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Archive - 2009

September 18th

Gene Therapy Cures Color Blindness in Monkeys--Wider Applications Seen

Researchers have successfully used gene therapy to cure red-green color blindness in adult squirrel monkeys. Red-green color blindness is the most common single locus genetic disorder in humans. One in 12 men and 1 in 230 women are affected, while 1 in 6 women is a carrier of the inherited condition. “We’ve added red sensitivity to cone cells in animals that are born with a condition that is exactly like human color blindness," said Dr. William W. Hauswirth, an author of the study. “Although color blindness is only moderately life-altering, we’ve shown we can cure a cone disease in a primate, and that it can be done very safely. That’s extremely encouraging for the development of therapies for human cone diseases that really are blinding.” “People who are colorblind feel that they are missing out,” said Dr. Jay Neitz, one of the senior authors of the study. “If we could find a way to do this with complete safety in human eyes, as we did with monkeys, I think there would be a lot of people who would want it. Beyond that, we hope this technology will be useful in correcting lots of different vision disorders.” In this work, the researchers wanted to produce a substance called long-wavelength opsin in the retinas of the monkeys. This particular form of opsin is a colorless protein that works in the retina to make pigments that are sensitive to red and green. “We used human DNAs, so we won’t have to switch to human genes as we move toward clinical treatments,” said Dr. Hauswirth, who is also involved in a clinical trial with human patients to test gene therapy for the treatment of Leber congenital amaurosis, a form of blindness that strikes children. Of further note is the fact that approximately 1 in 30,000 Americans has a hereditary disease called achromatopsia, which causes nearly complete color blindness and extremely poor central vision.

SNP Variant Associated with Clearance of Hepatitis C Virus

An international research team has shown that a particular SNP genotype (C/C) near the IL28B gene appears to be associated with the ability of some people to defeat hepatitis C virus (HCV) infection and get rid of the virus with no treatment. HCV infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. More than seventy percent of people who contract hepatitis C will live with the virus that causes it for the rest of their lives and some will develop serious liver disease including cancer. However, 30 to 40 percent of those infected somehow defeat the infection with no treatment. Previous work had shown that individuals with the C/C SNP genotype near IL28B were more likely to respond to treatment for hepatitis C, which can rid some patients of the virus. So, in the current work, the researchers investigated if the C/C variation—as opposed to the C/T or T/T alternatives—also played a role in some peoples' ability to get rid of the virus without the help of medication. To do this, the scientists assembled information from six different studies that had, over many years, collected DNA and hepatitis C infection information from people all over the world. The team then analyzed DNA in the IL28B gene vicinity from a total of 1008 patients: 620 persistently infected and 388 who had been infected but no longer carried any virus. DNA analysis revealed that of the 388 patients who no longer carried virus, 264 had the C/C variation. "This is the strongest clue to date to understanding what would constitute a successful immune response," said Dr. David Thomas, lead author of the article.

September 17th

Stem Cells Virtually Halt Rare Genetic Disease in Mouse Model

Scientists studying the rare and deadly genetic disease cystinosis, have shown that transplantation of adult bone marrow stem cells appears to virtually halt the disease in a mouse model. Cystine is a byproduct of the lysosomal breakdown of cellular components the body no longer needs. Normally, cystine is shunted out of cells, but in cystinosis a gene defect of the lysosomal cystine transporter causes cystine to build up, forming crystals that are especially damaging to the kidneys and eyes. The only available drug to treat cystinosis, cysteamine, while slowing the progression of kidney degradation, does not prevent it, and end-stage kidney failure is inevitable. "Cysteamine must be given every six hours, so children have to be woken up each night to take this drug, which has unpleasant side effects, and many others to treat various symptoms," said Dr. Stephanie Cherqui, the senior author of the study. "So although there is treatment, it is difficult treatment that does not cure the disease." In the study, the research team used bone marrow stem cell transplantation to address symptoms of cystinosis in a mouse model. The procedure virtually halted the cystine accumulation responsible for the disease and the cascade of cell death that follows. The researchers found that transplanted bone marrow stem cells carrying the normal lysosomal cystine transporter gene abundantly engrafted into every tissue of the experimental mice. This led to an average drop in cystine levels of about 80 percent in every organ. In addition to preventing kidney dysfunction, there was less deposition of cystine crystals in the cornea, less bone demineralization, and an improvement in motor function. "The results really surprised and encouraged us," said Dr. Cherqui.

September 8th

Molecular Mechanism of Rare Form of Diabetes Revealed

Researchers have uncovered the molecular mechanism underlying a rare and severe form of diabetes, i.e., permanent neonatal diabetes mellitus. Children with this genetic form of diabetes have symptoms by age six months and have a lifelong dependence on insulin to maintain proper glucose levels. To investigate the disease mechanism, researchers used animal and cellular models to focus on a mutation of the KATP gene that is known to be linked to the disease. The KATP gene codes for an ATP-sensitive potassium ion channel. "The KATP channel essentially functions as a gatekeeper for insulin secretion by pancreatic beta cells,” said Dr. Faith Kline, the lead author of the study. “Without proper regulation by this gatekeeper, the pancreatic beta cells are unable to efficiently regulate insulin secretion." The researchers showed that the chaperone molecule ankyrin is present in pancreatic beta cells and that the KATP mutation prevents most KATP channels from binding with ankyrin. This failure prevents the KATP channels from reaching their normal destination in the cell membrane. "Ankyrin proteins are like cellular taxi cabs that carry passenger channels to the cell membrane. In the case of this KATP gene mutation, the ankyrin and channels cannot interact properly, and so the channels basically 'miss their ride' and do not get to the desired location," said Dr. Peter Mohler, the article’s senior author. The team also found that the few mutant KATP channels that do reach the pancreatic cell membrane do not respond to alterations in cellular metabolism. As a result, the pancreatic beta cells do not release insulin appropriately. This work was reported in the September 8 week’s early online edition of PNAS. The findings may help identify new molecular targets for treating both rare and common forms of diabetes and hyperinsulinemia.

September 3rd

Addiction Gene Identified in Population Group

Researchers at the Yale University School of Public Health and Princeton University have identified a gene variant that is associated with addictive behaviors in white women of European origin. Genome-wide association studies revealed that a SNP variant of the PKNOX2 gene, located on chromosome 11, is associated, in these women, with multiple (two or more) dependencies involving nicotine, alcohol, marijuana, cocaine, opiates, and other drugs. While genes on other chromosomes have previously been associated with alcoholism and drug abuse in prior studies, this is believed to be the first time that the PKNOX2 gene has been associated with addiction in humans, said Dr. Heping Zhang, the paper’s senior author. The gene identified by the researchers had previously been associated with addictive behavior in mice. “This information can be used to design preventive and/or treatment strategies for addiction by controlling the environment exposure in the targeted group and/or by exploring and developing medications that modify the expression of the gene,” Dr. Zhang said. The researchers emphasized that their findings indicate that the associations are not as significant when individual outcomes for addiction are considered, underscoring the importance of considering multiple addiction types. The work was reported on August 31 in the early online edition of PNAS. [Press release] [PNAS abstract]

Epigenetic Changes Linked to Type 2 Diabetes

A research group at the Karolinska Institute in Sweden has shown that a key gene (PGC-1alpha) in the muscle cells of type 2 diabetics is chemically modified through DNA methylation. The scientists found that the gene was hypermethylated and had reduced expression in muscle cells taken from patients with early-onset type 2 diabetes. PGC-1alpha controls other genes that regulate the metabolism of glucose by the cell. DNA methylation is a form of epigenetic regulation, a process involving chemical modifications that are imposed externally on genes and that alter their activity without any change to the underlying DNA sequence. "This type of epigenetic modification might be the link that explains how environmental factors have a long-term influence on the development of type 2 diabetes," said Dr. Juleen Zierath, who led the study. "It remains to be seen whether the DNA methylation of this gene can be affected by, say, dietary factors." This work was published in the September 2 edition of Cell Metabolism. [Press release] [Cell Metabolism abstract]

September 2nd

Tbx5 Gradient Key to Development of Four-Chambered Heart

Research in turtles and lizards has revealed a tantalizing clue to the evolution of the four-chambered heart and the related ability of birds and mammals to lead a warm-blooded existence. The key appears to be varied expression of the transcription factor gene Tbx5 in the ventricles. In humans and other mammals, Tbx5 levels are high in the left ventricle and low in the right. The boundary of high and low is right at the septum, which forms to separate the two ventricles. When the researchers looked at the green anole lizard, which has just a three-chambered heart, they found that Tbx5 activity was essentially the same throughout the single ventricle and stayed the same throughout heart development. In the turtle, however, which has a primitive septum that partially separates its ventricle into left and right sides, distribution of Tbx5 was gradually restricted to the left side of the ventricle, resulting in a left-right gradient of Tbx5 activity. Further experiments in genetically engineered mice conclusively showed that a sharp line demarcating an area of high levels of Tbx5 is critical to induce formation of a septum between the two ventricles. "This is the first genetic link to the evolution of two, rather than one, pumping chamber in the heart, which is a key event in the evolution of becoming warm-blooded," said Dr. Benoit Bruneau, the senior author of the study. "The gene involved, Tbx5, is also implicated in human congenital heart disease, so our results also bring insight into human disease." The work was featured as the cover story of the September 3 issue of Nature.

Discovery of RAF Activation Mechanism May Aid Cancer Drug Development

A research team has shown that dimerization is essential for activation of the RAF protein kinase. When mutated, RAF protein kinase is responsible for more than 25 percent of human cancers. The research team believes that, by targeting the key dimerization process (specifically, the side-to-side dimerization of the kinase domain), it may be possible to develop new, more effective cancer therapies. "Protein kinases are the targets for some of the most successful anti-cancer drugs in the clinic," said Dr. Frank Sicheri, an author of the report. "Now that we have discovered how to turn off the RAF protein without interfering with other proteins, we may be able to design drugs that have unprecedented precision in targeting cancer cells while reducing the toxic side effects for patients." This work was published online in Nature on September 2. [Press release] [Nature abstract]

Teeth-Venom Combination Key to Lethality of Komodo Dragon Bite

A new study has shown that the effectiveness of the Komodo Dragon bite owes to a combination of highly specialized serrated teeth and venom. The authors dismiss the widely accepted theory that prey die from septicemia caused by toxic bacteria living in the dragon's mouth. Using sophisticated medical imaging techniques, an international team led by Dr. Bryan Fry from the University of Melbourne has shown that the Komodo Dragon has the most complex venom glands yet described for any reptile. The researchers conducted a comprehensive study of the Komodo Dragon bite, employing computer techniques to analyze stress in a dragon's jaws, and compared the results to those obtained for a crocodile. The dragons were found to have much weaker bites than crocodiles, but magnetic resonance imaging (MRI) of a preserved dragon head revealed complex venom glands and specialized serrated teeth which create deep lacerations for entry of the venom. "These large carnivorous reptiles are known to bite prey and release them, leaving the prey to bleed to death from the horrific wounds inflicted. We have now shown that it is the combined arsenal of the Komodo Dragon's tooth and venom that account for their hunting prowess," said Dr. Fry. "The combination of this specialized bite and venom seems to minimize the Dragon's contact with its prey and this allows it to take large animals." Komodo Dragons are native to the islands of Indonesia, with adult males weighing over 100 kg, and exceeding 3 meters in length. They have approximately 60 highly serrated teeth which are frequently replaced during their lifetime. The new research was published in the June 2 issue of PNAS. [Press release] [PNAS abstract]

August 29th

Three Genes Responsible for Coat Texture in Dogs

Researchers have found that variants in just three genes, acting in different combinations, appear to account for the wide range of coat texture seen in dogs. The study involved genome-wide SNP association analysis carried out in 1,000 individual dogs representing 80 breeds. "What's important for human health is the way we found the genes involved in dog coats and figured out how they work together, rather than the genes themselves," said senior author Dr. Elaine A. Ostrander, chief of the Cancer Genetics Branch in the National Human Genome Research Institute. "We think this approach will help pinpoint multiple genes involved in complex human conditions, such as cancer, heart disease, diabetes, and obesity." The authors noted that their work illustrates that an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes. Specifically, the researchers found that an alteration in the RSPO2 gene results in wiry hair that grows in a pattern that gives the dogs a mustachioed look with long details called furnishings. Examples of dogs with wiry coats are Scottish terriers, Irish terriers and schnauzers. Long hair that is silky or fluffy was linked to a variant in the FGF5 gene. Cocker spaniels, Pomeranians and long-haired Chihuahuas are examples of dogs with long coats. A variant in the KRT71 gene produces curly coated dogs, such as the Irish water spaniel. Finally, if all three variants are present, a dog has a long and curly coat with furnishings. Examples of this type of breed include poodles and Portuguese water dogs. This work was published online in Science on August 27. [Press release] [Science abstract]