Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
26
2010

Johns Hopkins Center of Excellence

In April 2007, HOPES researcher Justine Seidenfeld visited the Baltimore Huntington’s Disease Center (BHDC) in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, MD. The BHDC has been designated as a Center of Excellence by the Huntington’s Disease Society of America (HDSA). Centers of Excellence are recognized not only for the quality and scope of care they provide for their patients, but also for their clinical and basic research efforts, and the outreach services they provide to the general community. For more on the HDSA’s Center of Excellence program, please click here. The Baltimore Huntington’s Disease Center serves most of the mid-Atlantic region, providing services to Maryland, Pennsylvania, Delaware, New Jersey, Washington DC, and Virginia.

HOPES would like to thank the Baltimore Huntington’s Disease Center, particularly Mr. Abhijit Agarwal, Ms. Kit McFarland, Ms. Debbie Pollard, and the director of the Center, Dr. Chris Ross, for taking time out of their busy schedules to speak with us and share their perspectives on Huntington’s disease research.

Clinical Programs^

The Baltimore Huntington’s Disease Center is the only HDSA Center of Excellence based in a psychiatry department (instead of a neurology department) of a medical school or hospital. As such, the Center can pay special and expert attention to treating the psychiatric and psychosocial aspects of the disease, for which we now often have effective symptomatic treatment. However research focuses mostly on brain imaging, neurobiology, genetic mouse models and other basic science, and clinical trials of new therapeutic agents. For more information on the symptoms of HD, click here.

Ms. Debbie Pollard is the clinic coordinator at the BHDC, and she helps patients when they first come to the Center. Ms. Pollard performs full physical exams for each patient to initially determine what symptoms they have, takes a full family and personal health history, and helps to generally guide patients as to how the center works and what services they provide.

The Center runs two separate multidisciplinary clinical programs to provide services to incoming HD patients. Additionally, there are related social services (such as community resource referrals and housing assistance) available in both programs. Confidentiality is strictly upheld in all cases and practices.

One of the clinical programs is an “Evaluation and Research” program, which runs every Tuesday from 1-4pm. The program is over 25 years old, and is supported by the HDSA and the National Institutes of Health (NIH). Thanks to these research grants, all of the services are (presently) provided with no charge. Patients can either make an appointment to come in on their own, or they may be referred to the Center by other physicians or neurologists in the area. At the first meeting, a number of neurological and psychiatric evaluative tests are conducted in addition to the detailed medical and family history that Ms. Pollard takes. Individuals who do not know if they have the altered huntingtin gene, but are presenting some of the symptoms of HD, can take a genetic test for HD (or other potential neurodegenerative disorders) if they so wish. Other staff members of the BHDC may see the patients for follow up services like consultations, case management (including symptomatic treatments for chorea or anti-psychotics if appropriate), counseling, and referrals if it is necessary.

The second clinical program offered at the Baltimore Huntington’s Disease Center is the “Continuing Care Program”. This program offers ongoing medical care for HD patients, as well as counseling and social services for them and their families. The primary purpose of the clinic is to treat and manage HD symptoms through medication, counseling, and to help patients to adjust their environmental surroundings. Patients can be referred to see staff members at the center who serve as neuro-psychiatrist specialists, social workers, or be referred for occupational therapy and speech therapy. The goal of the staff is to work with patients and their families to develop a tailored program for care. As opposed to the “Research and Evaluation” program, services from this program must be paid for, but health insurance is accepted when it applies. However, a generous grant from the HDSA allows the BHDC to charge for services based on the patient’s ability to pay and provide services for free to individuals that cannot otherwise afford it.

The clinic also conducts genetic tests for family members of those with HD who want to know their gene status. Genetic testing is a serious issue, and should only be undertaken after much consideration and counseling- for more information about genetic testing for Huntington’s Disease, please click here. They also offer counseling to many asymptomatic individuals who have the altered HD gene, in order to help them adjust to the kinds of lifestyle changes they can anticipate when symptoms begin to appear. Ms. Pollard emphasizes that as a Center of Excellence, the clinic is open to anyone regardless of the ability to pay, so anyone may come in for these services.

Social Services^

Social worker Ms. Kit McFarland explains that the BHDC is mostly a research operation that also provides care to patients. A large part of Ms. McFarland’s job is to provide tailored information about HD to families or individuals who have specific concerns. She also puts together an initial package of basic information for those who are unfamiliar with HD to use before they need more specialized help. Much of the time, the people who come to her for advice are families who have just learned that HD runs in their family (usually after one member was diagnosed with it) and they desire more information.

Ms. McFarland feels her job as a clinical social worker is to generally help people learn how to best support and stay involved with their family members that have been diagnosed with HD. For example, she gives them tips to help them make certain that the member of the family with HD stays well-nourished, such as using Ensure shakes. For family members who act as caregivers, she often finds that it is difficult for them to understand how their loved one will change behaviorally throughout the course of the disease, and so she tries to provide ways for them to cope with this issue. They may commonly encounter violent reactions from the family member with HD, but sometimes it can be hard to tell if it is intended violence or a motion from chorea. For those afflicted with HD, one of the most difficult parts of the disease is the gradual loss of their freedom- particularly when in comes to driving. If it comes time for the HD patient to stop driving but they refuse, Ms. McFarland might tell the family members or caregiver that the patient needs to be taken for a driving test, and tries to get the family involved in this decision. For more on HD and driving, please click here.

Another one of Ms. McFarland’s chief tasks is to provide help to the outside community, particularly those who have reached the stage of HD where they need some kind of assisted living arrangement- either in nursing homes or other facilities. This is a difficult process because many individuals with HD are often not prepared to relinquish their independence, even when it is necessary. She also works directly with employees of nursing homes and assisted living facilities in the area to teach them skills they need to serve residents with HD. She explains that many of the issues that nursing home or assisted living facility employees will encounter with their HD residents are actually very common among individuals of that age- such as problems with getting residents to eat. The major differences in residents with HD, that pose greater problems to the staff, are very rapid weight loss and aggression. For more on the manifestations of aggression in HD, click here. Ms. McFarland is also highly involved in much of the Center’s efforts to provide help, information, and services to those patients who have difficulties with transportation and cannot come to the center themselves.

Clinical Trials^

Mr. Abhi Agarwal is the clinical research coordinator for the BHDC, and his job is to organize the enrollment and participation of patients in various clinical trials run through the Center. As Mr. Agarwal explains, the Center offers a wide range of opportunities for individuals and their families to participate in a variety of clinical research studies. Participation in these research trials is free of charge, thanks to a number of research grants from the National Institutes of Health (NIH), the Huntington’s Disease Society of America (HDSA), and the Huntington’s Disease Foundation (HDF).

Mr. Agarwal explains that they take a diverse array of approaches to looking at HD, conducting clinical studies that involve genetics, neuropathy, autopsy-based studies, fMRI studies, and basic research studies. He elaborates further on the clinical research studies currently being conducted at the Center:

1) The Longitudinal Core Study: This project is an observational study, which means that it is not intended to test potential treatments for HD, but rather is a study that will help advance our understanding of the natural onset and progression of HD. To enroll in the trial, the only requirement is to have undergone testing for the altered HD gene- participants don’t need to actually have HD, because control subjects are needed as well. Any patient that participates in the study at the BHDC is seen annually from their enrollment until their death, and at each yearly meeting they receive full neurological and psychological evaluations to assess the how far along motor, cognitive, and behavioral symptoms have progressed. They also receive functional magnetic resonance imaging, or fMRI scans on every other visit to look for structural differences in the brain over time (changes in the shape of the brain, usually related to nerve cell death), and to compare this to people who do not have HD. Because longitudinal studies often require large numbers of patients, the other goal for this study is to assemble a large database of patients who may be able to simultaneously participate in other clinical trials for HD. The Center has about 90 – 110 participants a year for this study.

Mr. Agrawal emphasizes that for observational longitudinal studies to get results, it takes time to be able to see statistically significant patterns that will further the understanding of HD. But these studies can provide critical information on the disease. For instance, the center has been able to demonstrate using sophisticated brain imaging, that striatal atrophy begins at least 10 years prior to clinical onset, that neuronal cell death correlates best with functional disability, and that the number of trinucleotide repeats in the huntingtin protein has an effect on the rate of HD progression. They found that individuals with the smallest number of trinucleotide repeats appear to have the best prognosis. For more about trinucleotide repeat lengths and the huntingtin protein, click here.

2) Genetic study for Huntington’s Disease-like 2 : Researchers at the Baltimore Huntington’s Disease Center are also very interested in looking for other genes that cause HD-like diseases. They have actually identified a number of these disorders, which are defined by having very similar symptoms to HD, but do not involve the altered HD gene- the HD gene can be perfectly normal and these symptoms may still appear. One of these diseases is called Huntington’s Disease-like 2 (HDL-2) and like HD, it is an adult onset neurodegeneration disorder, it is autosomal dominant, and it is characterized by chorea, cognitive, and psychiatric symptoms. It also involves neurodegeneration and inclusion bodies in the same parts of the brain as in HD. The Center is now working on a project to identify genetic markers for this disease, and to understand what kinds of mutations (other than the altered huntingtin mutation) could cause a disease like HD. They have recently published a paper in 2007, linking HDL2 to a glutamine/CTG repeat mutation on chromosome 16. This kind of mutation is related to, but not the same as the mutation involved in HD. They hope that by understanding the pathology behind HDL-2, it will shed new light on the pathology of HD and other neurodegenerative diseases.

3) Huntington Study Group trials : The BHDC participates in a number of multi-site clinical trials run by the Huntington Study Group. The Huntington Study Group is a non-profit organization composed of physicians, medical researchers and health-care providers from around the world. They have been organizing and conducting clinical trials for HD since 1993. In particular, the Center recruits participants for the observational PHAROS and COHORT studies, the PREDICT-HD study to find neurobiological markers of HD, and the completed TREND-HD study which is a therapeutic trial for Ethyl-EPA. For more on the Huntington Study Group, please click here, and for information on clinical trials in HD, please click here.

4) Memantine Study : The Center is also conducting a clinical trial with memantine, a drug that has already been approved by the FDA and marketed as Namenda for use in Alzheimer’s disease patients. However, not much is known about its use in HD, so the purpose of this clinical trial is to test if it will improve or delay cognitive symptoms of HD. The trial is sponsored by a company named Forest Pharmaceuticals, a company that produces drugs for cardiovascular diseases and CNS diseases like HD. This type of trial is a new indication study, and so it is run as a double-blinded, placebo trial over the course of 6 months. The Baltimore Huntington’s Disease Center started recruiting patients for this study in the fall of 2006, and as of March 2007 they have 72 participants. For more information on the use of memantine in HD, click here.

While anywhere from 150-200 people come in for clinical services in an average year, 2006 was an especially busy year for the clinic. Mr. Agrawal also explains that while many people come to the BHDC for genetic testing or patient care, about 25% to 50% of those who come also agree to participate in the clinical trials run through the Center. A good reason for any individual with HD to participate in the Longitudinal Core Study run at the Center is that there will be records of them kept in the Center’s database system, and so they can potentially be contacted to be recruited for any new therapeutic clinical trials if they fit the criteria needed to be included in the study.

Basic Research^

Dr. Chris Ross is the director of the Baltimore Huntington’s Disease Center, and runs a research laboratory that focuses on the neuronal biology and genetics of neurodegenerative and psychiatric disorders such as HD, Parkinson’s disease, schizophrenia.

Dr. Ross discusses a few of the research projects conducted in his laboratory. He explains that the primary purpose of basic research is to identify biological targets for HD, and to develop those targets into treatments. For more on the process of going from basic research to a treatment, click here. As such, his lab focuses their research projects around potential biological targets for HD, and mostly on the huntingtin protein itself.

1) One area of current studies focus on how huntingtin aggregates are formed, and at what point these aggregates are toxic and cause nerve cell death. They have hypothesized that the larger aggregates or neuronal inclusions are not the most toxic molecules, but rather that the intermediates proteins in this aggregation pathway (the early aggregates) may be the most lethal form. As such, they may be the best molecules to target for future therapies. For more information on huntingtin aggregation, please click here.

Dr. Michelle Poirier, another faculty member at Psychiatry at the Johns Hopkins University School of Medicine, is doing studies in her own laboratory to investigate the shape or molecular structure of these intermediate huntingtin proteins. One of the most recent theories of how huntingtin protein aggregates are shaped describes them as made up of a series of folded strands of amino acids, with each strand composed of seven or eight glutamine amino acids. In a paper published in 2005, Dr. Poirier collaborated with the Ross lab to create two tissue culture models based on this theory. They confirmed that the proposed structure does indeed occur, and that there is a correlation between the presence of this type of huntingtin aggregate in the tissue culture cell and the presence of cell toxicity. However, they suggest that it is entirely possible that the toxicity is not caused directly by these aggregates, but rather that any of the kinds of intermediate species formed throughout the aggregate pathway may be responsible for toxicity instead.

2) Another project in the Ross lab looks at what kinds of proteins are involved in cutting the huntingtin protein into fragments. This process is also implicated in nerve cell toxicity in HD – it is thought that a fragment of huntingtin is actually more toxic to the cell than a full-length huntingtin protein. For more information on huntingtin protein fragments, please see figure P-2 here. In collaboration with Dr. David Borchelt and his laboratory at the University of Florida’s College of Medicine, Dr. Ross’ lab developed one of the initial transgenic mouse models of HD. Dr. Ross’s lab has used this mouse model to look at which enzymes play the largest role in generating toxic fragments of huntingtin protein. In collaboration with Dr. Michael Hayden’s laboratory they have already determined that caspase-6 is one of the most commonly involved enzymes in huntingtin fragmentation (please click here for a HOPES article on that finding), but they are looking at the role of other caspases and calpains (another family of proteases) as well.

Tamara Ratovitski, a member of the Ross lab, leads a related project using tissue culture models to look for the specific points in the chain of amino acids in the HD protein where fragmentation occurs. She wants to understand exactly how many fragments are generated by each type of protease, and how long they are. The goal is to target the most important proteases for inhibition, which will reduce the number of fragments and (presumably) cell toxicity.

3) A third project at the Ross lab looks at the affects of the mutant HD protein upon gene transcription. It is thought that the altered huntingtin protein changes the patterns of how genes are transcribed and translated, especially the genes that are key for a cell’s survival- and this may contribute greatly to toxicity in HD. Several years ago, Dr. Ross’ lab identified an unusual interaction between the mutant HD protein and the CREB-binding protein (also known as CBP), a smaller regulatory protein that is key for cell survival. For more information on the role of CBP in HD, click here.

Currently, the lab is following up this project with another group of studies intending to demonstrate a direct connection between the altered huntingtin protein, altered gene transcription, and cellular toxicity. It may be that the interaction between CBP and the altered huntingtin protein is one of a group of similar interactions between proteins involved in gene transcription and the altered huntingtin protein. If their research conclusively demonstrates that altered gene transcription does lead to cellular toxicity, one possible therapeutic intervention would be to use HDAC inhibitors. For more information on the potential role for HDAC inhibitors, please click here.

When asked what he thinks about the role of basic scientific research in respect to the larger body of HD research, Dr. Ross illustrates his opinion by discussing what goes on at the Baltimore Huntington’s Disease Center. Dr.Wenzhuan Duan, an assistant professor in the Department of Psychiatry and Behavioral Sciences works on research in Huntington’s and Parkinson’s disease. He takes biological targets identified through basic research on HD, and develops potential therapeutic drugs based on these findings. For more information on the process of drug research and development in HD, click here. They have developed a tissue culture model using nerve cells with the altered huntingtin protein that can be used to test potential therapeutic compounds to see if they might be useful for treating HD.

Dr. Ross emphasizes that another one of the major goals in doing therapeutic research is not only to cure HD, but to delay its onset. The idea would be to intervene by using treatments before the cognitive, motor, or behavioral symptoms actually appear. Members of the BHDC have already demonstrated that a great deal of neurodegeneration occurs before symptoms actually appear, so it would be effective if treatment occurred before the identifiable “onset” of symptoms to prevent or delay them. The Center has submitted a grant to conduct a phase II clinical trial to look at the effects of coenzyme-Q10 on presymptomatic HD patients, to see if it does in fact, delay the onset of symptoms. For more information of co-enzyme Q-10, please click here. The focus on research and treatments for presymptomatic HD patients is a very new direction for the Center, and appears to be a promising one.

For further reading^

  • The Baltimore Huntington’s Disease Center.
    The website for this HDSA Center of Excellence.
  • Rosenblatt A, et al. The association of CAG repeat length with clinical progression in Huntington disease. Neurology. 2006;66(7):1016-20.
    This study demonstrates that individuals with the smallest number of trinucleotide repeats appear to have the best prognosis
  • Reading S, et al. Functional Brain Changes in Presymptomatic Huntington’s Disease. Ann Neurology 2004;55;879-883
    The 2004 publication demonstrating that there are significant structural changes in the brain in presymptomatic HD patients.
  • Rudnicki DD, et al. Huntington’s Disease Like-2 Is Associated with CUG Repeat-Containing RNA Foci. Ann Neurology 2007;61;272-282
    A follow-up study on HDL-2 demonstrating that it affects RNA function, and this may contribute to cell toxicity in HDL-2.
  • Schilling G, et al. Characterization of Huntingtin Pathologic Fragments in Human Huntington Disease, Transgenic Mice, and Cell Models. J Neuropathology 2007. Vol 66, No. 4; 313-320
    This publication demonstrates the location of significant sites of huntingtin fragmentation.
  • Poirier MA, et al. A Structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure. Human Molecular Genetics, 2005. Vol. 14, No.6: 765-774.
    This paper discusses the models for huntingtin protein aggregate structure, and further confirming the beta-strand/beta-turn model of aggregation.
  • Wang W, et al. Compounds blocking mutant huntingtin toxicity identified using a Huntington’s disease neuronal cell model. Neurobiology of Disease. 2005;500-508.
    This paper discusses a tissue culture model that has been demonstrated to be a good method to screen potential therapeutic compounds for treating HD.

-J. Seidenfeld, 8/21/2007