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.