

HD INSIGHTS: So Angelina Jolie is driving traffic to your center?

NGUYEN: Yes! The number of patients has increased by about 200 percent.

HD INSIGHTS: Tell us about your experiences with predictive testing for HD.

NGUYEN: Unlike the US, we do not have genetic counselors in Germany, so all the genetic testing and counseling is done by medical doctors. I do what a genetic counselor does in the US, but I also discuss potential treatments. I try not to talk too much about treatments with HD patients, because we don’t yet have any, but I try to give some hope, and some insight into ongoing research. We follow very strict guidelines for predictive testing. In the first session we usually just talk about HD, the family history, possible outcomes, treatment options, and so forth.

Patients also receive counseling with a psychiatrist and neurologist before we actually do the test. We give patients a bit of time to reflect on their decision to undertake predictive testing before they actually come in for the blood draw, and then a couple of weeks later, they can return for the results. I think predictive testing is more common here in Germany and in Europe compared with the US, possibly because of insurance issues. In Germany, testing is all paid for, and there is no possibility of people losing insurance. About 30 percent of patients who come in for predictive testing and counseling actually proceed with testing.

HD INSIGHTS: One of your primary research projects has been the development of the BACHD transgenic rat model. What are the benefits and disadvantages of this new model?

NGUYEN: Most people in the HD field work with mice, mainly because transgenic mouse models are easier to generate. However, a rat has several advantages compared with a mouse. First, rats are larger animals, so there are more possibilities for imaging studies in rats than in mice. Second, in rats you can do more biosampling, such as CSF, and you can also do longitudinal biosampling.

From a behavioral standpoint, most behavioral research has been done in rats and the research has just been adapted to mice. However, we actually don’t know that much about the physiology and neurological circuitry in mice. Early electrophysiology was also mainly done in rats, so we have a much better understanding of these kinds of things in rats than in mice. And last but not least, there are some compounds that have better pharmacokinetic dynamics in rats than in mice. For example, we were recently approached by a company that has an autophagy compound that they would like to test in rats rather than in mice because it was much more toxic in mice than in rats.

Of course there are disadvantages with rats. Cost is a problem, because rats are bigger animals and need more space, and treatment studies and compound testing may be more expensive in rats if you must use more compound. Another disadvantage is that it is much more difficult to generate a knock-in rat model than a knock-in mouse model. We are currently working with CHDI on generating a knock-in rat model, and that has been quite difficult.

HD INSIGHTS: Could you describe the differences between a knock-in animal model and a transgenic animal model?

NGUYEN: A knock-in animal model expresses the gene of interest in the same place as in the human genome. In the case of HD, this is on chromosome 4. A transgenic animal model can express the gene anywhere, and this may lead to disruption of other important genes, which may cause unexpected problems.

HD INSIGHTS: Has anyone looked to see whether current transgenic animal models have this problem?

NGUYEN: No, no one has done that research in detail.

HD INSIGHTS: There are also some other animal models of HD. What are your thoughts on those?

NGUYEN: There is a pig model that is especially interesting, and also non-human primate models developed by Anthony Chan at Emory. These models have the advantage of bigger brains compared with the rat and mouse model, and their brains are relatively similar to human brains. Again, the disadvantage is cost. You cannot breed pigs and non-human primates as easily as rats and mice, and they have longer gestation periods. With the non-human primate models, if you were to use the full human gene, you would have to wait years before you got the phenotype. So instead, you use a short fragment of the gene and over-express the fragment with a very high number of CAG repeats. These primates have a very severe phenotype and cannot reproduce. I think this model can be used for symptomatic and some treatment studies, but in the long run, you probably want a model that can reproduce from generation to generation, and that you don’t have to generate again and again, because every time you generate a transgenic animal, the gene may incorporate in a different region with different expression. Currently there is no non-human primate model that you can actually breed and keep for generations.

HD INSIGHTS: You have started to use your BACHD rat model to screen drugs. Can you tell us more about that?

NGUYEN: We are involved in some of the European projects funded by the European Commission, including one project called MitoTarget in which we are studying mitochondria-targeted drugs. A company called Trophos in Marseille, France, wanted us to test a compound called olesoxime they had hit upon that is actually already in the clinical phase for amyotrophic

lateral sclerosis (see “Meet the Compound,” p. 6). We knew that olesoxime somehow targets mitochondria and we thought we could test it in our rats. Surprisingly, we didn’t see much effect on the motor phenotype, but we saw improvement in the cognitive and anxiety-related phenotypes.

Olesoxime seems to work totally differently from what we had thought. It doesn’t work much on mitochondria – it made some changes to mitochondrial function, but what was more interesting to us was that at the biochemical and neuropathologic level, treatment with olesoxime increased the amount of full-length soluble huntingtin, which is mainly mutant huntingtin, and reduced the amount of fragmented huntingtin, and aggregation. This is one of the first compounds we have seen that decreases the cleavage of the full-length protein and actually changes the amount of mutant huntingtin, the main target of the disease.

Now we are working on understanding why this happens. We have found that calpain is activated in our transgenic rats, and use of olesoxime decreases calpain activity. There have been studies showing that calpain cleaves huntingtin into fragments. We showed that olesoxime’s inhibition of calpain activity reduces the cleavage of full-length huntingtin, which leads to the increased levels of full-length soluble huntingtin, reduced levels of huntingtin fragments, and reduced number of aggregates.This is our current area of research, and we are trying to figure out how it all works. It seems very promising to us.

HD INSIGHTS: What areas of science or therapeutic development are you most excited about?

NGUYEN: I’m very interested in treating patients, and in new treatments in general. In particular, I think the various gene silencing and huntingtin-lowering strategies have been quite successful in some studies.

These include the usual RNA interference or antisense oligonucleotide approaches, but we are also working with our collaborators in Leiden on some exon-skipping approaches that have been successful in some studies in Duchenne muscular dystrophy. The idea is that you actually skip an exon where you think there is an important cleavage site, so for example, you could think of skipping a whole region of the calpain cleavage site, or even the CAG repeats. There’s also some interesting work in post-translational modification coming from William Yang’s lab. I think these are some of the most interesting new strategies coming up now.

HD INSIGHTS: What about trials in premanifest HD? Do you think we are ready for those trials?

NGUYEN: I think that is the way to go. We probably have a better chance of modifying the disease if we treat sooner rather than later. Whether we are ready or not is a question for clinicians who actually run those clinics, but from what Sarah Tabrizi (see HD Insights, Vol. 1) and Ralf Reilmann (see HD Insights, Vol. 6) have found in TRACK-HD, there seem to be robust changes that could be used as biomarkers to track disease progression.

HD INSIGHTS: Any final thoughts on HD?

NGUYEN: I think we’re at a very exciting time right now for HD research. Clinical studies such as PREDICT and TRACK have given us a lot of information on the natural course of the disease, and prepared us very well for clinical trials. Now we can actually use this information to test more compounds. It is very exciting to be in HD at this moment; I hope that we can find something quite soon.

Meet the Investigator

Dr. Kenneth Marek

Dr. Kenneth Marek


NAME: Kenneth Marek, MD

CURRENT POSITION: President and Senior Scientist of the Institute for Neurodegenerative Disorders, New Haven, CT

OTHER POSITIONS: CEO of Molecular NeuroImaging, LLC; Member, Scientific Advisory Board, Michael J. Fox Foundation

EDUCATION: AB in Biochemistry, Princeton University, Princeton, NJ; MD, Yale University School of Medicine, New Haven, CT

HOBBIES: Cycling, relaxing and enjoying Cape Cod, particularly the smoked salmon!




HD INSIGHTS: Can you tell us about the Institute for Neurodegenerative Disorders? (IND)

MAREK: The IND is a research institute with about 80 staff in New Haven, Connecticut. Our focus for the last 12 years has been on evaluating neurodegenerative disorders such as HD, Parkinson disease and Alzheimer disease. In particular, we are developing imaging biomarkers to understand, diagnose, and monitor the progression of these diseases.

HD INSIGHTS: Why don’t we have such markers for HD?

MAREK: In a way, HD is ideal, because we have a genetic marker that tells us who will develop the disease. Until recently, however, opportunities for identifying a specific PET ligand were limited. One thing that has changed over the past five to ten years is that we now have a number of PET tracers that target different neurochemicals in the striatum, an important site of the pathology of HD. PET tracers are radioactively labeled compounds which are injected into the bloodstream and bind to a target brain chemical. We can then assess the activity of the target enzyme in different brain regions using a PET camera and a computer analysis. There are a number of potential targets that might help us to identify the neurodegenerative process in individuals with HD at the time of their diagnosis or even earlier, and to track that neurodegenerative process over time.

HD INSIGHTS: Which of these targets are most common?

MAREK: One of the most promising is adenosine 2A, because the adenosine receptor resides on the medium spiny neurons in the striatum, and we know those neurons degenerate in HD. Similarly, the metabotropic glutamate receptor, the mGluR5 receptor, has been another important target. Most recently we have looked at another target, the phosphodiesterase 10A (PDE10A) receptor. It’s possible to effectively target these phosphodiesterases using PET tracers. There is data to suggest this, too, may be a marker that changes very early in the course of HD.

HD INSIGHTS: At the most recent CHDI meeting, you presented results from your PDE10A imaging. Can you tell us a little bit about what you did and what you found?

MAREK: Our group has developed a PDE10A PET tracer, labeled with fluorine-18, that targets PDE10A with high specificity and high affinity. In human studies with our PDE10A tracer we see that there is a very specific and very robust signal in the striatal region. This localization of PDE10A in the brain is consistent with animal studies. In these studies, we began by validating the radio tracer by testing it in healthy subjects to ensure that the activity we detect in the brain does in fact reflect PDE10A activity. We also assessed safety, because there is a radiation load with a PET tracer. We wanted to make sure that we can inject this safely and repeatedly, because we would like to use this tracer to monitor changes over time. We then compared the activity that we detected in the striatum in healthy subjects to individuals with HD, and there was a striking reduction in the HD individuals. In individuals with relatively mild HD symptoms, there was a 60 to 70 percent reduction in their PDE10A activity compared to healthy subjects, consistent with the mouse model of HD. We also tested pre-symptomatic HD gene – positive individuals, and we could detect smaller but clear changes in PDE10A activity. The PDE10A PET imaging that we’ve done so far shows a very strong correlation between the relative loss of PDE10A and clinical measures of HD, including the UHDRS and the burden of pathology score that has been developed for monitoring HD.

HD INSIGHTS: So the next step is to see how PDE10A levels respond to a PDE10A inhibitor?

MAREK: Right. It would be interesting to evaluate whether PDE10A inhibition might modify the reductions we see in these subjects.

HD INSIGHTS: What are your other hopes for HD imaging?

MAREK: We hope to initiate a study soon, in which we evaluate PDE10A and additional targets in the same subject: in particular, the cannabinoid-1 receptor and the adenosine 2A receptor. We will try to track a number of measures of HD, to get a sense of the temporal pattern of how this type of pathology occurs.

HD INSIGHTS: The use of PET ligands in PET imaging is a relatively new field that you’ve helped pioneer. How did you first become interested in this area of research?

MAREK: PET imaging is an amazing opportunity to combine my interest in neurology with my interest in brain chemistry. It’s also been fascinating to explore, in real diseases and in real people, how the chemistry of the brain works. This interest was sparked by my interaction with Paul Hofer, who was a nuclear medicine physician at Yale University. He had Parkinson disease himself, and he was instrumental in pointing out the research possibilities of PET imaging. On a personal level, it was very gratifying to work on a project that was so relevant to somebody who was also a mentor.

Meet the Investigator

Dr. Michael Hayden

Dr. Michael Hayden


NAME: Michael Hayden, CM, OBC, MB, ChB, PhD, FRCP(C), FRSC CURRENT

Dr. Michael Hayden was recently appointed as the President of Global Research and Development and Chief Scientific Officer at Teva Pharmaceuticals. Dr. Hayden is the most highly cited author in Huntington disease. He is the founder and director of the Centre for Molecular Medicine and Therapeutics in Vancouver, and founder of three biotechnology companies (NeuroVir, Xenon Genetics, and Aspreva Pharmaceuticals).

POSITION: President of Global Research and Development and Chief Scientific Officer at Teva Pharmaceuticals

OTHER POSITIONS: Killam Professor of Medical Genetics at the University of British Columbia, Canada Research Chair in Human Genetics and Molecular Medicine, Founder and director for the Center for Molecular Medicine and Therapeutics in Vancouver, Canada, Program director of the Translational Laboratory in Genetic Medicine at the National University of Singapore, Founder of NeuroVir, Xenon Genetics, Inc., and Aspreva Pharmaceuticals, Inc

EDUCATION: MB, ChB, PhD, University of Cape Town, Post-doctoral fellowship, Harvard University

HOBBIES: Collecting art, photography, and enjoying creativity in other domains.

FAVORITE ARTIST: Ben Shahn, who was born in Lithuania and became a social activist in America. He is known for his works of social realism.


Meet the Investigator

Sarah Tabrizi, MBChB, PhD

Sarah Tabrizi, MBChB, PhD


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.