 THE "FRAGILE X" SPOT
Scientists correct a major cause of autism and mental retardation
New drug targets HIV assembly kit
PARIS
A prototype drug, tested on lab-dish samples of the AIDS virus, has shown great promise in attacking HIV from an unprecedented direction. The drug inhibits HIV at a key point-when it uses the hijacked machinery of an infected immune cell to reassemble its genetic code.
This process, called splicing, joins together sections of viral code to form premessenger RNA, which is a precursor for messenger RNA (mRNA). This molecule provides the blueprint for cranking out viral proteins and enzymes that are essential for replication. Once these are created, baby viruses can be reproduced en masse within the cell, eventually breaking out and heading into the bloodstream, where they go on to infect other cells.
Scientists found that a test molecule, called IDC16, interferes with a human splicing protein called SF2/ASF that is used to do the premessenger RNA cut-and-paste. As a result, the reproduction process was braked at the start. In lab-dish tests, IDC16 blocked replication of different strains of HIV-1, including samples from patients who are resistant to the famous "cocktail"-combination therapy-of anti-HIV drugs.
France's National Center for Scientific Research (CNRS), which is backing the project, said IDC16 was "extremely promising."
The "cocktail," first introduced in 1995, has been a lifeline for millions of people by attacking the protein gp120, which is on the surface of the virus, and enzymes that are used in other phases of the replication process. The problem, though, is that HIV mutates, making these proteins a shifting target for drug engineers.
The authors, led by Jamal Tazi of the Institute of Molecular Genetics in Montpellier, are confident that IDC16 throws up a way of sidestepping mutation.
"Instead of attacking the components brought along by the virus, we use the machinery that it uses in the cell," Tazi said, adding that by aiming at splicing, other viruses could be targeted.
"These findings may serve as the basis for a new strategy to develop a new class of anti-HIV drugs, the splicing inhibitors, and even of antiviral drugs in general, since any virus needing to splice its RNAs may be targeted," his team wrote in their paper published in the open-access journal Public Library of Science (PLoS) Pathogens.
Obesity linked to weaker immunity
CHICAGO
Obese mice are less able to fight off bacterial infection than lean mice, according to a study that supports emerging evidence of a link between obesity and a dysfunctional immune system.
In a study on laboratory mice infected with a bug that causes periodontal disease, obese mice had a blunted immune response to the infection and increased susceptibility to gum disease compared to lean mice. The obese mice also had much higher rates of bone loss. When researchers examined the rodents 10 days after they were infected with the bacterium Porphyromonas gingivalis, the heavier mice had a 40-percent increase in alveolar-bone loss than the lean mice.
The alveolar bone is the bone or ridge that contains the tooth sockets on the upper and lower jaw. Previous studies have shown that obese people are more likely to suffer from periodontal disease than their leaner counterparts and this study provided some clues as to why that is. Blood tests on mice that had been infected with the bacterium P. gingivalis revealed irregularities in the production of cytokines in the obese mice, compared with the "control" or lean mice. Cytokines are proteins or peptides that signal immune cells such as T-cells and macrophages to travel to the site of infection.
Researchers also analyzed the macrophages, the white blood cells that form a major line of antibacterial defense. They found that levels of key signaling molecules were significantly lower in the macrophages from the obese rodents and the expression profile of inflammation-related genes was altered compared to the control mice.
The researchers said it's not clear how obesity compromises the immune system, but they suspect a particular signaling pathway involving a transcription factor NF-kB may be involved. NF-kB plays a key role in the immune response to infection.
The study conducted by scientists in the School of Dental Medicine at the University of Boston Medical Center,appears in The Proceedings of the National Academy of Sciences.
Researchers correct autism symptoms in mice
WASHINGTON
US researchers say they have successfully corrected key symptoms of a type of autism and mental retardation in mice, a development that could offer sufferers a potential treatment. The tests carried out on mice aimed to correct "Fragile X syndrome," which affects some 100,000 Americans, said the study from the Massachusetts Institute of Technology (MIT) published in Neuron magazine.
Fragile X syndrome is the most common inherited cause of autism and mental retardation, which can be manifested in childhood epilepsy and abnormal growth. It is caused by the loss of a gene, known as the "fragile X mental retardation protein" (FMRP), which is believed to act as a brake on synthesizing proteins in the brain.
Researchers sought to prove that the loss of this protein allowed another one that stimulates protein synthesis, known as mGluR5, to act unchecked. Genetic-engineering tests proved that cutting the amount of mGluR5 in mice helped to reduce the abnormalities caused by the loss of the other key protein.
"Fragile X is a disorder of excess synaptic connectivity, protein synthesis, memory extinction, body growth, excitability-and remarkably all these excesses can be reduced by reducing mGluR5," said lead author Mark Bear of MIT's Picower Institute for Learning and Memory.
Although the team used genetic engineering to reduce the amount of mGluR5 in the mice, the research offers a hope of treatment by using a certain class of drugs that will soon be going on trial. "Insights gained by this study suggest novel therapeutic approaches, not only for fragile X but also for autism and mental retardation of unknown origin," added Bear.
Fragile X syndrome is passed down on the mother's genes and affects one in 4,000 boys. Those affected can be hyperactive or have a tendency toward autism. There are also certain facial characteristics such as an elongated face, and large, sticking-out ears.
New technique prevents organ rejection
WASHINGTON
Injecting bone marrow from an organ donor allowed kidney-transplant patients to be weaned of the intense immunosuppressant drugs usually needed to prevent organ rejection, a study in the New England Journal of Medicine found. The transplanted bone marrow produces immune cells that are tolerant of the donated organ even when it is a genetic mismatch.
"We are very encouraged by our initial success in inducing tolerance across the HLA (mismatched human leukocyte antigen protein) barrier, something that has been a major goal of transplant immunology for years," said senior author David Sachs of the Massachusetts General Hospital Transplantation Biology Research Center.
"While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced."
Sachs and his team have been working on a means to trick the immune system into regarding a donor organ as "self" for more than three decades. They discovered that transplanted bone marrow creates a state called mixed chimerism where the immune system blends elements of both the donor and recipient.
They first used this approach in 1998 with a woman whose kidney failure had been caused by bone-marrow cancer. She was able to stop using immunosuppressant drugs about two months after her sister donated bone marrow and a genetically matched kidney. She remains healthy nine years later. Six other patients with the condition have also become tolerant to genetically matched kidneys through this process.
The next step was to see if it would work on patients who received a genetically mismatched kidney. Five such patients were given the treatment. One developed early rejection and ultimate kidney failure while the other four were able to discontinue immuno-suppressives several months after their transplants. All four of the successfully transplanted patients continue to have normal kidney function from two to more than five years later.
Cat-and-mouse tactics for allergy vaccine
GENEVA
Swiss scientists searching for a vaccine against cat allergies have adopted the maxim "my enemy's enemy is my friend" by successfully testing their formula on every mog's foe-a mouse. Like a Tom and Jerry cartoon set in a lab, a team from the Swiss asthma and allergies research institute first tested their protein molecule-based vaccine on mice and have now received a green light from regulatory authorities for human trials.
Chief researcher Reto Crameri told Swiss news agency ATS that the new vaccine was 100 times more effective than the natural extracts currently used to treat cat allergies. Only three vaccinations are necessary, in contrast to the 20 to 30 jabs needed over three months under the current regime, which also entails a further monthly injection for the next three to five years.
Human trials are set to begin and will be run in conjunction with the University of Zurich and Germany's ImVision Institute.
3D scan detects genetic conditions
LONDON
British scientists have developed a technique that uses three-dimensional scans of children's faces to detect signs of rare genetic conditions. The technique works by picking up tiny changes in the shapes of noses, jaws, ears, and head shape of children and comparing them to the faces of healthy youngsters.
It can help to pick up conditions such as Fragile X syndrome more quickly. Fragile X sufferers have long faces and protruding ears and symptoms include learning disabilities and delays in speech.
The technology has a 90-percent success rate, according to Prof. Peter Hammond, a computer scientist at the Institute for Child Health at University College London, who worked on the research. "A lot of genes do a lot of different things in the body," Hammond said. "Some may affect your liver or lungs, and bone structure, but may also contribute to the face. Genes that affect the face may also affect other parts of the body. It's a complex picture."
Around 700 genetic disorders are known to have an affect on the face and Hammond's team has investigated 30 so far. They are about to start using scans to test 10 conditions in a clinical trial.
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