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There is no cure for Huntington disease and there is no effective treatment. But through research -- now, more than ever before -- there is tremendous hope.
In 1872, Dr. George Huntington published an article describing a disease which was later named after him. Over a hundred years later, and after arduous research, Dr. Jim Gusella's research team at Massachusetts General Hospital in Boston narrowed down the location of the gene that causes HD to chromosome 4. The discovery of this "marker" was a major breakthrough. In 1993, after ten more years of research, the same team found the gene.
Now that we know where the gene is, we are one step closer to effective treatment and ultimate cure. There are several areas of research scientists are studying:
All the tools of molecular biology and biochemistry are being used to analyse the HD gene and its protein product, huntingtin. Scientists are attempting to discover how huntingtin does its damage and what other proteins interact with it or change it. At least two other proteins have recently been identified; one is a key factor in the process by which cells convert sugar glucose to energy. Maybe huntingtin inhibits energy production.
The caudate nucleus and the putamen are the areas of the brain that are dramatically affected by HD. However, only a subset of the cells in these areas die and the rest remain alive and well. Are these cells that die committing suicide or being murdered by other cells? The answers could lead to interventions.
Research in transplantation is being done to try to replace the cells that have already died -- similar to the work already done in Parkinson's disease. Doctors take cells from a fetus and inject them into the area of the brain affected by the disease. Although this research is in the very early stages, it already shows some promise. At Good Samaritan Hospital in Los Angeles, transplantation surgery was performed in April, 1996 and scientists are monitoring the results very carefully. It remains to be seen whether this procedure has any potential benefit for HD patients.
Genetic engineering techniques are being used to create a mouse model of HD by inserting the abnormal HD gene into the DNA of mice. An effective mouse model will increase scientists' ability to define and understand the mechanisms of brain cell death and to evaluate medications and procedures in mice that cannot yet be tried in people.
A consortium of more than 100 clinical and basic scientists from Canada,
United States and several other countries, known collectively as The Huntington
Study Group, are looking at ways to slow the progression of the disease,
and ultimately to develop an effective treatment, through the use of various
drugs. A number of drug trials are being planned for the years ahead.
Huntington Study Group: The CARE-HD Trial
by Mark Guttman, M.D.
March 12, 1998
Last summer, a consortium of neurologists, neuropsychologists, psychiatrists and basic scientists known as the Huntington Study Group (HSG) launched the largest ever HD clinical trial.
Known as CARE-HD (Co-enzyme Q10 And Remacemide: Evaluation in Huntington Disease), this trial will involve 340 patients with mild to moderate symptomatic HD at 22 research sites. Four Canadian centres will participate: Vancouver, Calgary, Edmonton, and Toronto. The CARE-HD study is funded by a grant from the US National Institutes of Health (NIH). The HSG has also received generous support from the Huntington Society of Canada, which has enabled this work to move forward. The brain cell death which is the cause of HD may be caused by a number of abnormalities. Morest specifically, the process which leads to cell death is thought to be associated with the following problems:
over-activity of the natural brain chemical, glutamate; lack of normal cell energy production; the effect on the brain of harmful substances called free radicals.
Remacemide hydrochloride is an experimental drug that may be useful in treating HD by readjusting the activity of glutamate in the brain. Co-enzyme Q10, or CoQ, is a natural product which may be helpful because it increases cell energy and protects against free radicals. Remacemide is currently not available by prescription [check] but CoQ is available at health food stores. The CARE-HD study is designed to discover whether these compounds, individually or in combination, help to slow the progression of symptoms in this group of HD patients.
The study design involves following patients for 31 months, so it will be a fairly long time before the results are available. Patients will be divided into four equal groups by a blind randomization process, so that neither the patients nor the research team will know which medication is being given to which group. One group will receive 200 mg of remacemide three times daily; the next will receive 300 mg of CoQ twice daily; the third will receive both medications; and the final group will receive placebo for both drugs. The study is designed to reveal whether either medication, or a combination of both, will be effective, and over the course of the study, each participant will have a number of clinical assessments to monitor the signs and symptoms of HD. We do not expect that patients will experience any real improvement due to the medications, but we do hope that some of the treated patients will see a slowing in the progression of their symptoms over the course of the two and a half years they will be involved. Preliminary studies have shown both remacemide and CoQ to be safe for short periods of time, and we hope to find that they are safe over a much longer period.
The HSG is very excited about CARE-HD. However, research is a gradual process and we must be cautious about changing the way we treat patients until the results of the study are known. In dealing with the frustrations of a chronic, progressive disorder like HD, there is a temptation to try anything which may help. Most physicians practice according to evidence-based medicine that is to say, we prefer to have proof that a strategy works before we recommend it to our patients. For most experimental medications, the government puts barriers on the use of drugs until they have been approved for use. The CARE-HD study involves a somewhat different situation, since CoQ is already available through health food stores. Should someone with early symptoms of HD take CoQ? This is a difficult question impossible to answer authoritatively at this time. Most physicians practice according to evidence-based medicine that is to say, we prefer to have proof that a strategy works before we recommend it to our patients. Currently, Tthere is no proof that CoQthis compound slows the rate of progression of HD. There can be risks in taking any medication, including natural compounds which are widely available. In fact, during the preliminary studies at Harvard which preceded the launch of CARE-HD, more side effects were associated with CoQ than with remacemide. In addition, the dosage regimen in the CARE-HD trial is extremely high 600 mg per day and CoQ is very expensive. Insurance programmes do not cover this medication. Individuals who are interested in CoQ must therefore consider financial hardship, side effects, and lack of benefit, and they should discuss their plans with their HD physician.
There is still no drug which has been proven to slow or stop the progression of Huntington disease, and until the CARE-HD trial is over, we will not know whether remacemide or CoQ are helpful. In discussing the situation with my own patients, I do not recommend that they begin using CoQ until the study has been concluded. At the same time, I know that some of them have chosen to go this route and, like other HD physicians, I recognize that this decision can only be made by the individual affected by HD.
Important New Findings on Protein Balls
D Martindale, A Hackam, A Wieczorek, L Ellerby, C Wellington, K McCutcheon, R Singaraja, P Kazemi-Esfarjani, R Devon, S Kim, D Bredesen, F Tufaro, M Hayden. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nature Genetics (February, 1998).
Since the discovery in August 1997 that HD brain cells contain neuronal intranuclear inclusions (NIIs) so-called protein balls a great deal of attention has focused on understanding how these protein aggregates form, and on their relationship to cell death in Huntington disease. In the February edition of the prestigious journal, Nature Genetics, Dr. Michael Hayden and his colleagues at the University of British Columbia, NeuroVir Inc., the Burnham Institute in La Jolla, California, and the University of Saskatchewan have published intriguing new insights into the relationship between huntingtin protein and the formation of intracellular inclusions. The gene responsible for Huntington disease contains an expanded region of CAG repeats, and the huntingtin protein expressed by the gene contains an unusually long polyglutamine segment. Using test-tube and animal models, Dr. Hayden and his collaborators have discovered an important link between this polyglutamine expansion and the onset of cell death in HD. The full-length huntingtin protein, Dr. Hayden suggests, can be broken down into fragments by enzymes. One of the fragments the N-terminal fragment contains the expanded polyglutamine region, and this shortened version of the protein produces aggregates which have toxic effects on brains cells. Significantly, the level of toxicity seems to be related to the number of polyglutamine repeats.
This shortened huntingtin may then interact with other cellular proteins, gaining the ability to penetrate the nuclear membrane and form intranuclear inclusions.
Says Dr. Hayden, summarizing the announcement, it is possible that cleavage of mutant huntingtin leads to the development of aggregates which compromise cell viability and that their localization is influenced by protein length.
With these findings, a possible explanation of how mutant huntingtin protein causes brain cell death begins to unfold.
The exciting work of Dr. Hayden and his collaborators is critical to our emerging understanding of the pathogenesis of Huntington disease, and to the pursuit of new approaches to therapy. Specifically, these latest findings suggest that it may be possible to combat the onset and progression of HD symptoms by preventing protein fragmentation; by blocking the formation of protein balls; or by barring protein from entering the cell nucleus. RM
International Collaboration in the Fight Against HD
In early December 1997, many of the worlds most distinguished HD scientists and clinicians gathered in Santa Fe, New Mexico for a series of important meetings. Under the auspices of the Huntington Study Group, supported in part by the Huntington Society of Canada, and the Huntingtons Disease Society of Americas Coalition for a Cure project, the two-day meeting provided ample evidence of the escalating pace of the HD research effort. Special highlights included a keynote presentation from Dr. Gillian Bates of Guys Hospital in London on new findings being generated through the use of the HD mouse model [see Horizon #86].
The HDSAs Coalition for a Cure is a scientific network comprising six outstanding laboratories, including that of Dr. Michael Hayden of the University of British Columbia. [See Important new findings on Protein Balls intracellular inclusions in this issue of Horizon.] Under the scientific leadership of Dr. Chris Ross of Johns Hopkins University School of Medicine, the Coalition is helping to drive the scientific agenda in Huntingtons research, and the preliminary results reported at the meeting are extremely encouraging for all members of the HD community.
Drawing on the expertise of about 60 participants, the discussions focused largely on the recently-discovered nuclear inclusions or balls of crud which characterize HD brain cells. Investigators presented a range of stimulating hypotheses on the properties and behaviour of the huntingtin protein; novel animal and cell models for studying the disease; and important strategies for new forms of therapy. Dr. Erich Wanker of the Max Planck Institute in Berlin explained that one of these strategies, called high-throughput screening, has the potential to test very large numbers of compounds in a very short time, in a bid to identify molecules which inhibit the formation of nuclear inclusions.
Just as the HDSAs Coalition is playing a leading role in pursuing new scientific strategies for combatting Huntingtons disease, the Huntington Study Group is a leaderfrontrunner in delivering new clinical approaches to HD to individuals in need. Funded by the Huntington Society of Canada, Huntingtons Disease Society of America, Foundation for the Control and Cure of Huntingtons Disease, and the Hereditary Disease Foundation, the Huntington Study Group is meeting with much early success in attracting significant financial support from the US National Institutes of Health (NIH), and from industrial partners.
Members of the HD community may be most familiar with the Huntington Study Groups CARE-HD project, which is slated to involve 340 HD individuals in a clinical trial of remacemide and co-enzyme Q10. [See Huntington Study Group: The CARE-HD TrialHSG Starts Largest Clinical Trial in HD in this issue of Horizon.] However, the Huntington Study Group is actually leading a broad array of projects and trials, including the UHDRS, or Unified Huntingtons Disease Rating Scale, a tool forwhich is seeking to building a reliable statistical profile of the HD population, and one which will be increasingly important as a research resource in the years ahead.
With the support of colleagues from the Huntingtons Disease Society of America Mikal Kitchens, President, and Barbara Boyle, Executive Director the Santa Fe meeting also provided an opportunity for the Huntington Society of Canada to consult a working group of senior HD investigators with regard to the development of its new research programme, details of which will be announced in the Spring of 1998.
Participants enthusiastically agreed that holding the Huntington Study Group and Coalition for a Cure meetings in tandem was tremendously productive, and served to promote the sort of collaboration and discussion which will yield new treatments for HD in the shortest possible time. RM
Since 1977, the Huntington Society of Canada has funded basic and clinical (or applied) research annually. We are committed to supporting research until an effective treatment and eventual cure for Huntington disease are found.
HSC grants predoctoral scholarships and postdoctoral fellowships to help young scientists-in-training. Supporting them also puts another pair of hands in the laboratories of established scientists working on HD. Several of these students have become career scientists investigating HD and related disorders.
The Society's initial 1986 investment of $30,000 for each of two years in Dr. Michael Hayden's original pilot study of predictive testing in the Vancouver area (through the University of British Columbia) led to a grant of several million dollars to fund the Canadian Collaborative Study on Predictive Testing -- a study unique in the world. The 1993 gene discovery led to an improvement of the already-existing predictive test.
In 1993, HSC contributed funds to Dr. Jim Gusella's research team at Massachusetts General Hospital in Boston -- the team found the gene that causes Huntington disease. We are also proud of the fact that two Canadian scientists were part of the team.
The 1995-97 investment of $70,000 seed money into the Huntington Study Group is intended to assist researchers across North America to eventually secure several million dollars to fund drug trials. The goal is the identification of medications which will slow the progression of the disease and lead ultimately to effective treatment and a cure.
Research in communication and swallowing projects has been funded by HSC. Research by Estelle Klasner, a speech/language pathologist at Runnymede Hospital in Toronto, resulted in the publication of two booklets and three videos which HD families throughout the world find extremely helpful.
HSC founded and supports the Canadian Brain Tissue Bank (CBTB) which collects brain tissue at autopsy and distributes it to scientists conducting research into many diseases. It is the only national Brain Tissue Bank in Canada and one of only four in the world. HSC distributes a pamphlet on this subject. For further information, contact:
Vikramjit Singh Chopra (University of British Columbia)
Vik Chopra has held a Huntington Society pre-doctoral award since 1996, and his strong performance has been recognized by the Research Council with a third and final year of funding.
Under the supervision of Dr. Michael Hayden, Mr. Chopra's work focuses on a protein called HIP-1, or huntingtin interacting protein. As the name suggests, HIP-1 interacts with huntingtin, the protein produced by the HD gene, and an improved understanding of this compound may help to answer one of the central questions in HD research today: why does the defective version of huntingtin cause the selective death of brain cells?
In collaboration with other members of Dr. Hayden's group, Mr. Chopra has achieved significant progress in characterizing HIP-1, and he is now exploring some of the intriguing ideas which have been put forward about the relationship between HIP-1 and huntingtin. For example, it has been suggested that the interaction of these proteins may be central to the assembly and function of the structure which supports cells, called the cytoskeleton.
Having determined that HIP-1 is part of a family of genes, Mr. Chopra is working to isolate and analyze related genes in humans and in mice. His work will shed additional light on the normal function of HIP-1 and its relationship to the death of brain cells in Huntington disease, and may suggest new targets for therapeutic intervention.
Matthew Hebb (Dalhousie University)
In Dalhousie University's Department of Pharmacology, Matthew Hebb is producing important insights into the expression of the HD gene, and the possible role of the huntingtin protein in the normal adult brain.
Focusing on specific areas of the rat brain, Mr. Hebb has made the significant observation that production of the huntingtin protein seems to be increased, or up-regulated, in rats which have recently given birth - suggesting that hormones may be linked to protein expression.
In addition, preliminary studies indicate that the huntingtin protein may be intimately associated with the chemical cascade which leads to cellular differentiation during early development.
Further insights will help us to understand more about the role of the HD gene in the central nervous system - and perhaps how to block or circumvent the onset of the disease process.
Funded by the Huntington Society of Canada since 1996, Mr. Hebb is interested in pursuing his studies of Huntington disease at the post-doctoral level. His work has already encouraged his supervisor, Dr. Harold Robertson, to allocate increased laboratory time and attention to Huntington disease.
John Rubinstein (MRC Laboratory of Molecular Biology, Cambridge)
The discovery of the double helix structure of DNA, by Francis Crick and James Watson, is one of many scientific breakthroughs associated with the Medical Research Council Laboratory of Molecular Biology in Cambridge, England.
One of the outstanding scientists now working at this prestigious institution is Dr. John Walker, winner of the 1997 Nobel Prize in Chemistry and a Fellow of the Royal Society of London. Beginning this year, Dr. Walker will be supervising the work of John Rubinstein, recipient of the first Landmark Graduate Award to be granted through the NAVIGATOR programme.
Cell death in Huntington disease may be closely linked to dysfunction of a process known as electron transport. This process occurs in mitochondria -the small structures that serve as the energy generators of cells. Although electron transport is crucial to the survival of cells, the details of how it works and most of the structures of the protein complexes involved are unknown. Two protein complexes have been identified as potentially defective in HD, and Mr. Rubinstein will be subjecting one of them (known as complex I) to exacting scrutiny.
Using the techniques of electron microscropy, he intends to formulate a three-dimensional structural model of complex I - a model which could be important to the rational design of new therapeutic agents for Huntington disease. - RM
Volunteers and staff across Canada raise funds to support the work of the Society, including research. The Ralph M. Walker Research Fund was established by the HSC in 1983, to honour the Society's founder. This fund is intended to support innovative research into the causes, treatment of HD, and to search for a cure.
New Research Program Charts the Course to a Cure
NAVIGATOR
"There's no doubt in my mind that the Huntington Society's new NAVIGATOR project will be a formidable weapon in the fight against HD. This is just the sort of initiative which will enable the Canadian research community to reinforce and enhance its leadership role in the fight against genetic disorders, and to discover new treatments and, ultimately, a cure for Huntington disease."
With the launch of its NAVIGATOR research programme, the Huntington Society has charted a new course in the search for a cure for Huntington disease.
Approved by the Board of Directors in April, NAVIGATOR recognizes that we are at a watershed in HD research, and promises to advance the Society's ability to contribute to the development of innovative new treatments for the disease.
NAVIGATOR represents the outcome of a unique collaboration between the Huntington Society and the international scientific community. The Society's Task Force on Research - comprising HSC Vice President Elaine Taylor (Chair), Louise Picard of the national Board of Directors, and Sandra Russell, Director of the Northern Ontario HD Resource Centre - consulted broadly with clinicians and scientists at the forefront of the HD cause.
The outcome is a programme which addresses the leading priorities in Huntington's research, and which positions the Huntington Society of Canada to play a major role in the search for solutions to this devastating disease.
NAVIGATOR consists of a carefully-designed series of undertakings, intended to promote groundbreaking scientific research by our finest investigators; collaboration, resource-sharing, and cost-effectiveness; and balance between scientific, clinical, and psychosocial research.
The grants and awards to be offered under the auspices of the NAVIGATOR programme include:
Together, these grants and awards will enable the Huntington Society to achieve the all-important goals identified by the Task Force on Research:
To meet the most urgent needs in HD research today: NAVIGATOR enables the Society to fund research which is of immediate relevance to the most important research questions currently facing the HD community.
To produce the greatest possible value for every research dollar: NAVIGATOR maintains the Society's long-standing commitment to ensuring that all funds are put to the best possible use.
To invest only in the most outstanding people and projects: Through rigorous competitive review, NAVIGATOR will channel funds to those individuals and studies which are most likely to produce important results.
To leverage benefits from existing collaborations and networks: NAVIGATOR provides a framework for exciting new partnerships with other funding agencies and with the corporate community.
To cover the full continuum of research, from bench to bedside: By including clinical and psychosocial research within its mandate, NAVIGATOR permits the Huntington Society to cover the full spectrum of HD research.
NAVIGATOR is a competitive programme, and quality assurance is entrusted to the insights and expertise of the Society's Research Council.
The Council is composed of scientific and medical leaders of the international HD community, and includes expertise in such disciplines as genetics, molecular biology, neurology, psychiatry, biochemistry, pharmacology, and cell biology.
Together, the members of the Research Council will offer annual funding recommendations to the Board of Directors, with a view to building a research programme which is second to none.
With NAVIGATOR, the Huntington Society has accepted one of the most important challenges in its 25-year history. Scientific research will produce desperately-needed answers to HD, but it is an expensive business and success will depend on the Society's ability to generate new funds.
To ensure that the Society is able to provide the stable funding needed to attract new investigators and laboratories to the HD cause, the NAVIGATOR programme will be implemented incrementally over the next two years. But it remains clear that attracting additional revenue is the only way in which HSC can enhance its role in research, while maintaining its unwavering commitment to excellence in services for individuals and families in need.
The future has never looked brighter. The campaign against HD gained tremendous momentum in 1993, with the landmark discovery of the gene responsible for the disease; and there has been more progress in HD research in the last five years than in the entire period since the disease was first identified in 1872.
Recent breakthroughs have given rise to unprecedented optimism that solutions to HD are, at long last, on the horizon.
The NAVIGATOR programme promises to move us forward rapidly, along the course we have charted - toward a cure for HD. With the commitment of HSC volunteers across Canada, we will end the nightmare of Huntington disease. - RM