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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.
Posted by Dave at 08:46 PM | Comments (0) | TrackBack
April 08, 2005
Another Great Advance In Research
The rapid advance of science amazes me. The implications of this amazing bit of research for curing Huntington's Disease are obvious...
A team led by scientists at Sangamo Biosciences in Richmond, California, US, say they have corrected the single gene mutation that causes the fatal X-chromosome-linked severe combined immune deficiency (X-SCID) - or “bubble boy” disease - in human T-cells. They treated the cells in test tubes with the company’s proprietary type of “zinc finger nucleases” (ZFNs) and have published their results in Nature.ZFNs are proteins made up of “fingers” of around 30 amino acids and stabilised by a zinc atom. Each finger binds to a specific combination of DNA bases and is attached to a DNA-cutting enzyme called a nuclease.
By using different combinations of amino acids, they can be designed to latch on to DNA at exactly the place where the mutated gene lies and cut it. This triggers the body’s natural repair process, called homologous recombination, which corrects the gene where the DNA was cut, The researchers provided the cells with a copy of the correct gene as a template.
Posted by Dave at 06:08 PM | Comments (1) | TrackBack
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.
Posted by Dave at 03:09 AM | Comments (0) | TrackBack
April 06, 2005
A Passing
Derek Lowe's brother passed away on Monday. If that name sounds familiar to you it might be because I frequently link to his blog on pharmaceutical research.
You can read his heart-felt message on this here.
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April 05, 2005
Another Success for RNAi
The University Of Iowa is leading the world again in the race to treat Huntington's Disease. They just did a mouse model test using RNAi to target the huntingtin gene. Here's the money quote from their press release:
Detailed examination of the protein levels in the treated mice showed that levels of the toxic HD protein were reduced to about 40 percent of the level seen in untreated mice.
They have more animal testing to do before it goes to human tests but this is very good news! Here's the full press release:
U. Iowa researchers improve Huntington's disease symptoms in mice
Researchers at the University of Iowa Roy J. and Lucille A. Carver College of Medicine have taken another step toward a potential treatment for Huntington's disease (HD). Using an approach called RNA interference (RNAi), the scientists reduced levels of the disease-causing HD protein in mice and significantly improved the movement and neurological abnormalities normally associated with the disease.
HD is a devastating, inherited, neurodegenerative disease that is progressive and always fatal. The disease-causing gene produces a protein that is toxic to certain brain cells, and the subsequent neuronal damage leads to the movement disorders, psychiatric disturbances and cognitive decline that characterize this disease.
"Many of the current approaches aimed at treating HD are indirect and target the symptoms of the disease. RNA interference gives us the first opportunity to attack the fundamental problem and reduce protein expression from the disease gene," said Beverly L. Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine and UI professor of internal medicine, physiology and biophysics, and neurology. "Our study is the first demonstration that a therapy designed to inhibit protein production has a beneficial effect."
The study will appear this week in the Online Early Edition of the Proceedings of the National Academy of Sciences (www.pnas.org). Davidson is the senior author and Scott Harper, Ph.D., a postdoctoral researcher in Davidson's lab, is lead author.
Harper, Davidson and their colleagues used RNAi to treat a mouse model of HD. Viral vectors (stripped-down viruses) carrying the genetic instructions to make a RNA interference molecule were injected into the brains of genetically engineered mice before the disease symptoms appeared. The treated mice showed nearly normal movement, and the characteristic neurological damage also was significantly improved in comparison to untreated mice.
Detailed examination of the protein levels in the treated mice showed that levels of the toxic HD protein were reduced to about 40 percent of the level seen in untreated mice.
"It is very exciting that a partial reduction is sufficient to produce a very beneficial effect in the animal. It means that we don't have to turn the gene off completely," Davidson said. "For a disease that takes decades to develop, a partial reduction may slow down the disease-causing copy of the gene to such an extent that either disease progression is delayed or possibly even disease onset is prevented."
It may even be the case that a partial reduction of toxic protein levels allows the brain cells' machinery to "catch up" with the disease-causing protein and clear out the damage caused by the mutant protein.
The genetically engineered or transgenic mouse model used by the UI team carries a section of the human HD gene. These mice quickly develop movement and coordination abnormalities and they die young. Aggregates, or clumps of protein, also develop in certain brain cells.
Davidson explained that this mouse is very good for proof-of-principle experiments, allowing the researchers to ask a very pointed question – can RNAi improve HD-like symptoms in a mouse model in short order?
"Since our results are positive, we can now repeat the experiment in mouse models that develop disease more slowly and more closely resemble HD in humans," Davidson said.
Most genes are inherited as a pair, one from either parent. In HD, one mutated copy of the gene is sufficient to cause the disease. However, the normal Huntington gene produces a protein that is known to be critical in embryonic development. It is not known if the protein is critical in adult brain cells.
The RNAi molecule used in Davidson's current study would silence both the mutant and the normal gene. So, an important question that still needs to be addressed is whether adult neurons can tolerate and benefit from a partial reduction of both the toxic and the normal protein. If the normal protein is critical, then RNAi will need to be specifically targeted against the disease-causing gene.
Fortunately, RNAi is exactly the right tool to provide an answer regarding whether the normal gene is critical by silencing the normal gene in adult brain cells of HD models.
Despite the remaining hurdles, Davidson is optimistic about the potential of RNAi to treat HD and similar neurodegenerative diseases.
"If the benefit is confirmed in other mouse models of Huntington's disease, and it appears that we don't need to target the RNAi specifically to the disease-causing mutant gene, then I would think it might move to human testing within several years," she said.
###
The study was funded by the NIH, the Cure HD Initiative and the Hereditary Disease Foundation.
In addition to Davidson and Harper, the UI team included Patrick Staber, Xiaohua He, Steven Eliason, Ines Martins, Qinwen Mao, Ph.D., and Henry Paulson, M.D., Ph.D., associate professor of neurology. Robert Kotin, Ph.D., and Linda Yang at the National Heart, Lung and Blood Institute, also were part of the research group.
University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com.
STORY SOURCE: University of Iowa Health Science Relations, 5135 Westlawn, Iowa City, Iowa 52242-1178
Posted by Dave at 06:23 AM | Comments (0) | TrackBack
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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