January 03, 2006
Anti-Depressants Work
From the Washington Post:
The researchers found that the risk of attempted suicide was 60 percent lower in the month after treatment began and that it continued to decline. While the overall risk for suicide was higher for adolescents than adults, the reduction in risk was about the same for both groups. When the researchers specifically examined 10 of the newest antidepressants, such as Prozac -- the ones that have come under the most suspicion -- they found that the risk was even lower.
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November 30, 2005
FGF-2 Grows Brain Cells in HD Mice
This is exciting research news...
The mice, genetically engineered to develop HD, were treated with fibroblast growth factor-2 (FGF-2), a protein that has been shown to increase the growth of new blood vessels in human clinical trials. In the Buck study, the use of FGF-2 resulted in a 150 percent increase in new cells in the Huntington's mouse brain, compared to a 30 percent increase in wild type mice (non-genetically engineered). Treatment extended the lifespan of the affected mice by 20 percent; the animals also exhibited improved motor performance, decreased cell death and a reduction in the amount of toxic aggregates that typically form in the brains of those affected by HD.
The full press release:
Growth Factor Promotes New Neuron Growth and Increased Survival in Mice with Huntington's Disease
Buck Institute study shows potential for new avenue of treatment for incurable, hereditary brain disorder
Mice with Huntington's disease (HD) grew a significant number of new neurons and lived longer after treatment with a well known growth factor. The research, published the week of November 28, 2005 in the on-line edition of the Proceedings of the National Academy of Sciences (PNAS), highlights a potential new therapeutic approach for a fatal, hereditary, degenerative brain disorder that affects approximately 30,000 Americans.
The mice, genetically engineered to develop HD, were treated with fibroblast growth factor-2 (FGF-2), a protein that has been shown to increase the growth of new blood vessels in human clinical trials. In the Buck study, the use of FGF-2 resulted in a 150 percent increase in new cells in the Huntington's mouse brain, compared to a 30 percent increase in wild type mice (non-genetically engineered). Treatment extended the lifespan of the affected mice by 20 percent; the animals also exhibited improved motor performance, decreased cell death and a reduction in the amount of toxic aggregates that typically form in the brains of those affected by HD.
"Efforts to understand and encourage neurogenesis, the growth of new neurons, comprise an emerging area of study as we explore potential treatments for neurodegenerative diseases," said Lisa Ellerby, PhD, lead scientist of the study. "In this case, the new brain cells migrated to the area of the brain affected by Huntington's disease and assumed the features of the type of neuron commonly lost in HD," said Ellerby. The FGF-2 was administered subcutaneously (by injection under the skin) to the mice, indicating that the protein can cross the blood-brain barrier, another factor that shows promise in the development of new therapies for the disease, according to Ellerby.
There is currently no effective treatment or cure for HD, which is typically characterized by involuntary movements and dementia. The disease slowly diminishes a person's ability to move, think and communicate. Those affected eventually become totally dependent on others for their care and usually die from complications such as choking, heart failure or infection. The disease is hereditary; each child of a person with HD has a 50/50 chance of inheriting the fatal gene. Approximately 200,000 Americans are believed to be at risk of developing HD, a disease that affects as many people as hemophilia, cystic fibrosis or muscular dystrophy. The symptoms of HD typically begin to appear in mid-life, although the progression of the disease varies among individuals and within the same family.
""We welcome the encouraging knowledge generated by Dr. Ellerby's study that FGF2 improves neurological function and longevity in HD transgenic mice," said Carl Johnson, PhD, Executive Director for Science, Hereditary Disease Foundation. " We look forward to further studies aimed at clarifying how FGF2 protects either through neurogenesis or through direct neuroprotection or both. These are promising studies and should be pursued," said Johnson.
Nancy Wexler, President of the Hereditary Disease Foundation added, "Despite recent advances in understanding the pathogenesis of HD, therapeutics that significantly slow or stop the disease are lacking. We encourage research that facilitates the discovery and development of therapies and cures for Huntington's disease".
Joining Ellerby as co-authors of the paper are Buck Institute scientists Kunlin Jin, MD, PhD; Michelle LaFevre-Bernt, PhD; Yunjuan Sun, MD; Sylvia Chen, PhD; Juliette Gafni, PhD; Danielle Crippen, BA; Anna Loginova, MD; and David Greenberg, MD, PhD along with Christopher Ross, MD, PhD, of the Johns Hopkins University School of Medicine. The work was supported by grants from the National Institutes of Health, the Huntington's Disease Society of America, the Hereditary Disease Foundation and the Muscular Dystrophy Association.
The Buck Institute is an independent non-profit organization dedicated to extending the healthspan, the healthy years of each individual's life. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer's and Parkinson's disease, cancer, stroke, and arthritis. Collaborative research at the Institute is supported by genomics, proteomics and bioinformatics technology.
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October 20, 2005
NeurotrophinCell Moving Closer to Trials
Living Cell Technologies has announced they have filed a "Pre-IND" letter requesting a meeting with the FDA. This means they are planning to conduct clincal trials for this Huntington's Disease treatment and they are ready to talk with the FDA about applying for a "Investigation New Drug" (IND) study.
This would be for their NeurophrophinCell treatment that looks promising in repairing/reversing damage in the brain caused by Huntington's Disease.
Here's the press release:
Living Cell Technologies files Pre-IND Request Letter with FDA for its NeurotrophinCell Product
ASX Announcement – 20 October, 2005, Melbourne, Australia:
Living Cell Technologies Limited (ASX: LCT) today announced that it has filed a request for a Pre-IND Meeting with the FDA to seek guidance and feedback on the development program for its NeurotrophinCell product.
NeurotrophinCell (NtCell) is LCT’s injectable live cell product being developed for the treatment of patients with neurodegenerative diseases. NtCell is manufactured by LCT using natural porcine cells that are encased in a bio-polymer capsule developed from seaweed. The cells used are choroid plexus brain cells, which produce spinal cord fluid and a range of neurotrophins or growth factors, for the repair and function of the brain. The biocapsules act as an immune barrier, allowing for the cocktail of hormones to leave the capsule, but preventing the body’s immune system from rejecting the cells. No immunosuppression is required in the treatment.
LCT’s first targeted application of NtCell is Huntington’s disease.
Huntington’s disease is a devastating neurological disease that currently has no cure or treatment. It is an inherited disease that progresses rapidly with dementia and progressive movement difficulties. More than 1 in 100,000 people are affected by HD. Genetic screening can identify individuals that will ultimately suffer from HD.
The biocapsule cell treatment is administered intracranially through a catheter into the region of the brain predominantly affected by HD, known as the striatum.
“Our goal is to make sure that we have addressed all of the requirements outlined in the FDA’s Guideline on Xenotransplantation Products and other relevant guidance,” said Mr David Collinson, LCT’s Chief Executive Officer.
“The Pre-IND letter and associated information summary for NtCell represents a significant milestone for LCT. It indicates that LCT is on track with its goals and
milestones.”
Huntington’s disease currently has an annual cost to US healthcare at over US$2.5billion. NtCell has the potential to meet a $700m market opportunity.
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October 15, 2005
HD Researchers...Are You Paying Attention?
Turmeric, the Asian spice that makes curry yellow, not to mention French's mustard and Hindu priests' robes, has yet another life: It's a promising potential weapon against several cancers, Alzheimer's, cystic fibrosis, psoriasis and other diseases....At least a dozen clinical trials on humans are under way in the United States, Israel and England to test the safety and dosages of turmeric's main ingredient, curcumin...
The spice, which is a relative of ginger, comes from the stems of the root of a large-leafed plant widely grown in Asia, especially in the province of Maharashtra in southwest India. The stems are boiled, dried and crushed to a powder with a bitter woody taste that's widely used as a spice and in folk medicines to cure stomach ailments and skin lesions...
It's been demonstrated in animals to protect the liver, inhibit tumors, reduce inflammation and fight some infections. Curcumin has both antioxidant and anti-inflammatory properties, according to researchers, and may help lower cholesterol.
And the kicker...
A report in the Journal of Biological Chemistry in December found that in mice injected with a chemical that mimics Alzheimer's, curcumin reduced by half the buildup of knots in the brain called amyloid plaques, which have been linked to Alzheimer's.
Some one is (though I'm not finding studies that have been published):
Yet in another separate study, Marie-Francoise Chesselet, chair of the department of neurobiology at the David Geffen School of Medicine and Miriam Hickey, a postgraduate researcher, is studying the effects of curcumin on Huntington's Disease.Huntington's Disease is characterized by an abnormal genetic mechanism which results in accumulation of the Huntington protein similar to the build-up of beta amyloids in Alzheimer's Disease.
"We found that if we give curcumin to mice they will have less aggregate in their brains, but we don't know yet if that will improve symptoms," Chesselet said.
Since curcumin acts as an antioxidant, it can be additionally beneficial to those with Huntington's Disease.
"It is also safe because people can ingest a lot of curcumin and it's not bad for them," Chesselet said.
"The advantage is that it can be given in the food without being injected," she added.
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October 06, 2005
Prozac Protective Against HD?
Melbourne, Australia, scientists say they've found Prozac not only helps depression caused by Huntington's disease, but also improves learning and memory.The researchers at the Howard Florey Institute, led by Dr Anthony Hannan, also found fluoxetine, the drug contained in Prozac, restores the brain's process of neurogenesis -- the birth of new neurons -- to normal levels, which delays the onset of the inherited fatal disease.
...Now that we've found fluoxetine improves memory problems, or dementia, as well as depression in mice with Huntington's disease, further research can be conducted to see if the drug has the same benefits in humans with the disease, Hannan said.
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September 29, 2005
Miraxion Update
Amarin has released a few more details on Miraxion (formerly LAX-101).
They've posted a corporate presentation on their website that includes these tidbits:
They've started enrolling people in their Phase III trial for treating Huntington's Disease. The enrollment is expected to end 2Q '06. The last person is expected to finish the trial in 4Q '06 and it looks like they'll be presenting the results to the FDA around 1Q '07. This would indicate that a FDA (hopefully) approval for use in HD would come by 3Q '07.
In this trial Miraxioni is being tested on HD patients with a CAG count less than 44 and with mild to moderate HD symptoms. Roughly two-thirds of all HD patients have CAG counts less than 44. They are measuring the results based on the patient's TMS-4 scores (Time course motor skills).
In the first Phase III trial, those on the placebo showed their scores increase (not a good thing) by 5.7%. However, those taking Miraxion showed a DECREASE in their scores (a very good thing) by 22.7% over the course of the 12 month study. As mentioned previously here, doses are 1 gram taken twice a day.
Amarin estimates there is a potential worldwide market for Miraxion of $500 million. A recent research report (which cannot be considered reliable) estimates that the Amarin could generate as much as $150 million in revenue per year from US sales (if approved).
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September 12, 2005
FDA Blesses HD Phase III Trial
The Miraxion/LAX-101 trial, TREND-HD, now has the FDA's green light. If you or a loved one has got mild- to moderate-HD then call 1-800-487-7671 to see about enrolling in this study. (More Info Here.)
Here's some key information from Amarin's press release:
The U.S. and European trials will be multi-centre, randomized, double blind, placebo –controlled studies of Miraxion at 43 sites in the U.S. and up to 28 sites in Europe. The trials are expected to involve a total of up to 540 Huntington’s disease patients with approximately 300 in the U.S. Phase III trial and approximately 240 in the European Phase III trial over a 6 month period. Patients in the U.S. trial will participate in a further 6-month extension period. ...The primary endpoint of the trials will be to determine whether Miraxion taken 2 grams per day (1gram twice daily) results in clinically and statistically significant changes in the Total Motor Score-4 subscale of the Unified Huntington’s Disease Rating Scale (UHDRS).
Here's the full press release:
Amarin Receives Special Protocol Assessment From FDA For Two Pivotal Phase III Clinical Trials For Miraxion In Huntingdon's Disease
LONDON, United Kingdom, 12th September, 2005 -- Amarin Corporation plc (NASDAQ: AMRN) today announced that it has reached an agreement with the U.S. Food and Drug Administration (FDA) under the Special Protocol Assessment (SPA) procedure for the design of two pivotal Phase III clinical trials of MiraxionTM (ultra-pure ethyl-EPA) in Huntington’s disease. The Special Protocol Assessment (SPA) is a process under which the FDA provides evaluation and guidance on clinical trial protocols for Phase III trials.
Rick Stewart, Chief Executive Officer of Amarin, commented; "Reaching agreement with the FDA on the trial designs is a positive development for Amarin. This is a major milestone for the company and we look forward to immediate enrollment in the U.S. trial."
The U.S. and European trials will be multi-centre, randomized, double blind, placebo –controlled studies of Miraxion at 43 sites in the U.S. and up to 28 sites in Europe. The trials are expected to involve a total of up to 540 Huntington’s disease patients with approximately 300 in the U.S. Phase III trial and approximately 240 in the European Phase III trial over a 6 month period. Patients in the U.S. trial will participate in a further 6-month extension period.
The Huntington Study Group (H.S.G.), based at the University of Rochester, will conduct the U.S. clinical trial on behalf of Amarin. The H.S.G. is a non-profit group of physicians and other health care providers from medical centers in the U.S., Canada, Europe and Australia, experienced in the care of Huntington’s disease patients and dedicated to clinical research of Huntington's disease. The European clinical trial will be conducted in collaboration with EURO-HD and ICON, a leading contract research organization (CRO). EURO-HD is a non-profit group of physicians and other healthcare professionals dedicated to the research and care of Huntington’s disease patients.
The primary endpoint of the trials will be to determine whether Miraxion taken 2 grams per day (1gram twice daily) results in clinically and statistically significant changes in the Total Motor Score-4 subscale of the Unified Huntington’s Disease Rating Scale (UHDRS).
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September 11, 2005
Old Drug Shows New Promise
From the University of California - San Francisco:
Old drug shows new promise for Huntington's Disease
Clioquinol, an antibiotic that was banned for internal use in the United States in 1971 but is still used in topical applications, appears to block the genetic action of Huntington's disease in mice and in cell culture, according to a study reported by San Francisco VA Medical Center (SFVAMC) researchers.
The study, led by principal investigator Stephen M. Massa, MD, PhD, a neurologist at SFVAMC, was reported in the August 16, 2005 issue of Proceedings of the National Academy of Sciences.
Huntington's disease is a hereditary, degenerative, and ultimately fatal disease of the brain that causes changes in personality, progressive loss of memory and cognitive ability, and a characteristic uncontrolled jerking motion known as Huntington's chorea. There is no known cure or effective treatment. A person who carries the mutant Huntington's gene may pass it on unknowingly because the disease often manifests in early to late middle age after the carrier's children have already been born.
During the course of the disease, the Huntington's gene causes the production of a toxic protein, mutant huntingtin, in neurons (brain cells). Eventually the protein kills the neurons, causing the disease's degenerative effects.
In Massa's study, Clioquinol appeared to interrupt the production of mutant huntingtin. In the first part of his study, Massa and his research team tested the effect of Clioquinol on neurons in cell culture that contained a form of the mutant Huntington's gene. "We found that not only did cells look better and survive a bit longer when exposed to the drug, but they also seemed to make less of the toxic protein," observed Massa, who is also a clinical assistant professor of neurology at the University of California, San Francisco (UCSF).
Based on the in vitro results, Massa decided to test the drug in vivo, on mice bred to express the toxic huntingtin protein. The mice were given approximately 1 milligram of Clioquinol per day in water. After eight weeks of treatment, they had accumulated four times less toxic protein in their brains than control mice given water alone. The experimental animals lived 20 percent longer than the control animals, did better on tests of motor coordination, and had less weight loss.
"It's a limited study, in that we used the same drug dose on all the animals as opposed to comparing different doses, but fairly convincing," Massa concluded. "Together, the in vitro and in vivo results suggest that Clioquinol has an effect of decreasing the symptoms of Huntington's, its pathology, and perhaps even the actual production of the toxic protein."
However, he noted, "the drug's mechanism of action remains unclear." The clearer the mechanism of the drug, he explained, the better the chance that researchers might eventually be able to create a medication that is both safe and effective.
Like some other antibiotics, Clioquinol is known to be a chelator -- that is, it binds metals in body tissues, particularly copper and zinc, and removes them when it is excreted. Massa and other researchers believe that this chelation effect may interfere with production of the mutant huntingtin protein in some way. "But there are still a couple of explanations we need to rule out," he said.
To that end, Massa's next studies will involve the creation of an in vitro system in which toxic and non-toxic forms of huntingtin are made in the same cell. He and his team will then evaluate the effects of Clioquinol on several phases of protein synthesis within the cell. Massa hopes these experiments will confirm initial indications that Clioquinol preferentially interferes with synthesis of the toxic form of the protein. "Then we can move on to trying to isolate the actual mechanism of the drug," he predicted.
"However," Massa cautioned, "the record of successfully translating drugs from animal to human use is not good."
Clioquinol has shown promise as a potential treatment for Alzheimer's disease in recent studies in mice and humans. Apparently through chelation, it interferes with the creation of beta-amyloid plaque in the brain, which has been implicated in the progression of Alzheimer's symptoms.
Currently, Clioquinol is banned for internal use in many countries because of its side effects. In Japan in the late 1950s and 60s, the drug was found to cause a neurologic condition called subacute myelo-optico-neuropathy (SMON), with symptoms including visual loss, muscle weakness, and numbness, in several thousand people. However, noted Massa, the doses given in current clinical trials are much smaller than were commonly prescribed in Japan. In addition, he explained, it has been found that vitamin B12, when taken along with the drug, protects against its potential toxic effects.
Co-authors of the study were Trent Nguyen, PhD, and Aaron Hamby, BS, of SFVAMC and UCSF.
###
The research was funded by a grant from the U.S Department of Veterans Affairs.
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September 04, 2005
Vitamin E
The vitamin acted as an antioxidant in the mice, slowing the ageing process,” Boveris explains. They found that the mice that had received vitamin E showed reduced levels of free radical mediated reactions and oxidative damage in their mitochondria, the cell’s power packs, than other mice.“Normally in ageing there is an increase in products of oxidation, but the mice on vitamin E actually showed a reduction. And the protective effects were particularly noticeable in the brain,” Boveris says. He admits that he has increased his personal intake of the vitamin to 400 mg per day.
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June 27, 2005
Learning More On Protein Clumps
In recent months scientists figured out that the protein clumps we see in cells due to HD are part of the cell's protective mechanism. A study funded by the Medical Research Council has learned more which will help in developing effective treatments. From the press release:
The new research...has concentrated on tiny molecular motors called dyneins, which are known to be important for moving proteins around inside nerve cells. The researchers found that dyneins play a crucial role in the delivery of toxic proteins to the waste disposal units of cells. When dyneins are defective or absent, this waste disposal system is stalled, clumps of proteins appear, and cell function is compromised.The study found that failure of the dynein system causes the degeneration in a form of motor neuron disease, and that it is also involved in other conditions such as Huntington's disease. ... Enhancing the degradation of these protein clumps has the potential to delay the onset of, or even reverse, this group of diseases. This might be exploited in new approaches to prevention or therapy.
The full press release:
New clues to the causes of neurodegenerative diseases, with implications for motor-neuron and Huntington's disease
Scientists funded by the Medical Research Council (MRC), the Wellcome Trust, BBSRC and the EU have made an important discovery about the mechanisms underlying degenerative brain diseases. The findings, published in this week's edition of the science journal Nature Genetics, may have implications for therapeutic strategies for some forms of motor neuron disease, Huntington's disease and Alzheimer's.
Late-onset neurodegenerative diseases are a major health burden on the population, yet little is known about the chemical changes that trigger the degeneration of nerve cells. However, many of these diseases are characterised by accumulation, inside nerve cells, of clumps of toxic proteins. The new research - carried out at the Cambridge Institute for Medical Research, the MRC Mammalian Genetics Unit at Harwell and the Department of Genetics, University of Cambridge - has concentrated on tiny molecular motors called dyneins, which are known to be important for moving proteins around inside nerve cells. The researchers found that dyneins play a crucial role in the delivery of toxic proteins to the waste disposal units of cells. When dyneins are defective or absent, this waste disposal system is stalled, clumps of proteins appear, and cell function is compromised.
The study found that failure of the dynein system causes the degeneration in a form of motor neuron disease, and that it is also involved in other conditions such as Huntington's disease. It also provided further evidence for the idea, pioneered by the same group of scientists, that a key factor in the severity of these diseases is the rate at which these toxic clumps of protein can be removed. Enhancing the degradation of these protein clumps has the potential to delay the onset of, or even reverse, this group of diseases. This might be exploited in new approaches to prevention or therapy.
The lead scientist, David Rubinsztein of the Cambridge Institute for Medical Research, said:
"These findings provide us with real insight into the molecular basis of certain motor neuron diseases and the mechanisms by which toxic proteins accumulate and are broken down. They also contribute greatly to our understanding of possible therapeutic strategies for these diseases."
Journalists should credit the MRC as a source of this story
For further information, or to arrange an interview, please contact the MRC press office on 020 7637 6011
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June 16, 2005
Breakthrough In Growing Brain Cells
While politicians are busy arguing about embryonic stem cells we are seeing major advances in adult stem cell research.
cientists working in mice said they had found a way to identify master cells in the brain and grow them in large batches -- a potential way of helping patients grow their own brain tissue transplants.The scientists said they had found a process to make the cells multiply, which would be crucial in fighting degenerative brain diseases like Parkinson's and Huntington's.
...
These so-called adult stem cells could come from a patient himself so no donor and no immune system suppressing drugs would be needed.
...Writing in the Proceedings of the National Academy of Sciences, the researchers said they also found an efficient way to make the cells multiply.
"It's like an assembly line to manufacture and increase the number of brain cells," said Dr. Bjorn Scheffler, a neuroscientist at the University of Florida who led the study.
...
"As far as regenerating parts of the brain that have degenerated, such as in Parkinson's disease, Huntington's disease and others of that nature, the ability to regenerate the needed cell type and placing it in the correct spot would have major impact," said Dr. Eric Holland
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June 15, 2005
TREND-HD Study Now Enrolling
If you or someone you know has mild to moderate symptoms of Huntington's Disease and is over the age of 35, call the Huntington's Study Group at 1-800-487-7671.
They are enrolling for a new Phase III trial for Miraxion/LAX-101 called TREND-HD. In the last Phase III trial, those with a CAG count under 45 showed a 23% improvement after taking the drug for a year!
This study is being conducted at 43 locations in North America so there may be one near you. Those participating will either get Miraxion or a placebo the first six months. After that, all participants will get Miraxion the following six months. For more information visit the Huntington's Study Group website. You can also read Amarin's press release below:
Amarin Announces Commencement Of Recruitment By Huntington Study Group For Miraxion Phase III Clinical Trial
LONDON, United Kingdom, June 14th, 2005 – Amarin Corporation plc (NASDAQSC: AMRN) today announced that the Huntington Study Group ("HSG") has commenced recruitment for the U.S. Phase III clinical trial of MiraxionTM in Huntington's disease.
The HSG will be conducting a clinical study (TREND-HD) of ultra-pure ethyl-EPA in persons 35 years of age or older who have mild to moderate Huntington's disease. The HSG is a worldwide, not-for-profit group of physicians and other clinical researchers who are experienced in the care of Huntington's disease patients and dedicated to clinical research in Huntington's disease.
Huntington's disease is an inherited disease of the brain that usually begins between the ages of 30 to 50, and includes motor, cognitive and behavioral signs and symptoms. While there are medications to help relieve some of the disease symptoms, there is no known treatment to slow the progression of Huntington's disease, which affects about 30,000 people in North America.
Miraxion is thought to stabilize nerve cell membranes and improve neurological functioning, although the exact mechanism of action is not currently known. An earlier trial in subjects with Huntington's disease indicated that Miraxion at 2 grams daily was well tolerated over 12 months. This current trial is designed to determine the effect of this daily dose of Miraxion on motor (movement) signs and symptoms of Huntington's disease.
The current 12 month study includes a 6 month placebo controlled phase with research subjects being randomly assigned to receive either Miraxion (2 grams total daily dose) or a matching placebo. This will be followed by another 6 month observation phase in which all participants will receive Miraxion. Researchers at 43 sites in the United States and Canada will each enroll approximately 7-8 research subjects with early signs of Huntington's disease who are independently ambulatory (walking) and fully self sufficient in activities of daily living, such as eating, dressing and bathing.
There is no cost to participate in the study. Participants will be followed as "out-patients" at regular intervals for 12 months. Individuals with mild to moderate Huntington's disease who are interested in participating in this study should visit the Huntington's Study Group website at: www.Huntington-Study-Group.org or call the toll free number +1 (800) 487 7671.
Rick Stewart, chief executive officer of Amarin, commented; "commencement of recruitment to the Phase III clinical trial for Miraxion is a major milestone for Amarin. An immense amount of energy and dedication has been expended by all involved to achieve this significant objective."
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April 28, 2005
This Could Be Big
From the University of Wisconsin-Madison:
Shedding new light on brain-related diseases, UW-Madison scientists Jeffrey Johnson and Marcus J. Calkins have discovered a way to "re-engineer" the brain that may defend against such diseases as Alzheimer's, Parkinson's and Huntington's diseases. Johnson's team is pioneering a procedure that prevents oxygen from building up to toxic levels in the brain. ...The team transplanted cells with high levels of Nrf2 into the brains of mice. The mice were then exposed to toxins that mimic the destructive effects of Huntington's disease. The Nrf2, for the most part, protected the mice from toxicity.
Better yet, a single transplanted cell seemed to have a proximity effect--the toxicity defense spread into neighboring cells. This promising defense could lead to an effective surgical procedure for humans, but Johnson claims that a non-invasive drug may come sooner.
"We've screened over a million molecules that activate the [Nrf2] pathway," Johnson said. "I'm hoping a drug [that could be tested on humans] could be ready in two years." ...
If an effective Nrf2-activating drug were available, those anticipating Huntington's could prevent it entirely. With better detection methods for neural illnesses such as Alzheimer's, Parkinson's and Lou Gehrig's diseases, the fatal effects of these diseases could also be negated.
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April 07, 2005
Another Potential Treatment For HD
The group performed a genetic experiment known as a loss-of-function suppressor screen, which searches for genes that, when switched off, reduce the toxic effects of the mutant protein associated with Huntington's. One of the genes they identified encodes an enzyme, called KMO, that has been previously implicated in the disease. The enzyme functions in a metabolic pathway that is activated at early stages of the disease in people with Huntington's, as well as in animal models of the disease."The nice thing about this finding is that there is a chemical compound available that inhibits KMO activity," said Dr. Paul Muchowski, assistant professor of pharmacology at the UW, who led the study. "We're in the midst of testing that compound in a mouse model of Huntington's disease."...
In addition to finding a potential drug target for future Huntington's treatment, the study by Muchowski and his colleagues could take research on the disease in a new direction: towards microglial cells, which are immune cells in the brain. Previous research has focused exclusively on neuronal cells, but the enzyme KMO is found predominantly in microglial cells. Since inhibiting KMO activity has a direct effect on toxicity of the mutant protein associated with Huntington's, that could mean microgial cells are home to an important step in progression of the disease.
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April 01, 2005
Another Potential Treatment Option
Researchers have found that an enzyme that helps cells dispose of unwanted proteins may actually protect against a class of inherited brain disorders that includes Huntington's disease. ,,,"Then, we thought that maybe we could reveal a disease phenotype if we expressed normal ataxin-3 together with the pathogenic protein. Maybe we would see an enhancement or synergy of the pathology. But what happened, quite surprisingly, is that the normal ataxin-3 dramatically suppressed the disease. That says that the normal function of the pathogenic protein can help mitigate its own toxicity." ...
Importantly, when the researchers introduced ataxin-3 into fly models of other polyglutamine diseases, including Huntington's disease, they found a similar protective effect.
More at Medical News Today.
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February 04, 2005
Curry - It's Not Just For Breakfast Anymore
I was just kidding about the 'breakfast' part, but Jean Miller sends this piece she found from the UCLA newspaper on curry and Huntington's Disease. The upshot...curry seems to helpful in protecting the brains of those with Huntington's Disease.
I haven't seen the amounts that were used in the study...but if you're eating out tonight - Why not go for Indian food? A clip from the article:
et in another separate study, Marie-Francoise Chesselet, chair of the department of neurobiology at the David Geffen School of Medicine and Miriam Hickey, a postgraduate researcher, is studying the effects of curcumin on Huntington's Disease.Huntington's Disease is characterized by an abnormal genetic mechanism which results in accumulation of the Huntington protein similar to the build-up of beta amyloids in Alzheimer's Disease.
"We found that if we give curcumin to mice they will have less aggregate in their brains, but we don't know yet if that will improve symptoms," Chesselet said.
Since curcumin acts as an antioxidant, it can be additionally beneficial to those with Huntington's Disease.
"It is also safe because people can ingest a lot of curcumin and it's not bad for them," Chesselet said.
"The advantage is that it can be given in the food without being injected," she added.
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January 31, 2005
Promising Drug Treatment
This sounds interesting...
Drug treatment promising for halting Huntington's-related nerve deathDALLAS – Jan. 31, 2005 – Researchers at UT Southwestern Medical Center have discovered that drugs commonly used to treat psychiatric illnesses and blood disorders in humans may protect the brain cells that die in people with Huntington's disease, possibly delaying the onset and slowing the progression of the disease.
These findings, available online and in today's issue of Proceedings of the National Academy of Sciences, may offer new treatment options for Huntington's disease, which has no cure.
Huntington's disease is a neurological disorder in which the medium spiny striatal neurons, the nerve cells that control movement and certain mental functions die. Patients die within 10-15 years after onset of the disease.The disease is caused by a mutation in the gene that makes the protein huntingtin. The mutation creates a long chain of the amino acid glutamine at one end of the protein. The length of the chain directly correlates with age of onset of the disease, with longer chains leading to symptoms earlier in life.
In previous studies, Dr. Ilya Bezprozvanny, associate professor of physiology at UT Southwestern, established that one of the defects that leads to death of nerve cells with the mutant huntingtin protein is improper regulation of calcium due to errant signals in the cells. Calcium is inappropriately released from its storage area in the cells, and eventually the cells die.
"We have developed a model that links the mutation in huntingtin with degeneration of motor neurons," Dr. Bezprozvanny said. "The model connects all the dots between the Huntington's disease mutation, defective calcium signaling in the cell, and subsequent degeneration of medium spiny striatal neurons."
In the current study, using the medium spiny neurons of mice that carry a copy of the mutated human huntingtin gene, Dr. Bezprozvanny and colleagues found that treatment of the cells in culture with the drug enoxaparin prevented inappropriate calcium release, and prevented cell death. Enoxaparin is an anti-coagulant that is FDA-approved in humans for use in treating blood clots.
Because the signals that lead cells to die can come from multiple pathways, Dr. Bezprozvanny then determined which cell death pathway affected the nerve cells carrying mutant huntingtin. He found that the nerve cells' mitochondria, the parts of the cell that create energy, released a protein called cytochrome c through a pore just before dying. From other studies, it was known the drugs nortriptyline and desipramine, which are antidepressants, and trifluoperazine, an antipsychotic, block the mitochondrial pore through which cytochrome c and other death signals are released. By treating the mouse nerve cells containing the mutant huntingtin protein with these drugs, Dr. Bezprozvanny was able to block the nerve cells from dying.
The next step, according to Dr. Bezprozvanny, will be to work with other researchers to test these drugs in whole animal models of Huntington's disease, and see if cell death and loss of motor function observed in these models can be prevented.
In addition, the researchers would like to expand their drug search beyond molecules that block calcium release and the mitochondrial pore. "We're looking for drugs that will prevent the pathological association of mutant huntingtin protein with the calcium signaling proteins in striatal neurons," he said. "We have a nice model system set up where we can easily look for cell death of Huntington's disease neurons, so we can look for the most specific drug with the least side effects."
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Other UT Southwestern contributors to this study were Dr. Tie-Shan Tang, assistant instructor of physiology and Dr. Vitalie Lupu, postdoctoral researcher. In addition, Dr. Rodolfo Llinas of New York University School of Medicine, Dr. Bruce Kristal of Cornell University, and Dr. Michael Hayden of the University of British Columbia, who provided the mice used in the study, and members of their laboratories also contributed.The study was funded by the Robert A. Welch Foundation, the Huntington's Disease Society of America, the Hereditary Disease Foundation, and the National Institute of Neurological Disorders and Stroke.
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December 26, 2004
Making Headway
A very interesting and easy to read article on oligonucleotides and how they may be effective in treating Huntington's Disease. This article also references Tapestry Pharmaceuticals. An excerpt:
Parekh-Olmedo discovered that some of the oligonucleotides that Kmiec and his group synthesized seem to be able to break down the aggregate proteins that appear in Huntington's Disease, a degenerative neurological condition.This also may have implications for other neurological diseases, like Parkinson's or Alzheimer's.
Although it's in the early stages, the therapy is promising enough for Kmiec to have begun to collaborate with a doctor at Harvard, who will help test it.
"It just happened," Kmiec said of his discoveries. "We didn't expect it. We followed the data."
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November 28, 2004
Mithramycin and HD Brain Chemotherapy
Dr. Lavonne Goodman of HDDW sends along this commentary on the Mithramycin study. As is usual, this is a "must-read" for those in the HD community.
Mithramycin and HD Brain Chemotherapy
Drs’Robert Ferrante and Rajiz Ratan, with multiple collaborators, are lead authors of the recent article which details neuroprotective benefits of the drug mithramycin as found in “Chemotherapy for the Brain” (November 17 Journal of Neuroscience). Their elegant long story briefly summarized: Mithramycin extended survival of the HD R6/2 mouse longer than any other agent so far described. Likewise it improved motor performance more than any other agent. And most importantly, brain changes usually present in the R6/2 mouse were so much improved they were “essentially absent”. Though the authors use “comparatively large effect” as their careful language, these combined results are much better than for any other agent so far studied.
And, though mithramycin is not an easy drug to work with, it is already FDA approved. And accordingly the authors make the argument that mithramycin should be among the top priorities for testing in patients.
First: A Heartfelt Thank You
These researchers (and all those laid the groundwork to make this possible) are to be saluted for the long process that went first from scientific creativity, grant writing, the later through the long hours of laboratory work (that put this drug through a multitude of cell studies and more than a hundred HD mice) then through careful interpretation of results then finally to the report of this promising drug.
And this HD activist couldn’t agree more that it certainly makes good sense to promote this “best so far” drug for trials in HD people.
Next: A Heartfelt Ache
But, I’d go further: “Why hasn’t “best so far” gone farther than a thinking stage? The neuroprotective benefit of mithramycin (in combination with another drug gives even better survival numbers) in the R6/2 was known by these (and other HD research leaders) in early 2002. This data was not made public, but instead (presumably) the drug was taken back to the lab where attempts were made to elucidate molecular mechanism. The present article describes the many experiments done to show that it works (somewhere) far downstream in a broad neuroprotective way that remains to be defined.
From the research perspective, this is very good science. From the patient perspective it is downright exciting that researchers have found a drug that have virtually prevented nerve damage in the R6/2 mouse model. Of course a drug this good in the mouse model should be brought to clinical trial. The “heartache” part is that it was not brought to clinical trial closer to 2002. Is there an explanation that I have missed for why this drug is a better clinical trial candidate for HD people in 2005 than it was in 2002?
HD Needs “Sydney Farber” Docs
The Huntington’s community would benefit from docs like Sydney Farber who would do for HD what he did for childhood leukemia a generation ago. Sydney Farber wasn’t very popular with the traditional leukemia researchers of his day when he “bucked the system” and started small clinical trials in children with leukemia. But those same trials moved first successful treatments for childhood lymphocytic leukemia that began the success story of full treatment for this generation.
I bet an HD “Sydney Farber” type of doc would have taken a drug that looked as promising as mithromycin to a pilot clinical trial. But even if we had “Sydney Farber” docs (and I know we do), they don’t have a chance if information is withheld. Smart Docs can’t pick up the research ball and “run with it” if the researchers are doing “private “thinking” and don’t make promising results available to smart docs taking care of HD patients. And if the “Sydney Farber” docs don’t have a chance of picking up the treatment ball, then HD people have lost the game before the buzzer has sounded.
Maybe HD research is too good; maybe the researcher too powerful. It is the researcher, not the clinical docs, making (or not making) decisions on clinical trials for people. So it’s been back to the lab screening for the more perfect drug or homing in on molecular mechanism, etc. Good science for sure. But it is heartache for HD people that our disease has more drugs and fewer clinical trials than any other disease in the history of disease.
Thrilling research; suffering HD people. How good does a drug have to be before the powers (who are these people) that control HSG acts urgently? Though HD research may see HD “time” from the perspective of “large therapeutic window” HD people have a different perspective: The first year’s loss is devastating, the second year’s loss is devastating, and so on for the long, long duration of this illness.
Desperately Seeking . .
If a “Sydney Farber” doc would have had the chance to start closer to 2002, we wouldn’t still be at the stage of “thinking about thinking about” testing mithramycin in people: We would probably have had an answer. And maybe even a first treatment. More heartache: the same thing could be said for several other agents out there.
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November 27, 2004
NeurotrophinCell Update
Jean Miller has sent along the following on Living Cell Technologies promising treatment for Huntington's Disease. The timeframe seems overly optimistic to me, but the company says that if the current large-primate tests with Neurotrophincell go well they could be entering into Phase-I trials for humans next summer!
The details:
What did the trial involve?
The trial was conducted using a fairly standard rat model of Huntington's (The rats have quinolinic acid injected into the striatum (a part of the brain), which results in the rats displaying pathology and clinical presentation that mimics HD).
The rats were injected with either rat or piglet choroid plexus cell clusters (see attached abstract for details re: Choroid Plexus) encapsulated in alginate into the area immediately prior to inducing the lesions.
What were the results?
A remarkable prevention of the behavioural, pathological and clinical changes - around 80%. The animals recovered extremely well.
Where to from here?
The trials are being repeated in non-human primates first, using piglet choroid plexus - these should be completed by mid February 2005.
This is a necessary step to applying for regulatory approvals in order to begin Phase 1 human trials. How long these approvals take is uncertain. There are strong non-scientific prejudices against the use of animal cells, which may be difficult to overcome. In Australia we hope to hear from the regulatory body in December, as to whether or not they will be able to process an application.
Further research is also required to determine how long the treatment effect will last. The therapeutic cells are very hardy and last a long time (6 months) in artificial conditions (cell culture). The animal experiments that were conducted went for 6 weeks and the restorative effect remained for that time. It now needs to be determined if predictions can be made as to how long the treatment may last.
If the human trials are approved, what will they involve?
At present the trial would involve the injection of a small volume of encapsulated pig choroid plexus cells into the brain striatum of patients who are already experiencing severe symptoms of the disease. A small 'burr hole' would be made in the skull and a needle positioned by stereotactic means. An alternative might be to inject into the ventricles of the brain - this is yet to be determined.
What sort of time-frame are we looking at?
There are two stages. The company will know whether the treatment works or not in the larger (primate) animal model, hopefully by February 2005.
If it works, they will apply to do the human phase 1 study. The company is hopeful that phase 1 could be underway by the middle of 2005 - but this is in the hands of the regulators.
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November 25, 2004
Mithramycin - Read This
Thanks to HDLighthouse.org for this wonderful item!
Researchers have found that an already FDA-approved medication shows HUGE promise in treating Huntington's Disease. Dr. LaVonne Goodman's comments:
Mithramycin extended survival of the HD R6/2 mouse longer than any other agent so far described. Likewise it improved motor performance more than any other agent. And most importantly, brain changes usually present in the R6/2 mouse were so much improved they were “essentially absent”. Though the authors use “comparatively large effect” as their careful language, these combined results are much better than for any other agent so far studied.
Read the whole thing on HD Lighthouse's website.
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November 22, 2004
HD's Link To Other Diseases
I've said for some time that Huntington's Disease research, directly and indirectly, has advanced research for many other diseases. From an article on a recent study:
All of these diseases - Alzheimer's, Parkinson's, ALS, Huntington's - have the same unusual phenomena. Proteins - completely different proteins in each disease - assemble into ordered aggregates, amyloid fibrils, so that a vital organ, usually the brain, is crisscrossed by these structures,” Hall said. “This tells us that the problem has something to do with the general nature of proteins rather than with the specifics of the particular disease-associated proteins.”
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November 10, 2004
RNAi Takes Another Step Forward
They've now been able to lower cholesterol in animal tests with RNAi. Some tidbits from the latest article:
It ultimately could lead to a drug-like treatment for hereditary disorders such as Huntington's disease by injecting tailored snippets of RNA, DNA'S molecular cousin, to silence a specific gene. The approach also has promise for treating a range of diseases, including heart disease and cancer, that have genetic factors, specialists said. ...
The new study, published Thursday in the journal Nature, reports successful delivery of RNA pieces through the blood by chemically stabilizing them and attaching them to cholesterol molecules to help ease their entry into target cells. ...
RNA interference "has major potential for discovery and development of new medicines," said Nobel laureate Philip Sharp, a molecular biologist at the Massachusetts Institute of Technology and a co-founder of Alnylam. "It is the type of discovery that really only happens every decade or so."
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November 08, 2004
Eyesight & Huntington's Disease
Yes, Huntington's Disease can adversely affect vision. Researchers are finding the proof:
Fine-structural analysis and connexin expression in the retina of a transgenic model of Huntington's disease.
J Comp Neurol. 2004 Nov 8;479(2):181-97.
PMID: 15452853
Petrasch-Parwez E, Habbes HW, Weickert S, Lobbecke-Schumacher M, Striedinger K, Wieczorek S, Dermietzel R, Epplen JT. -Department of Neuroanatomy and Molecular Brain Research, Ruhr-University Bochum, D-44780 Bochum, Germany.
Elisabeth.Petrasch-Parwez@rub.de
Recent studies indicate that the visual system appears more frequently affected in polyglutamine diseases than expected previously. Here, we investigated retinal degenerations in adult transgenic R6/2 mice, a model for Huntington's disease (HD). Light microscopical analysis revealed retinal dystrophy all over the retina, with central areas showing major effects.
Electron microscopical analysis showed strong degenerations of outer and inner photoreceptor segments, shrinkage of photoreceptor cell somata, and signs of degeneration in photoreceptor terminals in the outer plexiform layer. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling showed hints of apoptosis. Mutant huntingtin and ubiquitin were expressed in all classes of retinal neurons, the pigment epithelium, and to a minor extent in neuropil structures.
For investigating possible links to functional impairments in the rod-cone pathway, expression levels of three connexins (Cx) were compared in R6/2 and wildtype mice retinae. In R6/2 mice, expression of Cx36, the major neuronal connexin in the retina, was slightly reduced in the outer plexiform layer, indicating affected photoreceptor terminals as detected at the electron microscopical level. In contrast, Cx45, a putative neuronal connexin in the retina, was remarkably reduced in the inner plexiform layer of R6/2 mice.
This result corresponded to fainter signals of Cx45 mRNA as documented by in situ hybridization and to a lower level of mCx45 cDNA as obtained by polymerase chain reaction after reverse transcription, suggesting functional deficits in spatial processing of Cx45-mediated gap junction coupling due to transgene-induced retinal degenerations. Thus, it is important to clarify the meaning of visual involvement in HD.
2004 Wiley-Liss, Inc.
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November 07, 2004
Celastrol
Check Out HD Lighthouse's article on celastrols. An excerpt:
"Heat shock protein 70 has been found to arrest neurodegeneration in a fruitfly model. Heat shock proteins got their name because they are produced when cells are stressed by heat or toxins; however, they have a maintenance role in cells as well, helping newly made proteins to fold properly (their chaperone function) and carrying old ones off for degradation.
Celastrol was found to induce heat shock protein 70 as well as 40 and 27 in a variety of cell types, including neurons. It also was found to be cytoprotective, inhibiting apoptosis (cell death) under conditions of severe stress. Because of these exciting results, research with the Bates HD mice will be starting soon. This is clearly a compound to watch."
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November 06, 2004
Autophagy
Researchers learning more every day:
A cell undergoing autophagy assembles tiny capsules called vesicles that surround and chew up parts of the cellular machinery from within. Autophagic vesicles have been seen in cells undergoing programmed cell death, but the evidence is not clear yet whether they're trying to protect the cell from apoptosis, or hastening its demise.
"Autophagy is the only way to get rid of damaged parts of the cell without trashing the whole thing. So in a nerve cell, for example, you'd want autophagy to correct problems without destroying the cell."
High levels of autophagic vesicles also have been noted in some forms of degenerative muscle disease, and in degenerative nervous system diseases like Huntington's, Parkinson's, Alzheimer's and ALS, (Lou Gehrig's disease). But it's not clear why the vesicles are accumulating. They may be building up because they aren't being used, or it may be that the distressed cells are producing more vesicles.
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November 05, 2004
Cannabinoids
There are so many "cautions" on this article, but I'll leave that for another time. Here's a piece on cannabinoids as a potential treatment for a variety of disease.
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November 03, 2004
HD Research Benefits Alzheimers & Parkinson's
Huntington's Disease research involves many fundamental processes that affect other diseases. The latest:
Research leads to one cause of Alzheimer's-like diseases
A team of scientists led by biology Prof. Richard Morimoto, former dean of Northwestern's Graduate School, recently made a key discovery in understanding the molecular processes of diseases such as Alzheimer's, Parkinson's and Huntington's. Such neurodegenerative diseases break down the body's nervous tissue.
While studying toxic proteins involved in Huntington's disease, the team discovered that a disease-causing protein partially inhibits proteasome, which normally eliminates damaged proteins from cells. These harmful proteins allow damaged ones to reside in the cell, where they can form toxic clumps that destroy cell function.
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October 26, 2004
Neural Stem Cell Research
Science Blog has an interesting article on the promise of stem cell treatments for various diseases, including Huntington's Disease. The excerpt below talks about the success of neural stem cells in Parkinson's and Huntington's Disease...
In other work, scientists at the University of Wisconsin at Madison have rescued the cells that are attacked by Parkinson's disease and Huntington's disease. Both diseases are movement disorders that specifically kill off neurons that use the neurotransmitter dopamine. ''Replacement of dopamine neurons using embryonic stem cells has long been the holy grail,'' says Clive N. Svendsen, PhD. ''But stem cell transplantation can introduce serious problems, including tumors and dyskinesia, or impaired, sporadic muscle movements.''
So instead of replacing the dopamine cells, she and her colleagues found a way to provide support to neurons under attack. Dopamine neurons require glial-derived neurotrophic factor (GDNF) to survive. So even if stem cells could be successfully introduced to an adult brain, chances are they would require GDNF. Yet in an earlier study, Berhstock's group showed that GDNF alone could restore function to the neurons affected by Parkinson's.
...
''We thought real cells might better deliver GDNF to the brain,'' Svendsen says. The group considered using embryonic stem cells, but realized they might lead to tumors and dyskinesia, so they tried neural stem cells. These cells don't have quite the enormous potential of embryonic stem cells, but they can become astrocytes, a type of glial cell found in the brain. Best of all, they do not induce tumors.
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October 23, 2004
NeurotrophinCell Press Release
Here's Living Cell Technologies official press release on their announcement that NeurotrophinCell reduced cell damage 86% in their Huntington's Disease model.
The press release:
LCT treatment protects the brain from damage by Huntington's disease
22 October 2004, Australia:
Living Cell Technologies (ASX: LCT), has today released results of pre-clinical studies demonstrating that its specialised therapy protects nerve cells in the brain from damage caused by conditions similar to Huntington's disease. Animals receiving LCT's treatment, NeurotrophinCell, showed 86 per cent less damage to the brain and showed dramatically improved use of their limbs.
This is the first time that technology of this kind has been proven in a controlled pre-clinical setting to prevent the degeneration of the brain due to Huntington's disease-like conditions. The details and data are to be presented at the Society for Neuroscience annual conference in San Diego this weekend and published in NeuroReport in November.
Huntington's disease is a devastating and fatal neurodegenerative condition that can be diagnosed very early in life, before symptoms appear, but for which there is no cure or intervention strategy available.
"These findings have major implications for enabling treatment of human neurodegenerative diseases such as Huntington's and stroke," said Dr. Dwaine Emerich, VP of Research at LCT BioPharma Inc1 and co-author of the paper detailing the findings.
"What we have done is successfully implant new choroid plexus cells (the cells that produce cerebral spinal fluid and a number of factors important for the health and survival of the brain) thereby protecting specific areas of the brain from damage" continued Dr. Emerich.
In LCT's proprietary product, NeurotrophinCell, the choroid plexus cells are encapsulated in a clear capsule derived from algae. This encapsulation hides the cells from the patient's immune system yet allows the cells to receive nutrients and chemical signals necessary for functionality and survival."
"NeurotrophinCell has effectively shown the ability of LCT's technology, to protect brain tissue that would otherwise die, potentially forestalling or preventing the debilitating consequences of this disease," said Alfred Vasconcellos, LCT BioPharma's CEO.
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October 16, 2004
Minocyline Study - Neuroprotective
There are a whole host of things that can cause a 14-person study to give bad results. As a result, such a small study can never be considered to offer conclusive evidence. Having said that...
This two year study followed 14 HD patients as they took Minocycline. The purpose of the study was to determine if the drug protected the brain cells from the effects of Huntington's Disease. The answer appears to be 'yes'. Testing showed that the patients stabilized and even showed improvement in psychiatric symptoms.
Here's the study abstract:
Neuroprotection in Huntington's disease: a 2-year study on minocycline.
Int Clin Psychopharmacol. 2004 Nov;19(6):337-42.
PMID: 15486519 [PubMed - in process]
Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP.
Department of Psychiatry, Graz Medical University, Graz, Austria.
Huntington's disease (HD), a relentlessly progressive neurodegenerative disorder, is characterized by a clinical triad of psychiatric, cognitive and motor disturbances. The antibiotic minocycline, a caspase inhibitor exhibiting antiapoptotic properties, has been shown to prolong survival in the transgenic mouse model of HD.
We administrated minocycline to 14 patients with genetically confirmed HD. The patients were psychiatrically, neurologically and neuropsychologically evaluated at baseline, and after 6 and 24 months of treatment, using the Unified HD Rating Scale and a neuropsychological test battery. After 12 months, three patients were lost to follow-up so that 11 patients were analysed at the endpoint.
Minocycline was well tolerated. Unlike the expected natural course of HD, patients exhibited stabilization in general motor and neuropsychological function at endpoint, after improving in the first 6 months. Moreover, we found a significant amelioration of psychiatric symptoms that was not apparent after the first 6 months.
In detail, the Mini-Mental State Examination, the Total Motor Score, the Total Functional Capacity Scale and the Independence Scale, as the most prominent scales in HD, were stabilized after 3 years of treatment. Our results confirm previous animal studies and indicate a neuroprotective effect of this agent in HD. A long-term, double-blind, placebo-controlled trial appears highly warranted for definitively establishing the value of minocycline in HD.
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October 14, 2004
Another Press Release On The Neural Cell Findings
Here's another press release, this time from the Gladstone Institute of Neurological Disease, on the neural cell study:
Gladstone researchers resolve key Huntington's disease mystery in Nature cover story
Use innovative robotic microscopy to image molecular processes in neurons
A mystery long associated with Huntington's disease has been resolved by a team of researchers at the UCSF-affiliated Gladstone Institute of Neurological Disease, thanks to a specially designed microscope that allows researchers to track changes in cells, including those associated with neurodegeneration, over long lengths of time.
As reported in the cover story in the current issue of Nature (Oct. 14, 2004), the team determined that abnormal deposits of mutant huntingtin protein, which appear in the brains of all Huntington's disease patients, aren't the cause of neuronal death. Scientists know that mutant huntingtin protein is responsible for the disease, but they have not known in what form it wreaks its havoc. They haven't known, for instance, whether the abnormal deposits of the protein, known as "inclusion bodies," were, themselves, causative, protective or incidental to the disease. In the current study, the Gladstone team determined that inclusion bodies are a beneficial coping response, possibly sequestering mutant huntingtin protein, thereby reducing levels of the protein elsewhere in the neuron, and thus prolonging neurons' survival.
The finding suggests that mutant huntingtin protein inflicts its damage in some form other than as inclusion bodies, which are insoluble, or resistant to being dissolved in liquid. Investigators may now focus attention on the possibility that the real culprit is a more soluble form of mutant huntingtin spread throughout the neuron, or nerve cell, among other theories.
"We are very excited by these results," says lead investigator Steven Finkbeiner, MD, PhD, an assistant investigator at the Gladstone Institute of Neurological Disease and assistant professor of neurology and physiology at University of California, San Francisco (UCSF). "They will help us to better focus efforts to identify the mechanisms by which the huntingtin protein causes Huntington's and may add to the understanding of other neurodegenerative disorders."
Traditionally, scientists have tried to illuminate the role of the mutant protein within neurons by taking one-time snapshots of individual cells, a slow process that doesn't allow researchers to track changes in any given cell over time. Beyond slowness, a fundamental problem with this conventional approach is that the snapshots are not only taken at different times but also each image is of a completely different population of cells than the other. Scientists have tried to use these images to piece together theories of disease progression, but have had great difficulty interpreting their results because of the lack of continuity between images.
To address these issues, Finkbeiner developed an automated microscope that allows researchers to track changes in individual neurons over time, thus enabling them to identify factors that predict the fate of the cell.
"With this new technology, we can examine neurons well before they die, make measurements of whatever we wish, and then determine which factors have prognostic value, whether they predict survival or neurodegeneration, and how strong the prediction is. This is a powerful new way to guide our investigation into the underlying mechanisms of neurodegeneration," he explains.
In their study, the scientists introduced fluorescently tagged versions of huntingtin protein into neurons. They then used the robotic microscope to monitor the accumulation of the abnormal protein into inclusion bodies, as well as to monitor the levels of intracellular huntingtin protein, and the length of survival of thousands of individual cells over time. Sophisticated statistical techniques for survival analysis were then used to determine whether a particular abnormality predicted early death and might be pathogenic, or predicted longer survival and might be beneficial.
The findings suggest, says Finkbeiner, that inclusion bodies lock up mutant huntingtin in other parts of a cell and keep it from interfering with the rest of the neuron in ways that can trigger cell death. These findings provide evidence that inclusion bodies in Huntington's disease, and possibly other neurodegenerative diseases, help neurons cope with toxic proteins and prevent neurodegeneration.
The approach developed by the Finkbeiner group -- combining the use of a robotic microscope with powerful techniques of statistical analysis -- could also be used in studies of other neurodegenerative diseases characterized by the accumulation of cellular proteins, including Alzheimer's disease, prion diseases, amyotrophic lateral sclerosis (Lou Gehrig's disease), Parkinson's disease, and a group of nine so-called polyglutamine diseases of which Huntington's is the most widely known.
Moreover, the approach could be used to measure the nature and magnitude of the relationship between any two biological events within a cell that are separated by time. With this tool, researchers can begin to answer such fundamental questions as:
Is there a relationship at all, or are the two events simply coincidental?
If there is a relationship, is one event possibly the cause or the effect of the other?
If it is a cause, is it a minor determinant or a major one?
These are questions that recur in all aspects of cell biology.
As Professor Harry T. Orr of the University of Minnesota explains in a companion Nature commentary, "In the long term, strength of this study lies in the approach itself. The capability to determine if a cellular feature of a disease is pathogenic, beneficial or merely incidental to a disease process will be of considerable advantage for understanding disease mechanisms. Will the results reported here end the debate on the pathogenic role of inclusion bodies in the polyglutamine diseases? If not, one wonders what would."
Huntington's disease is a hereditary, progressive neurodegenerative disorder characterized by the development of emotional, behavioral, and psychiatric abnormalities, loss of intellectual and cognitive functioning, and motor disturbances. Although symptoms typically become evident during the fourth or fifth decades of life, the age at onset is variable and ranges from early childhood to the 70s or 80s. It's named for the American physician who initially described the condition in 1872.
The paper, "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death," was co-authored by Finkbeiner and fellow GIND staff members Montserrat Arrasate and Siddhartha Mitra; Erik S. Schweitzer of the Brain Research Institute, UCLA; and Mark R. Segal of the Division of Biostatistics, UCSF. Primary support for this work was provided by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH). Additional support was provided by the National Institute of Aging within the NIH, and the J. David Gladstone Institutes.
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The Gladstone Institute of Neurological Disease is one of three research institutes of The J. David Gladstone Institutes, a private, nonprofit biomedical research institution affiliated with UCSF. For further information, visit www.gladstone.ucsf.edu/gind.
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October 13, 2004
NIH On The New HD & Neural Cell Findings
NIH Press Release on the new findings on HD & the inner workings of neural cells:
Study Using Robotic Microscope Shows How Mutant Huntington's Disease Protein Affects Neurons
Using a specially designed robotic microscope to study cultured cells, researchers have found evidence that abnormal protein clumps called inclusion bodies in neurons from people with Huntington's disease (HD) prevent cell death. The finding helps to resolve a longstanding debate about the role of these inclusion bodies in HD and other disorders and may help investigators find effective treatments for these diseases. The study was funded primarily by the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and appears in the October 14, 2004, issue of Nature1.
Inclusion bodies are common to many neurodegenerative disorders, including HD, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). The role of inclusion bodies in these diseases has long been controversial. Some studies suggest that they may be a critical part of the disease process, while others indicate that they may help protect the cells from toxic proteins or that they are merely bystanders in the disease process.
One problem in identifying how inclusion bodies influence disease is that researchers have been unable to track changes in individual neurons over time. "It was like viewing pictures of a football game and trying to imagine the score," says Steven Finkbeiner, M.D., Ph.D., of the Gladstone Institute of Neurological Disease and the University of California, San Francisco. "Much was happening that we couldn't see."
To overcome this problem, Dr. Finkbeiner and his colleagues wrote a computer program that allows a microscope to match images in a culture dish to images it has stored and to manipulate its controls to look at the same neurons over and over again — like time-lapse photography. This allowed the investigators to follow changes in a single neuron or a group of neurons over a period of days. They used this automated microscope to study neurons that contained a version of the huntingtin protein that causes HD. The huntingtin was fused to green fluorescent protein, a widely used marker that allows researchers to see where proteins accumulate.
Many neurons with the mutated HD gene died without forming inclusion bodies, the researchers found. The formation of inclusion bodies actually prolonged neurons' survival and lowered their overall risk of death. The rate of cell death was higher in neurons with larger gene mutations, but the death rate for each set of cells remained constant over time.
The researchers also examined the level of mutant huntingtin protein spread throughout the neurons, outside of inclusion bodies. They found that neurons with larger amounts of mutant huntingtin spread throughout the cell died more rapidly than cells with less of this protein. The amount of mutated protein decreased in other parts of the cell when inclusion bodies formed. Taken together, these findings suggest that inclusion bodies lock up mutant huntingtin and keep it from interfering with the rest of the neuron in ways that can trigger cell death.
These findings provide evidence that inclusion bodies in HD, and possibly other neurodegenerative diseases, help neurons cope with toxic proteins and avoid neurodegeneration. Many researchers have been working to develop ways of interfering with inclusion body formation as potential treatments for HD and other disorders. This study suggests that finding ways to remove mutant proteins diffused throughout the cell might be a more effective approach.
"This approach provides a way to connect cellular changes to fate," says Dr. Finkbeiner. The automated microscope system could be applied to sort out many important questions about how cellular changes or abnormalities affect disease, he adds. He and his colleagues are now planning studies to examine the role of proteasomes — enzyme-filled compartments that break down and recycle proteins — in HD.
The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation' primary supporter of biomedical research on the brain and nervous system.
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1 Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S. "Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death."Nature, October 13, 2004, Vol. 431, No. 7010, pp. 805-810.
Posted by Dave at 04:13 PM | Comments (0) | TrackBack
Rethinking Huntington's Disease
This study could have profound implications in the future of HD research. If this turns out to be true, this will help further focus research.
Read the article, but here's an excerpt:
He also points out that the aggregation of huntingtin might still play a detrimental role in the disease. But the extremely large protein clumps that form inclusion blobs appear to be a sign of cells fighting back, he says.
The result could change the development of HD therapy. Researchers are already looking for drugs that keep huntingtin from aggregating. But some of these drugs might prevent the formation of protective inclusion bodies while allowing the smaller – and possibly lethal - groups of huntingtin to form. "One prediction of ours is that some of these drugs could actually make the disease worse," he says.
Posted by Dave at 11:25 AM | Comments (0) | TrackBack
October 11, 2004
More On NeurotrophinCell
"This is the first time that technology of this kind has been proven in a controlled pre-clinical setting to prevent the degeneration of the brain due to Huntington's disease-like conditions,"...
The technology protects the cells from attack by the body's immune system.
This allowing them to produce several factors important to the health and survival of the brain.
Alfred Vasconcellos, chief executive of Living Cell Technologies's US operation, LCT BioPharma, said the work had shown "the ability of LCT's technology to protect brain tissue that would otherwise die, potentially forestalling and preventing the debilitating consequences of this disease".
LCT chief operating officer Roger Coats said the company had another 12 months or so of pre-clinical trials to complete before moving into clinical trials.
Posted by Dave at 10:20 AM | Comments (0) | TrackBack
October 05, 2004
Stem Cell Treatment For HD
ReNeuron, a British stem cell research and development company, has an HD stem cell therapy they intend to enter into Phase I trials.
The therapy, ReN005, is derived from the same stem cell line as their stroke therapy 'ReN001'. They would be surgically implanted into the brain and, hopefuly, produce dopamine. This potential treatment is not a 'cure', but it has the potential of possibly slowing the progression of the disease.
It will take many years for ReN001 to come to market (assuming it is successful in doing so).
No thanks to the press and politicians, there is confusion on the subject of stem cells. This therapy uses 'adult' stem cells that were taken from fetuses and grown into this line. These are not 'embryonic' stem cells which have the problems of forming tumors.
Here's the press release with more information:
ReNeuron Business Update and Funding Plans
Tuesday October 5, 7:0