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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
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||A4Study.org|
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. https://clinicaltrials.gov/ct2/show/NCT01998841. 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). https://clinicaltrials.gov/ct2/show/NCT02565511. 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). https://www.clinicaltrials.gov/ct2/show/NCT01760005. Accessed May 10, 2016.
7Clinical Trial of Solanezumab for Older Individuals Who May be at Risk for Memory Loss (A4). https://clinicaltrials.gov/ct2/show/NCT02008357. 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). https://clinicaltrials.gov/ct2/show/NCT01931566. 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.
By: Lise Munsie, PhD
In human studies…
Human studies provide the most useful research data and help to elucidate the natural history, biology, and potential molecular mechanisms of disease, which inform treatment development.
Dr. Jong-min Lee’s group investigated the correlation between CAG repeat length in the mutant and wildtype alleles, and age at death and disease duration.1 Similarly for age at onset of motor symptoms of HD, age at death had a strong negative correlation with mutant allele CAG repeat length. Interestingly, CAG repeat length did not correlate with disease duration, even in juvenile HD.
Nielsen and colleagues investigated the hypothesis that metabolic changes characteristic of HD may be caused in part by liver damage.2 The group used a range of common blood tests to evaluate liver function in symptomatic HD patients. Although the study has some limitations—including using data from patients on medications that may impair liver function—they found evidence of increased liver dysfunction in symptomatic HD patients. More sensitive markers of liver failure may be needed to solidly ascertain how and when the liver is affected over the course of disease.
De Souza and colleagues investigated the role of differential DNA methylation in HD, characterizing tissue specificity by examining genome-wide methylation changes in brain and liver tissue samples from HD patients.3 The study revealed DNA methylation differences in the HTT gene region between matched brain and liver samples. The study also found evidence that the transcription factor CTCF participates in DNA methylation and contributes to tissue-specific methylation patterns near the HTT proximal promoter.
1Keum JW, Shin A, Gillis T, et al. The HTT CAG-expansion mutation determines age at death but not disease duration in Huntington disease. Am J Hum Genet. 2016;98(2):287-298.
2Nielsen SM, Vinther-Jensen T, Nielsen JE, et al. Liver function in Huntington’s disease assessed by blood biochemical analyses in a clinical setting. J Neurol Sci. 2016;362:326-332.
3De Souza RA, Islam SA, McEwen LM, et al. DNA methylation profiling in human Huntington’s disease brain. Hum Mol Genet. 2016 Mar 6. pii: ddw076. [Epub ahead of print].
In animal models…
With the exception of using patient data, model organisms are the most biologically relevant method for studying disease. In an article published in Nature Neuroscience, Langfelder and colleagues used a variety of HD models—mainly murine—to perform tissue-, CAG length-, and age- dependent, large-scale, transcriptome and proteome comparisons.1 They identified a set of genes and corresponding proteins that are affected in a tissue- , CAG-, and age- dependent manner. The set includes previously identified genes such as CTCF, validating this method. All the data is freely available for viewing or data mining at www.hdinhd.org.
Although mammalian models have shed light on many aspects of HD, the classic models have yet to elucidate the neural mechanism by which striatal degeneration leads to a movement disorder. The Mooney group published their work exploring this mechanism in an unusual model—the songbird—in Proceedings of the National Academy of Sciences.2 They used lentivirus to express mHTT exon1 in the basal ganglia nucleus of a male zebra finch, and analyzed the bird’s vocal behaviors. They uncovered the affected neural pathways, and infer how this relates to movement disorders in human HD.
Although mice are easy to use in the lab, larger animal models are more indicative of human pathology. To this end, a transgenic HD sheep has been created. Though the sheep is not itself symptomatic, it can be used to study presymptomatic HD. In Nature Scientific Reports, Handley and colleagues describe their work examining metabolic profiles in different tissues from the HD sheep using gas chromotography mass spectrometry.3 They found specifically that amino acids in the cerebellum were altered, whereas fatty acids in the liver were altered. Their results suggest a hyper-metabolic defect in the sheep.
1Langfelder P, Cantle JP, Chatzopoulou D, et al. Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice. Nat Neurosci. 2016 Apr;19(4):623-633.
2Tanaka M, Singh Alvarado J, et al. Focal expression of mutant huntingtin in the songbird basal ganglia disrupts cortico-basal ganglia networks and vocal sequences. Proc Natl Acad Sci USA. 2016 Mar 22;113(12):E1720-7.
3Handley RR, Reid SJ, Patassini S, et al. Metabolic disruption identified in the Huntington’s disease transgenic sheep model. Sci. Rep. 2016 Feb 11;6:20681.
In cell models…
Huntingtin knockdown in either a pan- or allele-specific manner is one of the hottest areas of HD research. Using fibroblasts derived from HD patients and new techniques in genome editing, the Nolta group identified single nucleotide polymorphisms (SNPs) specific to the mutant allele, and were able to deliver transcription activator-like effector nucleases (TALEN) to the cells to specifically silence the mutant allele.1 The group identified a novel method for targeting and shortening the polyglutamine tract, particularly in the mutant allele.
Although knocking down the wild-type Huntingtin gene (HTT) may be therapeutic, off-target effects remain unknown. Lopes and colleagues used neural precursor cells derived from HD human embryonic stem cells to investigate the impact of mHTT on HTT’s normal function in regulating molecular motors and spindle pole orientation.2 They demonstrated that a repeat length of 46 has aberrant effects on mitotic spindle orientation, and that HTT is required for normal distribution of mitotic components, arguing for allele-specific silencing as a therapy. This work also demonstrates that using physiologically relevant CAG-repeat lengths (between 36-60) can be important when modeling HD.
Another way to optimize allele-specific silencing is by optimizing the chemistry of oligonucleotides. Thiophosphonacetate (thio-PACE) modifications replace a non-bridging oxygen molecule with an acetate and a phosphorothiate substitution, modifications hypothesized to increase uptake and hybridization of the oligonucleotide with its target. A recent article describes the delivery of these altered oligonucleotides to fibroblasts derived from HD patients and to an immortalized striatal cell model.3 Although oligonucleotides with different numbers of these modifications were able to silence mHTT, not all oligonucleotides had positive results compared to the unmodified control. These results allude to the importance of, and potential to modify, the chemistry of oligonucleotides for silencing mHTT.
1Fink KD, Deng P, Gutierrez J, et al. Allele-specific reduction of the mutant huntingtin allele using transcription activator-like effectors in human Huntington’s disease fibroblasts. Cell Transplant. 2016;25(4):677-686.
2Lopes C, Aubert S, Bourgois-Rocha F, et al. Dominant-negative effects of adult-onset huntingtin mutations alter the division of human embryonic stem cells-derived neural cells. PloS one. 2016;11(2):e0148680.
3Matsui M, Threlfall RN, Caruthers MH, Corey DR. Effect of 2′-O-methyl/thiophosphonoacetate-modified antisense oligonucleotides on huntingtin expression in patient-derived cells. Artif DNA PNA XNA. 2014;5(3):e1146391.
By: Nancy R. Downing, PhD, RN
The fact that HD involves a single gene mutation inherited in an autosomal dominant pattern can lead to a sense of genetic determinism among HD patients, their families, physicians, and researchers. However, increased knowledge about the impact of lifestyle and environment on health provides support for the potential to extend healthy functioning for persons with the HD gene mutation. In observational studies of people with HD, there is evidence that lifestyle and environmental factors contribute to variation in the age of onset (AO).1-4 Increased understanding of epigenetic modifications5 supports the potential for lifestyle and environment manipulation to alter AO and disease progression.
While there is a negative association between the number of CAG repeats in the mutant huntingtin gene and AO,6,7 CAG repeat length is estimated to account for only 50–70% of the variance of AO;4,8,9 however, some of these data are limited by how AO was defined or determined. In the PREDICT-HD study,10 225 participants were diagnosed using the UHDRS motor exam.11 In this analysis, there was a correlation of 0.53 between CAG repeat length and age at diagnosis.10 The range of age at diagnosis also varied widely at each CAG repeat length (e.g. a range of 31 years for CAG = 40). While in general the variation decreases with increasing CAG repeat length, 80% of affected people have 40– 48 repeats.10,12,13 Therefore, many could potentially benefit from interventions to delay AO.
My recent observational study comparing 48 people with prodromal or early HD and 27 controls was designed to provide preliminary data to support randomized controlled trials (RCTs) of lifestyle interventions to delay AO or disease progression. We collected data on physical activity using FitBit activity trackers, on diet using 3-day 24-hour diet recall, and on body composition using dual x-ray absorptiometry (DXA). Our first paper provided support for the hypothesis that physical activity is positively associated with cognitive function.14 Preliminary data exist to support positive effects of physical exercise in other neurodegenerative diseases such as Parkinson disease, with a need for further studies.15 The most promising data on the potential impact of physical exercise comes from studies of people with mild cognitive impairment, with some evidence of improved cognitive function that could potentially delay Alzheimer disease in these patients.16 Further analyses will examine lean and fat mass, branched-chain amino acid levels, dietary intake, and supplement use, to identify potential targets for intervention. An interesting finding in our data is that 34/48 (70.8%) of participants with prodromal HD reported use of dietary supplements, and half of them said they did so to prevent or delay HD. Seventeen participants stated they were advised by physicians to take the supplements, and seven of these respondents stated it was because of HD (see Table).17 The participants stated that in most cases they thought the supplements were working. However, because we collected these data as part of the 3-day diet recall, we did not obtain further details about supplement use or why participants thought they were working.
There are many challenges to studying the impact of lifestyle behavior on AO and disease progression. Recruitment for RCTs in a relatively rare disease is challenging. Middle-age adult onset and the long disease trajectory make it difficult to study the long-term impacts of interventions. Due to these limitations, it is not surprising that RCTs of these interventions are limited. For example, a 2009 Cochrane review of pharmacological and non-pharmacologic therapeutics (including supplements) to modify HD disease progression found only eight RCTs that met their criteria,18 and none that demonstrated effectiveness.
My research team is currently conducting a systematic review of the literature about lifestyle and environmental factors with the potential to modify AO or disease progression. Due to the dearth of RCTs on this topic, we included all human studies with quantitative data—including observational retrospective case studies and case series in addition to RCTs—and broadly defined health-related behaviors. Our initial search of PubMed, CINAHL, and PsychInfo yielded 449 possibly relevant papers. After reviewing the abstracts, we selected 70 papers for full review. Over half of the papers were related to nutrition and nutritional supplements, about a quarter to physical activity, physical therapy, and speech and swallowing therapy. There were no RCTs of exercise to delay HD onset. However, there is reason to be hopeful. Findings from studies such as PREDICT-HD have identified sensitive markers of disease progression that can circumvent some of the limitations of a long disease trajectory.19 An NIH-funded RCT involving an exercise intervention to slow HD disease progression in prodromal HD using motor and neuroimaging outcomes is now underway at the University of Iowa (1R21NS091055-01A1, Magnotta, PI). If successful, this study could open the way for more RCTs of lifestyle interventions to delay AO, and/or slow disease progression in HD.
Targeted genetic approaches represent the most exciting pharmaceutical interventions currently being developed for HD;20 however, these therapies have not yet been proven effective, and no disease-modifying treatment currently exists. Many individuals at risk for HD decline genetic testing, but could be counseled to make simple dietary and lifestyle modifications regardless of their gene status that might not only help them to lead healthier lives, but delay the onset of HD. Lifestyle interventions could be useful as adjuvant therapy, do not require at-risk individuals to know their gene status, and are available to most people for little or no cost, with minimal side effects. The potential benefits of these approaches clearly warrant further consideration and investigation into their efficacy.
Dr. Nancy Downing was featured in HD Insights in Fall 2015 as a “Next Generation” HD Scholar. She is now an Associate Professor at the Texas A&M University College of Nursing.
|Table. Supplement Use Among Participants (n=17) Who Took Supplements Because of HD|
|Supplement||No. of Users||Proposed Mechanism of Action||Participant Reports Working as Expected?|
|CoQ10||10||Enhances mitochondrial function||6||4|
|Fish Oil||6||Neuroprotection, enhances mitochondrial function||4||2|
|Antioxidants||2||Reduces oxidative stress||2|
|Probiotics||1||Promotes neuroimmune function||1||1|
|Creatine||3||Antioxidant, enhances mitochondrial function, supports muscle health||2||1|
|Coconut Oil||1||Promote ketones as alternative energy source for brain||1|
|Multivitamin||1||Various depending on vitamin (e.g. antioxidant, anti-inflammatory, energy metabolism, etc.)||1|
|Melatonin||1||Antioxidant, neuroprotection, sleep aid||1|
1Buruma OJ, Van der Kamp W, Barendswaard EC, et al. Which factors influence age at onset and rate of progression in Huntington’s disease? J Neurol Sci. 1987 Sep;80(2-3):299-306.
2Byars JA, Beglinger LJ, Moser DJ, et al. Substance abuse may be a risk factor for earlier onset of Huntington disease. J Neurol. 2012 Sep;259(9):1824-31.
3Friedman JH, Trieschmann ME, Myers RH, Fernandez HH. Monozygotic twins discordant for Huntington disease after 7 years. Arch Neurol. 2005 Jun;62(6):995-7.
4Trembath MK, Horton ZA, Tippett L, et al. A retrospective study of the impact of lifestyle on age at onset of Huntington disease. Mov Disord. 2010 Jul 30;25(10):1444-50.
5Valor LM. Transcription, epigenetics and ameliorative strategies in Huntington’s Disease: a genome-wide perspective. Mol Neurobiol. 2015;51(1):406-423.
6Duyao M, Ambrose C, Myers R, et al. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet. 1993;4(4):387-392.
7Snell RG, MacMillan JC, Cheadle JP, et al. Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington’s disease. Nat Genet. 1993;4(4):393-397.
8Andrew SE, Goldberg YP, Kremer B, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nat Genet. 1993;4(4):398-403.
9Rubinsztein DC, Leggo J, Chiano M, et al. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc Natl Acad Sci USA. 1997;94(8):3872-3876.
10Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington’s disease with clinical and imaging measures: a prospective observational study. Lancet Neurol. 2014;13(12):1193-1201.
11Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Disord. 1996;11(2):136-142.
12Langbehn DR, Brinkman RR, Falush D, et al. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet. 2004;65(4):267-277.
13Langbehn DR, Hayden MR, Paulsen JS. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):397-408.
14Wallace M, Lourens S, Mills J, et al. Is there an association of physical activity with brain volume, behavior, and day-to-day functioning? A cross sectional design in prodromal and early Huntington disease. PLos currents Huntington disease. 2016.
15Murray DK, Sacheli MA, Eng JJ, Stoessl AJ. The effects of exercise on cognition in Parkinson’s disease: a systematic review. Translational neurodegeneration. 2014 Feb 24;3(1):1.
16ten Brinke LF, Bolandzadeh N, Nagamatsu LS, Hsu CL, Davis JC, Miran-Khan K, Liu-Ambrose T. Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial. British journal of sports medicine. 2015 Feb 1;49(4):248-54.
17Sparbel K. Nutritional supplementation self-management and rationale by persons with a positive gene mutation for Huntington disease. 2015 ISONG World Congress, Pittsburgh, Pennsylvania 2015.
18Mestre T, Ferreira J, Coelho MM, et al. Therapeutic interventions for disease progression in Huntington’s disease. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD006455.
19Paulsen JS, Long JD, Johnson HJ, et al. Clinical and biomarker changes in premanifest Huntington disease show trial feasibility: A decade of the PREDICT-HD study. Front Aging Neurosci. 2014;6:78.
20Glorioso JC, Cohen JB, Carlisle DL, et al. Moving toward a gene therapy for Huntington’s disease. Gene Ther. 2015;22(12):931-933.
NAME: Helen Budworth, DPhil
TITLE: Senior Science Officer, California Institute for Regenerative Medicine
EDUCATION: BSc, Genetics and Microbiology, University of Liverpool; DPhil, Biochemistry, University of Oxford, UK
HOBBIES: Enjoys spending time outside on the beach and in the mountains
Dr. Budworth, recognized by HD Insights last year as a “Next Generation” HD Scholar, has recently become a Senior Science Officer at the California Institute for Regenerative Medicine (CIRM). She sat down with HD Insights to describe her own HD research and funding opportunities available through CIRM. The following is an edited transcript of the conversation.
HD INSIGHTS: Tell us about your scientific interest in HD.
BUDWORTH: I was a researcher at Lawrence Berkeley National Lab doing basic and translational research into the molecular underpinnings of HD, and working toward therapies that could ameliorate this condition.
HD INSIGHTS: What did you find through your research?
BUDWORTH: We were looking at the DNA repair mechanisms that act on the CAG repeat in HD, and investigating the role of oxidative DNA damage in initiating the CAG repeat expansion. Based on this research, we were investigating antioxidant therapies to counteract the effect of that oxidative DNA damage.
HD INSIGHTS: I noticed that you were one of the first Huntington’s Disease Society of America (HDSA) Human Biology Fellowship Award winners. Could you tell us about that experience?
BUDWORTH: I was funded in 2013 by HDSA to look at metabolic biomarkers in the blood of HD patients. Since blood is a very easily accessible bodily tissue with which to study progression of disease, we were looking to find not only things that could be detected in the blood, but that could be tracked with disease progression. We used a combination of molecular biomarkers, looking at gene expression levels through RNA, and looking at metabolites in the blood. We found distinct differences between the blood of HD patients and healthy controls. We showed that changes in fatty acid metabolism and the genes that regulate it were one of the signs of the disease.
HD INSIGHTS: You recently transitioned from Berkeley Lab to join the California Institute for Regenerative Medicine (CIRM). What prompted the transition?
BUDWORTH: CIRM is the California Stem Cell Agency, and they are working to accelerate stem cell treatments to patients with unmet medical needs. The mission of CIRM was something that really gelled with my own scientific mission and career direction. With the scientific office and the therapeutics team at CIRM, I am now able to contribute to a much broader range of projects, and much more translational and clinical projects, aimed at bringing results of scientific discoveries to the patients who need them. CIRM was funded by Proposition 71, which was passed in 2004 in California, with the goal of developing stem cell treatments and cell therapies for conditions that do not have other effective treatments. We aim to meet unmet medical needs using cell-based therapies. CIRM is looking to fund the most promising research projects at all levels, from discovery through to clinical-stage projects, to bring the science to patients.
HD INSIGHTS: What is CIRM’s interest in HD?
BUDWORTH: The neurodegenerative nature of the disease is one that stem cell researchers have been interested in for a number of years. CIRM has funded a variety of HD projects over the years, and we are looking to continue this. We want to enable cell-based therapies to progress through clinical trials then into the clinic, actually helping patients with HD. To date we have funded projects in the early stages, translational projects in HD, and some early stage clinical trials. Details of these can be found on the CIRM website (www.cirm.ca.gov). We know the history of HD, and understand the importance of having a new promising therapy come through into the clinics, so this is one of our priorities. We are hoping that stem cell therapy will be a real benefit.
HD INSIGHTS: Tell us about CIRM version 2.0, and how researchers who have been interested in stem cells can become engaged with CIRM.
BUDWORTH: CIRM 2.0 is a change in the way that we do business, aimed at introducing faster and more efficient systems for funding. This is part of our effort to accelerate the development and delivery of therapies for people who need them. We now have continuous funding cycles in the clinical stage, where each month, clinical applications are accepted and can be funded within a matter of months, something that used to take a lot longer. We have really streamlined our process for clinical stage awards. We also have translational awards that are offered every six months, and we also maintain our discovery program with some of those programs every six months and every year. CIRM 2.0 is intended to push and partner our projects to get them through what they need to do to bring therapies to patients.
HD INSIGHTS: I understand that CIRM is interested in seeing clinical trials of promising stem cell therapies for HD and other neurodegenerative conditions. Who is eligible to apply for research funding from CIRM?
BUDWORTH: We accept applications from researchers and from companies, any promising projects with stem cell therapies that are moving through translational and clinical phases. We have local requirements in that California-based organizations can use CIRM funds for all eligible project costs. Non- California-based organizations are also eligible to apply, but in those cases, the CIRM funding can be used for expenditures incurred within California. For example, in the case of a clinical trial, a clinical trial site within California would be funded for that work. More details about eligibility can be found on the CIRM website. Funding is based on the project, the promise of the stem cell therapy, and the unmet medical need. The CIRM website details all our funding programs. It also details projects we have funded to date, along with projects we are currently funding. The database can be searched by disease, so you can look up what we are doing in HD. When an application is submitted it will go through review, and successful applications will be managed and helped by the science office to assist the applicants to succeed.
HD INSIGHTS: Thank you and CIRM very much for your investment, and trying to identify new therapies for a wide range of conditions including HD.
Prion-like protein spread in neurodegenerative diseases of the CNS and development of therapeutic approaches
To date, Huntington’s disease has been considered to be cell autonomous, with a secondary inflammatory response as the cells die. However, our recent post mortem analysis of brains from HD patients who received fetal neural grafts has revealed the presence of mHtt aggregates within the genetically unrelated grafted tissue. Additionally, we have shown in these same patients that mHtt can be found in perivascular macrophages, and that in animal models of HD the blood-brain barrier (BBB) is leaky. These unique findings coupled to our work, and that of others, showing that mHtt is expressed in peripherally circulating monocytes raise questions as to whether mHtt is capable of passing from cell to cell, and as such the disease pathogenesis involves a non-cell autonomous component.
We believe that mHtt is capable of being transferred between cells through transynaptic and immune cell mediated processes and thereafter cause pathology. The purpose of this project is thus to study various mechanisms of transmission of pathological mHtt protein using a multidisciplinary approach which include the use of transgenic animals, immunohistochemistry/immunofluorescence, confocal microscopy and two-photon real time intravital imaging, flow cytometry, cell culture, and various molecular biology techniques and biochemical analyses. If reached, this will radically change our concepts on the pathogenesis of Mendelian neurodegenerative disorders of the CNS and with this the prospect of novel disease modifying therapies.
Requirements and conditions:
- Highly motivated student or post-doctoral fellow
- Highly adaptable. Efficient and respectful of deadlines. Capable of teamwork.
- For master students: must have completed a bachelor degree in a relevant discipline with a grade point average superior to B +
- For PhD students: must have completed a master degree with laboratory experience in a related field
- For post-doctoral fellows: relevant experience in neurodegenerative diseases of the CNS and related technical training is requested. Candidates with expertise in any additional imaging, cell culture and molecular biology training are encouraged to apply.
- The student must be admitted to one of the following programs:
- Master’s with thesis in neurobiology
- PhD in neurobiology
- Funding has been secured to carry out the proposed project and insure salary support
- Health-related fields
- Biochemistry and Microbiology
- Medical Research
- Curriculum Vitae
- Cover letter
- Letters of references (at least 2)
Francesca Cicchetti, PhD
By: Govinda Poudel, PhD and Nellie Georgiou-Karistianis, PhD on behalf of the IMAGE-HD study team
Neuropsychiatric disturbances in HD can appear before clinical diagnosis, and usually become worse with disease progression. The most commonly reported neuropsychiatric symptoms are obsessions and compulsions, irritability, apathy, depression, and anxiety. These symptoms contribute to reduced brain function, disability, and impaired quality of life.
Measurement of brain activity using functional magnetic resonance imaging (fMRI) is an important tool to investigate altered brain activity, and offers avenues for new discoveries. In particular, fMRI can be used to investigate whether any functional disruptions in brain circuits are associated with the development and severity of neuropsychiatric disturbances in HD.
We aimed to investigate whether functional brain responses during the performance of a working memory task were associated with neuropsychiatric disturbances during the presymptomatic stages of HD. We used fMRI and neuropsychiatric data acquired from the IMAGE-HD study, and focused our analysis on 35 presymptomatic HD gene carriers (18 far from onset, 17 close to onset) and 32 healthy controls. Data from a battery of neuropsychiatric tests included measures of obsessions, compulsions, and pathological impulse (SCOPI); the frontal systems dysfunction (FrSBE); and anxiety and depression (BDI and HADS). fMRI activity was measured during an N-BACK working memory task with baseline (0-BACK) and two load levels (1- and 2-BACK). Participants who performed below 70% accuracy on the low-load (1-BACK only) task were excluded to ensure that all included participants had understood task instructions and had been sufficiently motivated to perform the task. Given the important role of frontal cortical areas in working memory function, and their known association in several neuropsychiatric disorders, we used the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) as brain targets for further investigations of the interplay between the neuropsychiatric disturbance in pre-HD and the fMRI response during working memory. We performed partial correlations between average fMRI activity in each brain region of interest, and scores on each neuropsychiatric inventory (including subscales), controlling for age, gender, and accuracy.
We found that in individuals close to predicted HD onset, increased symptoms of obsessions and compulsions are associated with decreased neural activity during working memory in the right DLPFC and ACC (see Figure.) Increased symptoms of depression and anxiety, in particular, are associated with reduced neural activity during 2-BACK working memory load.
While these findings are correlational in nature, they nevertheless support the association between the development of neuropsychiatric symptoms and impaired brain function during cognitive tasks in HD. The association between neuropsychiatric function and brain activity is more readily detectable during higher (and more challenging) working memory loads, and becomes more pronounced as individuals approach onset of clinical symptoms of HD. Fresh insights into such brain mechanisms may open up new avenues for biomarker and treatment options for neuropsychiatric impairments in HD. Importantly, more research is needed to identify whether neuropsychiatric symptoms accelerate progression to symptomatic HD.
Original Article: Poudel GR, Shannon D, Domínguez D FJ, Stout JC, Churchyard A, Chua P, Egan GF, and Georgiou-Karistianis N. Functional brain correlates of neuropsychiatric symptoms in presymptomatic Huntington’s disease: The IMAGE-HD study. J Huntingtons Dis. 2015 Dec 27;4(4):325-32. doi: 10.3233/JHD-150154
By: Lise Munsie, PhD
CHDI began this year’s conference with a pre-session where members discussed what was happening at the foundation. The session started with an update from Dr. Tom Vogt, Vice President of Discovery and Systems Biology, about ongoing work on large-scale systems biology in HD. Dr. Vogt mentioned in particular the large study analyzing genetic modifiers of HD, which has opened up a data-mine for drug discovery research (data can be accessed through http://www.HDinHD.org). Following this, Dr. Celia Dominguez, Vice President of Chemistry, gave an update on drug development efforts, while Chief Clinical Officer Dr. Cristina Sampaio, who is involved with Enroll-HD, gave an update on that registry and the potential for clinical trial enrollment.
The first science session of the meeting reviewed how studying the huntingtin protein (HTT) has generated therapeutic leads. Dr. Fred Saudou presented his work looking at the little-studied C-terminus of HTT, and how C-terminal truncations may affect BDNF trafficking through aberrant interactions with dynamin 1. Dr. Ihn Sik Seong updated attendees on the techniques he uses to purify full-length HTT, and the progress his group has made on structural modeling. The next session shifted focus from protein to nucleic acid. Dr. Steve Hovarth opened the session explaining his epigenetic clock, which uses DNA methylation to age tissues. He has found that DNA from HD brains appears older than DNA from control brains of the same chronological age. Dr. Vanessa Wheeler spoke about CAG somatic expansion, while Dr. Laura Ranum described how a phenomenon called “RAN-translation” occurs in protein products of genes with triplet repeats. Her team has identified this phenomenon when a CAG-expanded HTT allele is present. Dr. Ray Truant closed the session, describing unpublished work his group has done on DNA damage repair in HD.
The next session focused completely on targeted therapies for HTT-knockdown, a very popular topic at the conference. Dr. Ignacio Munoz from CHDI spoke specifically about CHDI-sponsored work that recognizes biomarkers that can be used to monitor HTT-knockdown in the brain. Dr. Feng Zhang, one of the individuals originally involved with discovering the CRISPR/Cas9 system, gave a web-conference on CRISPR, which is a potential new method for in vivo gene silencing. Dr. Eric Reits closed the session, describing how the proteasome might be used as an intracellular method for silencing mHTT.
The next session was an exciting clinical trials update that featured talks on four different ongoing trials. Dr. Neal Simon described Azevan’s trial of SRX246, which targets psychological symptoms. Dr. Marielle Delnomdedieu from Pfizer described the company’s ongoing trials of a PDE10A inhibitor (see HD Insights, Vol. 5) in collaboration with the Institut du Cerveau et de la Moelle épinière (ICM) in Paris. Dr. Maurice Zauderer from Vaccinex presented on the SIGNAL trial, which is investigating the use of a monoclonal antibody to block the activity of SEMA4D in HD patients (see HD Insights, Vol. 12). The session ended with an exciting talk by Dr. Sarah Tabrizi of University College London about the Phase I/IIa trial of IONIS-HTTRx, the first trial to evaluate the safety and tolerability of intrathecal antisense oligonucleotides in patients (see HD Insights, Vol. 13).
The final day of the conference featured an introductory session on regenerative medicine in HD. Dr. Ali Brivanlou spoke about his work using embryonic stem cells to study development. By using precise gene editing technology, he induced the HD mutation in his cell line to study the role of mHTT in development. Dr. Paola Arlotta spoke about techniques her group uses to directly re-program neuronal subtypes, and how this may be a potential therapy for HD. Dr. Steve Goldman finished the session with a presentation on glia. His group developed a murine model in which the glial cells express mHTT but the neurons do not, and he finds pathology in the brain in this system.
The final session of the conference focused on modeling using clinical data. Dr. Doug Langbehn, the statistician for the TRACK-HD study, opened the session by describing how to properly set up clinical trials. Dr. Tiago Mestre gave a follow-up talk describing how clinical rating tools can be translated into a scaling system for rating the progression of symptoms in HD. Dr. Jianying Hu gave the final talk of the conference, describing his work that uses machine-based learning to analyze the huge amounts of data involved in accurately diagnosing and assessing prodromal HD, which would be used in moving forward clinical trials and assessing outcomes in pre-symptomatic patients.
Welcome to the fourteenth edition of HD Insights, released at the beginning of the 20th International Congress of Parkinson Disease and Movement Disorders in Berlin, Germany. We are grateful to you, our readers, and to our sponsors, for your continued support of our mission to promote, disseminate, and facilitate research in HD.
This edition examines the promise and potential pitfalls of evaluating interventions in patients at-risk for HD. In an interview with Dr. Diana Rosas, we discuss clinical trial designs pioneered by the PRECREST study, which allow at-risk individuals to participate in therapeutic trials without the difficult burden of genetic testing. Dr. Nancy Downing, featured in HD Insights, Vol. 12 as a “Next Generation” HD Scholar, describes her work evaluating lifestyle-based interventions to improve quality of life and potentially delay onset of HD, while Drs. Govinda Poudel and Nellie Georgiou-Karistianis detail their recently published analysis of data from the IMAGE-HD study evaluating imaging markers of neuropsychiatric symptoms in individuals at-risk for HD. Dr. Lise Munsie brings you the highlights of this year’s CHDI meeting, and continues to synthesize the latest HD research in her Research Round-Up feature. As always, we continue to update you on ongoing and recently concluded clinical trials in HD.
This edition of HD Insights also introduces efforts to further connect and encourage HD research collaborations. Dr. Helen Budworth, also featured in HD Insights, Vol. 12 as a “Next Generation” HD Scholar, shares funding opportunities available through the California Institute for Regenerative Medicine. Additionally, through our new Job Opportunities section, we hope to provide another resource for our colleagues in academia and industry to connect to one another and share opportunities. If you have an opportunity you would like featured in HD Insights, please send us an email at firstname.lastname@example.org. As always, we welcome your suggestions, comments, and feedback, and invite you to subscribe electronically by visiting our new website. Thank you for your continued support.
— Ray Dorsey, Editor in Chief
Ray Dorsey’s disclosures: Dr. Dorsey receives grant support from Prana Biotechnology, Teva, Roche, Biomarin, Raptor Pharmaceuticals and the Huntington Study Group.