Stanford has recently been recognized by the Huntington’s Disease Society of America (HDSA) as a “Center of Excellence,” a designation reserved for medical clinics providing the highest standard of care to Huntington’s disease (HD) patients. Two neurologists, Drs. Veronica Santini and Sharon Sha, direct the Stanford Multidisciplinary HD and Ataxia clinic, which has received the designation. Dr. Santini specializes in Movement Disorders, while Dr. Sha specializes in Memory Disorders, and together they lead a team of diverse experts to treat the wide variety of symptoms associated with HD.
The HDSA “Center of Excellence” (COE) is a competitive designation requiring a lengthy application process. The title is reserved for clinics that meet the criteria for exceptional quality of care as recommended by the HDSA. In some circumstances, it also allows for additional funding of HD-related services. Although the clinic has provided extraordinary care for patients with HD for many years, they were only newly designated as a COE in January of 2015. For Dr. Santini, being a COE means providing the “gold” standard of care to her patients with Huntington’s disease. This means providing the total emotional, cognitive, psychosocial, and physical supports that each patient needs. Stanford is able to provide this holistic care through a multidisciplinary team approach with a large and dedicated team (listed below), made up of a genetic counselor, a clinical social worker, a neuropsychiatrist, and a nurse coordinator. The team also has speech, occupational, and physical therapists on call and with plans to move into the new neuroscience building on Stanford’s campus, these services will be available at each clinic visit. The clinic would not be able to offer these wonderful services to patients without the generosity of a local private donor. The new designation of Stanford as a COE reinforces the clinic as a beacon of treatment and information for patients and families throughout the Northern California area. The COE designation also makes the Stanford clinic a place for education of clinical trial participation for new therapeutics and research. Dr. Santini and Dr. Sha wish to begin offering clinical studies in shortly.
The large team at Stanford holds their HD and Ataxia clinic every Friday. The clinic is now located on the third floor of the Stanford hospital and clinics, but will be moving to the new neurosciences expansion that is currently under construction and is due to open in November of 2015. The HD and Ataxia clinic will be on the first floor providing better accessibility for HD patients and other patients with limited mobility and movement disorders. The open floor plan of the new clinic will better allow patients to see multiple specialists on the HD team per visit, further reinforcing the holistic care model, for which the clinic was already known.
A conversation with Dr. Santini revealed that the collaborative nature of team is what is most striking about the Stanford COE. Dr. Santini says that each member shows incredible initiative in their roles and everyone has their heart in it to take the best possible care of each patient.
For more information on the new Stanford “Center of Excellence”, visit their website by clicking here:
List of Team Members:
Veronica Santini, MD, MA, Clinical Assistant Professor of Neurology
Sharon Sha, MD, MS, Clinical Assistant Professor of Neurology
Vala Paladottir, MD, Movement Disorders Fellow
Victoria Tanoury, RN, CNRN, Clinical Nurse Coordinator
Carly Siskind, MS, LCGC, Genetic Counselor
Andrea Kwan, MS LGC, Genetic Counselor
Amee Jaiswal, MSW, Clinical Social Worker
Sepidedeh Bajestan, MD, PhD, Neuropsychiatrist
John Barry, MD, Neuropsychiatrist
In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.
The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.
HD is a unique disease because it is one of few diseases where patients who choose to test and do test positive for the mHTT gene will almost inevitably develop symptoms, making cohorts of premanifest HD subjects a valuable group for scientists to study, because the age of disease onset, severity of symptoms, and progression of the disease varies substantially. While it is valuable to study this population, studies of premanifest HD patients are complicated by the fact the line between pre-symptomatic HD and diagnosed HD is difficult to distinguish at times. So the need for biomarkers and a better description of premanifest and early stage HD needs to be outlined and to reach a consensus among physicians and researchers because the first treatment of HD will likely lie in delaying the onset and reducing the severity of HD rather than finding a cure.
Table of Contents:
1.Premanifest HD (Karl Kieburtz, United States)
2.Motor Assessment Reviewed (Ralph Reilmann, Germany)
3.Neuropsychology in Premanifest HD (Julie Stout, Australia)
4.MRI biomarkers in Premanifest HD (Rachael Scahill, United Kingdom)
5.Overview of pridopidine DRF Study design (Karl Kieburtz, United States and Anna Wickenburg, Sweden)
Premanifest HD (Karl Kieburtz, United States)
One of the first speakers at the Congress began his discussion of the success of other diseases and their associated biomarkers to confirm a diagnosis. One example, autosomal dominant Alzheimer’s disease (ADAD), common in a small population in Colombia has specific biomarkers: amyloid protein aggregation and hippocampal volume. ADAD is similar to HD, since it is a neurodegenerative disease in which the patient’s children have a 50% chance to inherit the disease because the disease is caused by the genes on one of the alleles that the patient possesses. For more on the genetics of HD click here. The amyloid protein aggregates and decreased hippocampal volume indicates the neurodegenerative effects of ADAD. ADAD has biomarkers that serve as diagnostic criteria that are parallel to biomarkers in HD patients that could potentially be used for diagnostic criteria for HD. The measure of hippocampal volume in ADAD corresponds to the decreased striatal and white matter volume measured by MRI in HD and premanifest HD patients. The functional test and imaging tests for ADAD in a 2- year randomized study of 210 ADAD patients in a Colombian population confirmed the diagnostic viability of these two tests. Kieburtz ended his discussion with a suggestion of what the HD community needs to find similar diagnostic criteria to ADAD. He called for a consensus and definition for both premanifest and active HD. He suggested the community needs a test that measures cognition, but also has an imbedded functional component. Finally he said that biomarkers of clinical features such as MRI images need discussion, definition, and universal acceptance.
Motor Assessment Reviewed (Ralph Reilmann, Germany)
Following up Dr. Kieburtz discussion, Dr. Reilmann elaborated on the disadvantages of the standard HD evaluative test, the UHDRS-TMS, and described specific tests that could potentially be useful in the diagnosis of HD. The UHDRS-TMS is useful but does not catch sudden changes in HD progression and ultimately has a profound placebo effect because it focuses primarily on motor symptoms. Still motor symptoms studies are useful because they are common to the phenotype of the disease and are not influenced by a language barrier like cognitive and behavioral tests. The Track-HD study uses the Tapping Force Assessment (TFA), which encompasses two tests, having patients both tap as fast as they can and tapping in a metronomic pattern, meaning they try to keep a specific pace that is first set by a beeping in their ear. The patient then has to keep the same pace of the tap with their index finger after the beeping stops. Dr. Reilmann suggested that TFA was more sensitive to changes of HD progression than the UHDRS-TMS test.
Neuropsychology in Premanifest HD (Julie Stout, Australia)
Dr. Julie Stout discussed the evidence of small but significant cognitive and behavioral deficits in premanifest HD, as well as profound structural effects in the brain. Classical cognitive symptoms of HD include slowed thinking, forgetfulness, apathy, and problems with decision-making. Stout found that these symptoms existed in patients well before they were diagnosed with HD but only at a minor level. These results are picked up by very specific cognitive tests and Stout claims that an average patient’s life would not be significantly changed by such small decreases in cognition. However, these cognitive impairments accelerate quickly before diagnosis and thereafter, according to the Hopkins Verbal Learning test, visual spatial, transformation, motor, visual working memory, attention, and spoken reading speed tests. These deficits can be detected 10 to 15 years before the onset of HD. Unlike cognitive deficits; Stout says that MRI scans reveal profound structural changes in brain volume which can be detected up to 20 years in premanifest HD patients. However, Stout says that neural activity increases in some areas of the brain in premanifest HD patients, perhaps compensating for neurodegenerative effects that have already taken a toll on white matter and striatal volume. So while decreased brain volume is correlated with decreased cognitive and motor effects, the latter takes a longer time to manifest because of brain elasticity and compensatory activity.
MRI biomarkers in Premanifest HD (Rachael Scahill, United Kingdom)
Dr. Scahill discussed structural MRI as a leading option for biomarkers in HD. The usefulness of MRI is that is a common machine in most hospital and clinic setting. It is relatively inexpensive compared to other imaging options such as PET, fMRI, and diffusion metrics. MRI imaging of decreases in striatal volume is highly correlated with symptom progression. However due to individual variation in initial amount of grey and white matter it is difficult to make MRI a definite clinical feature. Ultimately Rachael suggests that MRI images have to taken into account along with functional and behavioral tests of HD patients. However it is still an essential measure of disease progression. Meanwhile other imaging techniques are getting better, more common, and less expensive.
Overview of pridopidine DRF Study design (Karl Kieburtz, United States and Anna Wickenburg, Sweden)
Kieburtz and Wickenburg end the discussion of premanifest HD by discussing the ongoing study of pridopidine in HD. Pridopidine is a drug that stabilizes dopamine levels in the nervous system. The MermaiHD and HART studies suggest that pridopidine reduces inflammation in the brain in HD patients and improves motor symptoms overall. While the drug is well tolerated in patients and moving on in development, there is a small concern about dangers with anthemia and seizures, so the next study is testing higher doses of pridopidine in the hopes that higher doses will create greater clinical results.
W. St. Amant
Huntington’s disease (HD) takes a unique form in France. France has a reduced prevalence of 3 to 7 people in 100,000 compared to 10 in 100,000 people in the United States. Because of the small population in France, less than 2,000 people are diagnosed with HD, which makes a much smaller affected group than in the United States. This low prevalence makes it difficult for France to focus its efforts in either research or treatment of HD. On the other hand, France has what many consider to be the best healthcare system in the world, with its government subsidizing the majority of patient care through taxes on employers. Similarly, efforts for treatment and finding a cure for HD and other rare disease are centralized in a “reference center”, the teaching hospital Henri Mondor.
Insurance and Treatment
All citizens of France are required to subscribe to the national health insurance plan, which is funded from the revenue of the social security tax on workers and an even larger portion is paid through contributions from employers. Many people also purchase supplemental private insurance to cover dental, dermatological, optometric, and other specialized care. The French National Health Service generally refunds patients about 75% of their total healthcare costs. Despite this aid, healthcare can still be a great financial burden for patients with chronic conditions such as HD. HD falls within the long-term illness coverage plan known as the list of Afflictions of Long Duration (ALD30), which covers 100% of the costs of treatment for 30 chronic diseases or disease categories. Initially, the ALD30 plan was a purely a financial plan, but now following major reforms to the healthcare policy in 2004, the plan encompasses a treatment plan known as a “care pathway” for each of the 30 disease categories. The reform to the French healthcare system refocused treatment on the general practitioner who then refers patients to specialized doctors, such as neurologists for HD patients. The National Health Service will not fully subsidize patients who seek a specialist without consulting a general practitioner. In this way HD patients have a primary care physician in charge of their health from the start.
The care pathway for HD falls under category 9 of the ALD30, “severe forms of neurological or muscular conditions”. In the past ten years, this system in which the general practitioner acts as a gatekeeper to other practices has strengthened the bond between hospitals and specialized services, medical or otherwise. HD patients can receive advanced neurological and medical treatment, along with other non-medical services that are of use to HD patients such as: psychological, social, and genetic counseling. In a conversation with Dr. Jean Marie Fessler, president of a collection of 33 public health and medical establishments known as MGEM in France, he said that France’s resources for those with HD are “the best, but without doubt not sufficient”, noting that departmental homes, psychiatric care, and hospice care are all under the umbrella of fully subsidized care for those with incurable diseases.
While the guidelines for physicians and the care pathway for HD patients are sufficient, there is sometimes a disconnection between theory and practice. Because of a lack of patient education and community resources, care can be fragmented, and there is still no great incentive for the general practitioner to follow-up with the patient even though the infrastructure and resources are in place. Research also lags behind in France, even though the reference center for HD has a cohort of patients and runs clinical trials. Funding for research is a fraction of the funding put towards HD in the United States. This is due to France having a smaller affected population, smaller GDP, and less available funding overall.
A proactive HD patient can reap great benefits in healthcare in France. The burden is not financial so much as it is self-education and a commitment to seeking the many medical and social services. For a disease without a cure, the subsidized therapeutic treatment, counseling, and end-of-life care puts France among the leaders in the treatment of Huntington’s disease around the world.
The Global HD research and articles received partial support from the Bingham Fund for Innovation in the Program in Human Biology.
For an extensive overview of France’s management of chronic diseases, read Chapter 4 of the European Observatory’s Study Series.
W. St. Amant
This article will discuss the advantages and disadvantages of using transgenic monkeys to model Huntington’s disease (HD). Most HD animal research utilizes mouse models of the disease. While there is much that we can learn from mice, animals that are more similar to humans, such as monkeys, could offer more pertinent insights into HD and serve as brand new and promising avenues for HD research. Along these lines, transgenic rhesus macaques carrying a human mutant huntingtin gene have been developed at Yerkes Primate Center in Atlanta, Ga. In addition, transgenic marmosets carrying a fluorescent protein have recently been developed at Keio University, in Japan. Researchers plan to use marmosets to create either a Parkinson’s or HD model in the near future. The new models offer a host of advantages that no other animal model has provided, but they are also constrained by cost, ethical considerations, and time.
Advantages of using a Monkey Model
Monkeys are more genetically similar to humans than rodents. As a result, they have a similar lifespan, metabolism, and physiology to humans. For these reasons, monkeys will probably be better models for monitoring disease progression and the effectiveness of experimental drugs. The transgenic monkeys with the mutant huntingtin gene exhibit an HD phenotype closer to humans and more closely mirror the physical, behavioral, and cognitive symptoms of the disease than any other HD animal model so far.
A variety of established behavioral and cognitive tests are used to assess the monkeys. One such test is the HD primate model scale, modified from the HD scale used for humans. The scale ranges from 0 to 80, in which 80 describes the most severe symptoms and is used to track the number of involuntary movements in the transgenic rhesus macaques. The test shows that the monkeys display chorea and dystonia more clearly than many HD mouse models.
In addition to physical tests, non-invasive fMRI procedures are used to monitor neurodegeneration, and intranuclear huntingtin inclusions, as well as other features of the disease at the neural level. Monkeys have larger brains than rodents, so neural changes can be monitored more accurately. Moreover, a germline of macaque pluripotent stem cells with the mutant huntingtin gene has been developed and is currently being studied by the same researchers. These stem cells can be coaxed into becoming neurons, which could then demonstrate the neural symptoms of the disease. Ethical concerns have prevented the development of a similar human germline, so the transgenic rhesus monkeys provide both an in vivo and in vitro avenue to study the neural progression of HD.
Disadvantages of using a Monkey Model
Many of the advantages of monkey models come hand in hand with their problems. Primate models are more expensive, take more time, and raise more ethical concerns than mouse models. The rhesus macaque for example has one baby at a time, a gestation period of 150 to 160 days, and a long puberty of 3 to 4 years. The constraints and labor involved in natural and artificial reproduction make the cost of transgenic monkeys significantly higher than transgenic mice. Similarly, monkeys are much larger than mice, so their housing and food costs are more expensive. Because monkeys display HD symptoms several years after they are born, these costs for monkeys are exponentially greater than those for mice. Because macaques and marmosets are similar to humans in terms of emotions, cognition, and behavior, the use of monkeys in lab research raises more ethical concerns and media interest than other animal models. The monkeys are protected by stringent ethical guidelines and procedures determined by the National Institute of Health and the Institutional Animal Care and Use Committee. The use of monkeys in research sparks public interest more than rodents, which can bring both positive and negative attention to transgenic primate research and HD animal model research in general.
Different types of monkeys have their advantages and disadvantages. The rhesus macaque is more closely related to humans than the marmoset but the reproductive traits of the marmoset make it an attractive model in its own right. The marmoset can have 80 babies over its lifetime, compared to that of 10 offspring for the macaque. The marmoset also has a shorter pregnancy and a faster sexual maturation, making the marmoset model perhaps a more efficient model for studying HD. The marmoset is also smaller making housing and feeding them more manageable economically. However, the marmoset has a smaller brain, making it more difficult to track neurodegeneration on an MRI. Both of these monkey species have far longer pregnancies, pubertal periods, and fewer offspring than a female mouse, who can have up to 10 litters of 3 to 14 mice per year. However, animal models more similar to humans could not only accelerate discoveries in the field, but could potentially reduce the total number of animal models needed in research.
Method of Transgenesis
There are a variety of animal models that are designed through genetic engineering in order to study HD. The only type of monkey model so far is the transgenic model. In this type of model, a transgene is integrated into the animal’s genome. An example of the method used for the transgenic macaques is as follows. A mutant human huntingtin gene with 84 CAG repeats is inserted into rhesus macaque egg cells through a viral vector. The viral vector is a modified lentivirus, which is a virus commonly used for gene delivery because it infects non-dividing cells. The lentivirus contains the gene encoding for the mutant huntingtin gene as well as a gene encoding green fluorescence protein (GFP) to serve as a marker, so that the scientists can tell whether or not the transgene was integrated into the genome of the monkey. Many of these HD eggs are then artificially fertilized and implanted into female surrogate monkeys. The gene is integrated randomly into the embryo’s genome through reverse transcriptase. Of the HD monkeys that are born, each will vary in terms of the location of the human mutant huntingtin gene on the chromosomes, the number of CAG repeats, and severity of the HD phenotype. Essentially, HD manifests differently in each monkey due to the nature of the transgenic procedure. However, the mutant huntingtin gene is still heritable and dominant despite its variable location in the chromosomes so natural and artificial offspring of transgenic monkeys can also be used to study HD.
The advantages of transgenesis through the lentivirus vector are that it is very effective and that HD animal models can be produced in high yield. However, through this method the mutant human huntingtin gene could be integrated anywhere in the genome rather than where the gene is normally located. Some knock-in mice have been produced in which the human gene replaces, at least in part, the mouse’s huntingtin gene in the correct location on the chromosome. They should, in theory, be more accurate models than transgenic mice. A knock-in monkey is theoretically feasible, but the laboratory techniques are not yet efficient enough to make this cost-effective.
Current and Future Research
There are currently only two branches of research on transgenic non-human primates at this time: macaques and marmosets. The first successful transgenic monkey was developed in 2001, when Dr. Anthony Chan and his colleagues at Oregon Regional Primate Research Center inserted a GFP gene into an embryo of a rhesus macaque via a retrovirus. Chan then moved to Emory University where he developed the first HD macaque model in 2008. Five transgenic monkeys were born and four of those expressed HD symptoms. The macaques had integrated human mutant huntingtin genes that varied in CAG repeats and integration location. Two of these monkeys died within the same day of birth, probably because they had longer CAG repeats. This feature is known to cause a quicker onset of symptoms in humans, and thus expressed a more severe phenotype –motor impairment and difficulty breathing– than the others. They both also had multiple mutant huntingtin integration sites, which may have lead to the overexpression of the huntingtin gene as well. One monkey is still living today. Its huntingtin protein had only 29 CAG repeats, within the range of a normal huntingtin gene, so it will probably not develop the disease. The other two monkeys had 83 and 84 CAG repeats and lived long enough to be studied by the researchers. All the monkeys were studied based on their physical behaviors of dystonia, chorea, difficulty swallowing and difficulty breathing. These symptoms manifested in varying degrees in all monkeys except the monkey with 29 CAG repeats.
The lab now has a second generation of monkeys that are currently being studied. They are from the same germline of one of the monkeys from the first generation, meaning they are genetically related. Though the research is unpublished, the new group of monkeys model HD even better, reflecting a delayed onset of the disease and milder phenotypes. The macaques’ brains will be studied through fMRI, which is non-invasive. The macaques could potentially be used to study promising HD medications.
In 2009, Japanese researchers developed the first transgenic marmoset model expressing GFP. Five monkeys made up the first generation of transgenic marmosets. The marmosets glow under a specific wavelength of light because, like the macaques, they carry the GFP gene derived from jellyfish DNA. The researchers hope to use the same techniques to integrate genes coding for Parkinson’s, but are also considering HD. Because the marmosets reproduce more frequently and in larger numbers, transgenic marmosets could even further accelerate HD research.
HD is easier to study than some other diseases because it involves a mutation in one gene, where as Parkinson’s, ALS, and Alzheimer’s have more complex genetic origins. So HD is, in many ways, a gateway for all neurodegenerative research. As more labs start working with transgenic non-human primate models, advances in understanding the progression, physiology, and neurobiology of HD are sure to follow. Because HD monkeys are also an intermediate between mouse and humans, they serve as a new avenue for drug research, which could reduce the time it takes to bring a new drug to market. The new monkey models put HD research on the cusp of major breakthroughs for both understanding and treating the disease.
Anthony W.S. Chan, Pei-Haun Cheng, Adam Neumann and Jin-Jing Yang (2010) Reprogramming Huntington Monkey Skin Cells into Pluripotent Stem Cells. Cellular Reprogramming (In Press). Dense and unnecessary to read.
Anthony W.S. Chan (2009). Transgenic primate research paves the path to a better animal model: are we a step closer to curing inherited human genetic disorders? J Mol Cell Biol 1(1):13-14. PMID:19671628. Great article that discusses the advantages of a monkey model and is easy to read.
Anthony W.S. Chan and Shang-Husn Yang (2009). Generation of Transgenic Monkeys with Human Inherited Genetic Disease. Methods 2009 May 23 [Epub ahead of print] PMID: 19467335. Scientific research and difficult read but helpful for understanding setting up a germline.
Bachevalier, Stuart M. Zola, Shihua Li, Xiao-Jiang Li and Anthony WS Chan (2008) Toward a Transgenic Model of Huntington’s Disease in the Nonhuman Primate. Nature 453(7197): 921-924. PMID:18488016. Scientific and dense but excellent description of methods used for transgenesis.
B.Snyder, A. M. Chiu, D. Prockop and Anthony W.S. Chan (2010) Human Multipotent Stromal Cells (MSCs) Increase Neurogenesis and Decrease Atrophy of the Striatum in a Transgenic Mouse Model for Huntington’s Disease. Dense and unnecessary to read.
Chan, A. W. Personal Interview. 4 Jan. 2013.
Cyranoski, David. “Marmoset Model Takes Centre Stage.” Nature.com. Nature Publishing Group, 27 May 2009. Web. Good summary article of more difficult published research.
Nature 459, 523-527 (28 May 2009) | doi:10.1038/nature08090; Received 27 September 2008; Accepted 30 April 2009. Difficult but worthwhile read on the marmoset models.