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Research Breakthrough
Drug Delays Age of Onset in Mice with Huntington�s, Extends Life
from Horizon 93, Summer 1999
In a major breakthrough at Harvard Medical School in Boston, scientists have succeeded in delaying the onset of Huntington�s in mice genetically programmed to develop the disease, and extending their total life span.
Dr. Robert Friedlander and colleagues report in the 20 May issue of Nature that they have found a way to interfere with the process of cell death that destroys brains cells in Huntington disease.
The report shows how symptoms in mice suffering from an early-onset version of Huntington�s disease can be delayed by blocking an enzyme called caspase-1, which cleaves the huntingtin protein into smaller pieces and is involved in a series of events leading to cell death.
The researchers used genetically engineered mice carrying a portion of the mutant huntingtin gene. Normally, these mice show symptoms such as irregular gait, shuddering movements and epileptic seizures. The researchers crossed these mice with a second strain of mouse with a different genetic mutation, which blocked the function of caspase-1.
When the two different strains of mice were bred, their offspring did develop Huntington�s-like symptoms, but these symptoms developed later than in mice with just the mutant huntingtin gene. Friedlander�s group then tried injecting mice with the mutant huntingtin gene with drug that blocks the action of caspase-1 and found similar results.
By blocking the action of caspase, the researchers found they could delay the onset of the disease until roughly 10% later in life, dealy the appearance of so-called �protein balls� in the cell nucleus, improve the motor performance of the mice, and increase their life span by approximately 20 percent.
According to Dr. Michael Hayden of the Centre for Molecular Medicine and Therapeutics in BC, �In 1996, Canadian researchers first showed that huntingtin was cleaved by caspases and raised the possibility that caspase inhibitors could be effective modes of therapy for the disease. This new evidence from Boston shows caspase inhibitors can slow the onset of symptoms in mice with the exon-1 portion of the huntingtin gene. Clearly what is now needed is to conduct similar experiments on mice with the full huntington gene.�
In an accompaniment to the Nature article, University of Munich biochemist Christian predicts that �Caspase inhibition may turn out to be the magic bullet against neurodegenerative disease.�
What it means:
This is the first demonstration that a drug can delay the onset of HD and slow the progress of the disease in an animal model. The results will now need to be repeated in other animal models of the disease, and if similar results are obtained, small-scale trials on humans could follow.
For more detailed information:
Ona, V, L Mingwie, JP Vonsattel, LJ Andrews, SQ Khan, WM Chung, AS Frey, AS Menon, XJ Li, PE Stieg, J Yuan, JB Penney, AB Young, JJ Cha, RM Friedlander. 1999. �Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.� Nature 399: 263-267.
Piecing It Together: Rod Morrison reports on an international meeting of HD researchers
from Horizon 92, Spring 1999
In November 1998, medical and scientific leaders of the Huntington�s cause gathered in Palm Beach, Florida for the meetings of the Huntington Study Group, an international clinical research consortium, and the Huntington�s Disease Society of America�s Coalition for the Cure initiative.
One of the special features of the conference was a joint meeting of investigators involved in both projects. This provided an invaluable opportunity for scientists and clinicians to exchange views and information; and underscored the commitment of the entire research community to work collaboratively to develop and deliver new treatments for Huntington disease.
The Science of HD
The Coalition for the Cure is playing a leading role in unravelling the mysteries of Huntington disease. This year�s meeting -- which included representation from the United States, Canada, England, Germany, and Italy -- made it clear that the pace of discovery continues to accelerate.
One of the most important scientific themes to have emerged over the past year is the relationship between protein aggregates (see Horizon 86:1997; 88:1998) and cell death in HD, and many of the presentations explored and illuminated specific facets of this relationship.
The picture which is emerging is by no means straightforward, but it appears that cell death in Huntington disease involves three processes:
Noting that we do not yet understand how these three processes fit together, Dr. Marcy MacDonald (Massachusetts General Hospital/Harvard University Medical School) proposed three models of cell death which highlighted the leading questions in HD science today:
It is expected that the year ahead will see significant progress toward answering these questions, and understanding how and why cell death occurs in Huntington disease.
Critical to continued progress will be new cell and animal models, and the Coalition for the Cure meeting underscored the vital importance of these research resources.
Only two and a half years have elapsed since Dr. Gill Bates announced the development of the first mouse model of HD. Yet numerous other cell and animal models, which complement the Bates mouse, have already been added to the repertoire. Three recent examples are Dr. Marcy MacDonald�s �knock-in� mouse; Dr. Michael Hayden�s YAC (yeast artificial chromosome) mouse, which enables scientist to work in vivo with the full length version of the huntingtin protein; and Dr. Nancy Bonini�s (University of Pennsylvania) Drosophila or fruit fly model (see Horizon 91:1998), which opens exciting new possibilities for research.
Delivering new treatments to patients
Each new scientific development moves scientists closer to new forms of therapy for HD. And as these new interventions appear, the Huntington Study Group will form the bridge between the laboratory bench and the patient�s bedside.
The first meeting of the Huntington Study Group in April 1993 was attended by about 20 individuals representing 11 sites. The 1998 meeting was attended by more than 150 people representing 50 sites, including Vancouver, Edmonton, Calgary, Toronto, and Montreal. Under the dynamic leadership of Dr. Ira Shoulson of the University of Rochester, this international collaboration -- to which the Huntington Society of Canada has provided seed funding -- is moving rapidly forward in clinical studies of Huntington disease. Initiatives which are being pursued include:
The HSG meeting provided an opportunity for investigators to discuss these and other studies, to formulate priorities for the future, and to pursue projects under the auspices of a series of working groups. In addition, participants heard presentations from Dr. Steven Hersch on protein aggregates and from Dr. Marc Peschanski from the H�pital Henri-Mondor in Creteil, France on cell transplantation as a potential therapy for central nervous system disorders, including Huntington disease.
The Huntington�s community in Canada and around the world can draw much hope from the recent achievements of the international scientific and medical community. The future looks very bright indeed.
Protein balls and cell death in HD
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Groundbreaking Work in Brain Cell Regeneration
from Horizon 92, Spring 1999
If Huntington disease destroys brain tissue, why not just replace the dead cells with healthy ones? That�s the rationale behind brain cell implantation, and several recent discoveries have brought the possibility of transplant therapy one step closer to reality.
First, a little background.
The concept is simple. A tiny hole is drilled in the patient�s skull, a needle containing healthy cells is inserted through the hole, and the cells are injected into the areas of the brain where Huntington�s has killed off the patient�s own cells.
In theory, the implanted cells will grow and multiply, form connections with the existing brain cells, and eventually take over the function of the cells that have died. The difficult bit is ensuring that the implanted cells actually do this.
One popular approach has been to use brain cells from fetuses. Because these cells haven�t matured, they have the capacity to grow and specialize into the appropriate type of brain cell.
Several studies on animal models of HD have shown this can be done successfully (see Horizon 1998:90), and a few centres around the world have performed fetal brain transplants on individuals with HD. The Good Samaritan Hospital in Los Angeles reports that one year after surgery, patients did not exhibit any adverse effects, and showed some improvement in motor, behavioural and functional capacities.
But fetal tissue is not easy to obtain, and because it comes from aborted embryos, it raises a number of ethical issues. Thus, until recently, the possibilities for implantation therapy have been limited.
In the last few months, however, there have been a number of exciting discoveries that have created the possibility of generating large quantities of brain cells without relying on an ongoing supply of fetuses. Several of the discoveries centre on �stem� cells -- unspecialized cells in the human body that have the potential to become different types of tissue. Others focus on the ability of adult brain cells to regenerate -- contrary to long-held scientific beliefs.
So here�s a run-down of some recent announcements:
*****
Researchers from the University of Wisconsin-Madison have converted stem cells derived from a human embryo into bone, muscle, neural and gut cells and shown that these cells will grow and multiply indefinitely. This opens the door to the possibility of growing transplant tissue �from scratch� in a laboratory rather than relying on organ donors. Although this is an exciting step forward, the researchers caution that clinical applications are years to decades away. �Although a great deal of basic research needs to be done before these cells can lead to human therapies, I believe that, in the long run, they will revolutionize many aspects of transplantation medicine,� says Dr. James Thomson of the Wisconsin team.
*****
In a similar feat, scientists from John Hopkins Medical Institution have isolated and identified human stem cells and shown that they could give rise to muscle, bone and nerve cells. Unlike the Wisconsin team, the Hopkins researchers used �primordial germ cells� -- cells that would eventually give rise to egg or sperm cells -- which are even less specialized than embryonic stem cells.
*****
Dr. Fred Gage of the Salk Institute for Biological Studies has shown that new brains cells are created in humans, even in individuals in their 70s.
Gage�s study examined terminal cancer patients who had undergone a diagnostic procedure that labels dividing cells. After the patients died, their brains were examined. All showed evidence of new cell growth.
According to Dr. Ben Barres, a neurobiologist at Stanford University Medical Center, �If even a few cells with the power to regenerate could be harvested from stroke patients and patients with brain diseases, doctors might be able to induce them to grow in a laboratory dish and then graft them back into the diseased area, in the same way some burn victims can be treated with grafts of freshly grown skin cells.�
*****
Swedish researchers recently discovered the site in the human brain that is the source of stem cells. They found evidence that ependymal cells, which line the fluid-filled ventricles of the brain, are in fact neural stem cells and give rise to a number of different types of cells, including neurons.
�Although there is much research that needs to be concluded before neurological stem cell therapy may reach the clinic, the identification of the stem cell in the adult brain and spinal cord is a significant leap that will facilitate the development of this field,� says Dr. Ann Marie Janson of NeuroNova, a Swedish company that plans to develop therapies based on stem cells.
*****
Evan Snyder of Harvard Medical School and his colleagues reported that they have cloned a human neural stem cell. Snyder and his colleagues then took the cloned cells and grafted them into different areas of a developing mouse brain. Following signals from their new environment, the human stem cells migrated to various areas of the brain and matured into the appropriate type of brain cell.
It is too early to tell if new cells function properly, but if they do, it opens up all kinds of possibilities for treating neurodegenerative diseases. Potentially, thousands of identical neural stem cells could be grown in a laboratory. Doctors could then �reseed� a brain with these cells, which would mature into whatever sort of brain tissue was needed.
The researchers now plan to study how well the human cells work in animals models of various diseases.
*****
At the Cedars-Sinai Medical Center in Los Angeles, Michel Levesque and Thomas Neuman are developing a process to remove brain cells from a patient, culture them in the laboratory, and re-introduce them into the patient�s brain.
�While it is true that brain cells don�t regenerate in situ,� says Levesque, �we have found that a very small number of cells, harvested and placed into a special environment, can be stimulated to regenerate, and that regeneration continues when the cells are re-introduced into the brain.�
Surgery is used to remove a small amount of brain tissue, which is then carefully cultivated in sterile incubators and bathed in various growth factors. Once the cells have grown and divided, they are ready to be implanted back in the patient.
A human protocol is scheduled to be completed in six months, at which point cell regeneration and re-introduction treatments can begin on patients with spinal cord injuries.
*****
What does it mean?
According to Levesque, the implications of being able to regenerate brain cells in patients with neurodegenerative diseases like Huntington�s are �enormous�. Doctors will no longer have to rely on tissue from aborted fetuses, avoiding a number of ethical dilemmas, and an enhanced supply of cells makes clinical trials much more feasible.
There are a lot of important work still to be done to demonstrate that brain cell implantation works, and even more to make such a therapy widely available -- things like how many cells to transplant at one time, exactly where to implant them, and how best to ensure they grow and make the proper connections -- but the early results are very promising.
For more detailed information:
Eriksson PS, E Perfilieva, T Bjork-Eriksson, AM Alborn, C Nordborg, DA Peterson, FH Gage. 1998. �Neurogenesis in the adult human hippocampus.� Nature Medicine 4(11): 1313-1317.
Flax JD, S Aurora, C Yang, C Simonin, AM Wills, LL Billinghurst, M Jendoubi, RL Sidman, JH Wolfe, SU Kim, EY Snyder. 1998. �Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes.� Nature Biotechnology 16(11): 1033-1039.
Brustle O, K Choudhary, K Karram, A Huttner, K Murray, M Dubois-Delcq, RD McKay. 1998. �Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats.� Nature Biotechnology 16(11): 1040-1044.
Johansson CB, S Momma, DL Clarke, M Risling, U Lendahl, J Frisen. 1999. �Identification of a neural stem cell in the adult mammalian central nervous system.� Cell 96(1): 25-34.
Shamblott MJ, J Axelman, S Wang, EM Bugg, JW Littlefield, PJ Donovan, PD Blumenthal, GR Huggins, JD Gearhart. 1998. Derivation of pluripotent stem cells from cultured human primordial germ cells.� Proceedings of the National Academy of Sciences USA 95(23): 13726-13731.
Thomson, JA, J Istkovitz-Eldor, SS Shapiro, MA Waknitz, JJ Swiergiel, VS Marshall, JM Jones. 1998. �Embryonic stem cell lines derived from human blastocysts.� Science 282(5391): 1145-1147.
Kendall AL, FD Rayment, EM Torres, HF Baker, RM Ridley, SB Dunnett. 1998. �Functional integration of striatal allografts in a primate model of Huntington�s disease.� Nature Medicine 4(6): 727-729.
Kopyov OV, S Jacques, A Lieberman, CM Duma, KS Eagle. 1998. �Safety of intrastriatal neurotransplantation for Huntington�s disease patients.� Experimental Neurology 149: 97-108.
Fruit flies make good models
from Horizon 91, Winter 1998
by Dr. Nancy M. Bonini, University of Pennsylvania
What do fruit flies have in common with Huntington disease? According to our latest research, it may be quite a bit.
It turns out that humans share a lot in common with fruit flies. Fruit flies have a complex brain, capable of learning, memory, and other tasks, just like us. Flies share almost all of their genes with us as well, with some of them being so similar to human genes that they are nearly identical.
The advantage to using fruit flies to study genetics is that they grow and reproduce quickly (developing from egg to fly in about ten days), so researchers can grow large numbers of them easily. What that means for diseases like Huntington's is that if it's possible to create flies with a polyglutamine repeat disease, it will be possible to use the flies to screen rapidly for drugs that can stop the disease, or for other genes that can prevent the toxic effects of the disease proteins.
In our lab, we took the human gene that causes a polyglutamine repeat disease similar to Huntington's and put it into flies. We used the human gene for Spinocerebellar Ataxia type-3 (also called Machado Joseph disease) -- one of eight or so human diseases of the same type as Huntington disease. By putting the human disease gene into the fruit fly Drosophila, we were able to determine whether the mechanisms of polyglutamine repeat disease were present in fruit flies.
In our experiments, we created two groups of flies. In one group we expressed a normal protein with a normal polyglutamine repeat. In the other group, we expressed a mutant protein with an expanded polyglutamine repeat like that found in Huntington disease. Whereas the normal protein had no effect at all, the protein with the expanded polyglutamine repeat caused degeneration of neurons remarkably similar to that seen in human brain cells. Like the human disease, the degeneration began relatively late in life and became progressively worse as the flies aged.
The flies also exhibited another feature of the human disease: abnormal balls of protein, known as �aggregates� or �nuclear inclusions�. Researchers have found that in humans with polyglutamine repeat disease, the mutant protein clumps together to form balls, usually within the nuclei of the cells. These balls of protein are thought to be toxic to the cells, eventually causing or contributing to their death.
In fruit flies, as in humans, the mutant protein with the expanded polyglutamine formed balls of protein in the nucleus which became larger and larger with time. Eventually, the neurons began to degenerate, and ultimately died.
These studies show that the human disease proteins, when expressed in flies, can cause neurodegeneration with features strikingly reminiscent of those seen in humans with polyglutamine repeat disease: the neurons are born fine, but then undergo slow, progressive degeneration, with the protein accumulating abnormally within the cells, forming nuclear inclusions.
The similarity indicates that at least some of the mechanisms by which these disease proteins cause neural degeneration in humans are also found in flies. This means that it is possible to use the flies, which are much more available and more easily manipulated than humans, to learn about how these disease proteins cause neural degeneration.
In addition, the flies can be used to find ways to slow or prevent the disease altogether. Once possible treatments are found in flies, they can then be tested for ability to slow or stop the disease in transgenic mouse models, and eventually humans.
We have already found that the abnormal protein balls recruit other proteins into the aggregates, a process that has also been observed in human disease tissue and other transgenic models. These recruited proteins include other proteins that have a normal polyglutamine repeat within them. That means that the aggregates may be recruiting other proteins that are critical to the neuron's normal cellular functions -- in effect, removing those proteins from their normal tasks within the cell. As an example of what can be done in flies, it is now possible to ask whether releasing the proteins from the aggregates will slow neurodegeneration.
Most efforts are being directed toward using the flies as a tool to screen for other genes that can slow or stop the degeneration. To do this, we are making new mutations in fly genes, then crossing those flies to the flies bearing the human disease protein. Most of the flies in the next generation show the same degeneration as their parents, but a few flies do not, despite the fact that they still have the disease proteins. These healthy flies must have mutations in other genes that are preventing the effects of the toxic protein.
The goal is then to find out the identity of the mutated �suppressor� genes that are blocking the toxic protein, first from flies and then from humans. In this way, we hope that the common fruit fly can provide us with new ways to slow, and hopefully prevent altogether, neurodegeneration caused by diseases like Huntington's.
What it means:
A good animal model, such as mice or fruit flies, gives scientists an important tool for studying the development of HD and the process of brain cell death that occurs in the disease. Once drugs and other therapies are developed, they can be tested on the animal model to make sure they are safe and effective before they are used on humans.
For more detailed information:
Warrick JH, HL Paulson, GL Gray-Board, QT Bui, KH Fischbeck, RN Pittman, NM Bonini. 1998. �Expanded polyglutamine protein forms nuclear inclusions and causes neural degeneration in Drosophila.� Cell 93: 939-949.
Reddy PH, M Williams, V Charles, L Garrett, L Pike-Buchanan, WO Whetsell, G Miller, DA Tagle. 1998. �Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA.� Nature Genetics 20(2): 198-202.
And So Do Mice
from Horizon 91, Winter 1998
Scientists at the National Institutes of Health, the National Human Genome Research Institute (NHGRI), and the Vanderbilt University Medical Center have announced a better mouse model for Huntington disease.
By injecting the human gene for HD into mouse embryos, the researchers were able to create mice that mimicked the behavioural and pathological changes of HD as they matured.
According to William Whetsell, a neuropathologist at Vanderbilt University Medical Center, �This transgenic animal appears to be the most faithful model to study Huntington�s disease thus far. The course of presentation of the clinical symptoms very closely parallels that seen in patients with Huntington�s.�
The mouse embryos were placed into three different groups. The first group were injected with a normal HD gene, containing 16 CAG repeats. This group formed the control. The second and third groups received the mutated form of the gene: group number two received an HD gene with 48 CAG repeats, and the third group received a gene with 89 repeats. As the embryos developed, the genes became active.
Researchers found that the transgenic mice with 48 or 89 repeats exhibited the first symptoms of the disease 8 to 10 weeks after birth. The mice became hyperactive, running in circles and performing backflips. Later, they became progressively slower and more inactive and lost interest in their surroundings. Eventually they died. The symptoms were most severe in the group with 89 repeats.
Post mortem analysis of the mice with 48 or 89 repeats revealed loss of brain cells in the striatum and cortex -- areas of the brain that are typically affected by HD.
According to Dr. Danilo Tagle of the NHGRI, �These mice will be terrific models for examining the early events that occur in HD and how this ultimately leads to cell death.�
Cell Replacement Therapy Update:
The Cambridge Centre For Brain Repair
from Horizon 90, Fall 1998
In Cambridge, England, Dr. Stephen Dunnett and his colleagues at the Medical Research Council�s Cambridge Centre for Brain Repair are achieving some extremely promising results in their efforts to develop brain cell transplantation as a viable treatment strategy for Huntington disease.
In the June 1998 edition of Nature Genetics,1 Dr. Dunnett�s group reported good results in experiments with cell transplantation in a primate model. Embryonic cells from marmosets were injected into the putamen region of the brain of six adult animals. These animals exhibited dramatic improvement compared to controls.
More specifically, the marmosets which received the cell transplants experienced a recovery of motor skills -- as measured by means of the �staircase task�, which involves �reaching, grasping and retrieving pieces of sweet food from two series of steps� -- for up to nine months. Furthermore, the implanted cells were found to survive for up to 12 months in the absence of immunosuppression.
The precise placement of the grafts in the recipient brain, the investigators found, was extremely important to the success of the transplants.
All in all, says Dunnett, the recovery of skilled motor performance combined with graft integration into the host brain and good survival of the implanted cells suggests that we may be one step closer to a viable form of therapy for Huntington disease.
This work represents an important advance on studies to date in rats, and will doubtless encourage further efforts to achieve clinically-significant results in humans with Huntington disease.
Progress will depend on the successful interaction of experts in the scientific and clinical arenas. As suggested in a commentary in Nature Genetics, �it is important to realize that animal models of neurodegenerative disease mimic only some aspects of these disorders. This is precisely why there must be cross-talk between clinical and basic researchers. Discussion based on a wealth of knowledge accumulated both in the clinic and in the laboratory is crucial for successful treatment of patients with neurodegenerative diseases.�2 -- RM
1 Kendall AL, Rayment FD, Torres EM, Baker HF, Ridley RM, Dunnett SB. Functional integration of striatal allografts in a primate model of Huntington�s disease. Nature Genetics (June 1998).
2 Horellou P, Mallet J. Neuronal grants for Huntington�s disease. Nature Genetics (June 1998).
Huntington Study Group:
The CARE-HD Trial
by Mark Guttman, M.D.
from Horizon 88, Spring 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. More specifically, the process which leads to cell death is thought to be associated with the following problems:
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 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 placebos 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. 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, there is no proof that CoQ 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
from Horizon 88, Spring 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.
New technique for repairing brain damage
from Horizon 87, Winter 1997
In an announcement with exciting implications for the entire Huntington's community, scientists in England have revealed the outcome of more than a decade of research -- a promising new technique for repairing damage to the brain.
Dr. Jeffrey Gray and his colleagues at London's Institute of Psychiatry induced brain damage in rats -- damage which resulted in a host of memory and learning difficulties. After being injected with brain cells taken from mouse embryos, however, the rats staged a remarkable recovery, regaining the abilities they had lost.
The successful outcome of this project -- described in the November issue of the journal, Neuroscience -- represents a potentially revolutionary advance in treating brain damage like that caused by Huntington disease, and may hold out much more hope than other experimental techniques developed to date, mainly for Parkinson's disease.
Until now, it has been necessary to harvest large quantities of just the right type of fetal cells, at an opportune developmental stage. By contrast, the new technique allows for the needed cells to be grown, or cultured, in a laboratory setting.
Dr. Gray and his colleagues used neuroepithelial stem cells (NESCs) from mice -- these are progenitor cells, which are able to develop the same characteristics and play the same role as the brain cells which die as a result of Huntington disease.
Through the novel use of a cancer-related gene, which switches on only when subjected to temperatures below that of the body, Dr. Gray's group has found a way to culture huge numbers of cells suitable for implantation, while avoiding the ethical problems which have arisen from the use of fetal cells.
Another important feature of Dr. Gray's research is that the implanted cells moved to the site of damage within the brain. Having migrated to the correct location, the implants took on the traits and functions of the cells which had died.
This new technique could have dramatic implications for individuals with HD, but also for people suffering from Parkinson disease and Alzheimer disease -- and from damage caused by strokes.
Through a newly-established company, called ReNeuron, Dr. Gray and his
colleagues expect to pursue further animal studies as aggressively as possible;
and, contingent on the results, to move to clinical trials in humans within
the next three years.
--RM
| What is a stem cell?
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