RxPG News : Cystic Fibrosis

Cystic fibrosis-related diabetes is due to functional abnormalities in beta cells

Mon, 10 Jul 2006 06:20:37 PST

( from http://www.rxpgnews.com ) A growing number of cystic fibrosis patients are battling a second, often deadly complication: a unique form of diabetes that shares characteristics of the type 1 and type 2 versions that strike many Americans.

Many of these patients are teens who take enzymes to help digest their food and undergo daily physical therapy to loosen the thick, sticky mucus that clogs their lungs. But despite treatments that are helping thousands to live decades longer than ever before, when diabetes strikes, their life expectancy plummets -- on average by two years for men and an astounding 16 for women.

Now a University of Florida study in animals suggests diabetes in cystic fibrosis patients is not caused by the destruction of insulin-producing cells in the pancreas -- as is often the case in patients with the traditional form of type 1 diabetes -- but by differences in how these cells function.

Cystic fibrosis patients with diabetes produce some insulin on their own, but they require daily injections to boost their levels when eating so they can properly use sugar and other food nutrients for energy. At times they also become very resistant to the insulin they do make, similar to people with type 2 diabetes.

"For the longest time, the development of diabetes in cystic fibrosis has been thought to be chronic destruction of pancreas, so eventually you get loss of the insulin-producing beta cells," said Michael Stalvey, M.D., an assistant professor of pediatrics at UF. "Our study provides some early evidence to suggest there is an inherent difference in beta cell function."

Cystic fibrosis patients suffer recurrent episodes of infection and inflammation that slowly destroy the lungs. The pancreas is also affected, interfering with proper digestion. The disease stems from a faulty gene that blocks the normal passage of salt and water through the body's cells. It is this gene deficiency that is proposed to cause insulin-producing cells to malfunction, Stalvey said.

About 30,000 Americans have cystic fibrosis, making it the nation's most common lethal hereditary disorder. On average, they will not live past 35, though some are living through their 40s and even into their 60s. As each year passes, the likelihood they will develop diabetes increases. As many as 16 percent of all patients with cystic fibrosis also have diabetes, a number that is expected to rise as overall life expectancy for cystic fibrosis patients increases. Half will show signs of diabetes by age 30 and will suffer a rapid decline in overall health and lung function, muscle mass and body mass index.

"It's becoming more and more frequent because of the increasing age of patients," Stalvey said. "That's part of the reason why new recommendations call for screening patients 14 years and older yearly with an oral glucose tolerance test. Each year we know their likelihood of developing diabetes gets higher and higher.

"These young people, teenagers or young adults in their early 20s, have been fighting all their lives to stay healthy and keep their nutrition up," he added. "Now they've just been given something that potentially will overwhelm them. It's a huge thing for them, given the consequences that diabetes means to their underlying condition."

In the UF study, researchers developed the first animal model for the study of cystic fibrosis-related diabetes. They used mice that scientists from the University of North Carolina engineered to be missing the gene that makes the protein responsible for transporting salt and water across the cell membrane. People with cystic fibrosis have a mutated form of this protein.

UF scientists administered a low dose of a chemotherapy drug that weakened insulin-producing cells but did not destroy them. They then tested the animals' ability to regulate their blood sugar while fasting and after receiving glucose, simulating the rise in blood sugar that occurs after eating food.

Animals with the protein deficiency were more sensitive to the effects of the chemotherapy drug and had more difficulty regulating blood sugar levels, both while fasting and after receiving glucose. Mice that were still able to produce the crucial protein that prevents cystic fibrosis were able to maintain normal blood sugar levels, even after the drug had damaged some of their insulin-producing cells.

"This goes beyond improving our understanding of patients with cystic fibrosis-related diabetes; it also will help us improve our understanding of other forms of diabetes and help us work on strategies for a future cure," Stalvey said.

"Twenty-five percent of adolescents and 40 percent of adults with cystic fibrosis have diabetes, and diabetes is associated with poorer survival in this population," said Antoinette Moran, M.D., division head of pediatric endocrinology and director of the Pediatric Diabetes Program at the University of Minnesota Medical School. "The cause of cystic fibrosis-related diabetes is not completely understood, but it is clearly different from other forms of diabetes. The study by Stalvey and colleagues is important because it is the first to show that there are intrinsic abnormalities in the insulin-producing cells of the pancreas related to the genetic defect that causes cystic fibrosis."

No evidence for inhaled corticosteroids efficacy in cystic fibrosis

Thu, 15 Jun 2006 16:56:37 PST

( from http://www.rxpgnews.com ) In comparison to cystic fibrosis (CF) patients who regularly use inhaled corticosteroid, those who did not use these drugs for six months exhibited no positive or negative effects in terms of major disease factors. Such factors include amount of lung function decline, number of antibiotics prescribed, time to onset of acute chest exacerbation or frequency of using a bronchodilator.

Ian M. Balfour-Lynn, M.D., F.R.C.P., of the Department of Pediatric Respiratory Medicine at Royal Brompton Hospital in London, and six associates concluded that it is safe for CF patients to stop using inhaled corticosteroids in order to lower their drug burden, to reduce potential adverse side effects, and to save money.

According to the authors, 52 percent of children and 55 percent of the adults with CF in Great Britain have been prescribed inhaled corticosteroid medication for their illness.

CF, an inherited disorder, is characterized by the production of thick, sticky mucus that frequently obstructs the lungs. The problem can lead to life-threatening lung infections and difficulties with the pancreatic ducts, preventing normal digestion and causing patient malnutrition. Because of improved treatment techniques in recent years, however, patient survival has increased from 25 to 33 years.

"Oral corticosteroids slow the progression of CF lung disease, but long-term use is precluded by unacceptable side effects," said Dr. Balfour-Lynn. "A systematic review of inhaled corticosteroid use in CF revealed 10 randomized controlled trials, with six having been published. The trials studied 293 adults and children. Although there was variable methodological quality among the studies, the conclusion was that there was 'no evidence from existing trials to support the practice of prescribing inhaled steroids in cystic fibrosis.'"

The authors noted that 52 percent of the patients were on high-dose inhaled corticosteroids (1,000 micrograms or more per day). At those levels, the drug can lead to significant symptoms related to adrenal suppression and insufficiency. Also, among pediatric patients, slowing of linear growth has been a problem for individuals taking the drug for a year or more.

Over a 6-month period, the researchers studied 84 CF patients (median age 14.6 years) who were using an inhaled corticosteroid (fluticasone) and 87 CF patients (median age 15.8 years) who were not.

"Replacing the inhaled corticosteroids with a placebo was found to be safe as there was no significant increase in lung-related adverse effects leading to withdrawal from the study, nor an increased need for oral corticosteroids," said Dr. Balfour-Lynn.

The researchers stressed that they were not advocating stopping inhaled corticosteroid use in all CF patients, but urging clinicians to assess the need in each individual.

"If there is objective evidence that a patients benefited when inhaled corticosteroids were first started, then it is likely they should be continued on the drug," said Dr. Balfour-Lynn.

Hcp1 plays a critical role in cystic fibrosis infection

Sat, 10 Jun 2006 13:42:37 PST

( from http://www.rxpgnews.com ) Harvard Medical School researchers have discovered one way that a hardy disease-causing bacteria could be surviving in the lungs of chronically infected cystic fibrosis (CF) patients.

"This work is important because pathogenic bacteria such as Pseudomonas aeruginosa (PA) use protein secretion systems to cause disease in their hosts," said Joseph Mougous, lead author of the study published in the June 9 issue of Science. "In the case of Pseudomonas aeruginosa, the host may be a cancer patient with a weakened immune system, a burn patient, or a person with cystic fibrosis (CF)."

Pseudomonas aeruginosa (PA), a pathogen that infects more than 80 percent of cystic fibrosis patients, is a leading cause of these patients' death. PA is difficult to treat because it is resistant to many drugs.

"Since we know so little about what this bacterium is up to while it's engaged in these chronic infections, the discovery of this protein secretion system might lead to finding a new target for treatments," said Mougous, a research fellow in the Harvard Medical School (HMS) Department of Microbiology and Molecular Genetics.

Researchers at Argonne National Laboratory (ANL) provided one of the clues that contributed to the HMS discovery. Working through a number of pathogenic proteins, ANL protein crystallographer Marianne Cuff saw a bagel-shaped pore that might be involved in transferring toxins into cells. She deposited the structure of the protein, called Hcp1, into the Protein Data Bank, a resource used by biologists worldwide to find information about the proteins they are studying.

While exploring the Protein Data Bank, Mougous, who was studying PA in the laboratory of department chair John Mekalanos, recognized that the amino acid sequence of Hcp1 in PA closely resembled that of Hcp1 in Vibrio cholerae. The Mekalanos lab had previously discovered that the Hcp1 protein of V. cholerae is released from the bacterium via a novel secretion pathway. Because Hcp1 proteins from both pathogens belong to the same protein family, Mougous wondered whether the Pseudomonas Hcp1 might also be secreted via this pathway.

The Harvard and Argonne researchers quickly formed a collaboration and confirmed the hypothesis. They then turned their attention to Hcp1 in cystic fibrosis patients to gain more insight in the role of Hcp1 during infection.

Working with cystic fibrosis patients at Children's Hospital Boston, the HMS researchers sought and found Hcp1 in the sputum of patients with P. aeruginosa. They also found Hcp1 antibodies in the patients' blood further evidence that Hcp1 plays a critical role in the infection. The human immune system creates antibodies to pathogens it is exposed to.

"CF patients are particularly susceptible to PA," Mougous said. "The bacterium thrives in the excess mucus that accumulates in their lungs. Once a PA infection in a CF patient's lung has been established, these hardy bacteria are difficult or impossible to clear, which over many years eventually results in the death of the patient. Our paper provides evidence that the protein secretion system we discovered represents at least one way this bacterium could be promoting its own survival in the lungs of CF patients."

"This finding provides a possible drug target to fight the infection in cystic fibrosis patients," added Andzrej Joachimiak, director of Argonne's Structural Biology Center and of the Midwest Center for Structural Genomics based at Argonne.

Cystic fibrosis research could benefit from multi-functional sensing tool

Mon, 27 Mar 2006 16:16:37 PST

( from http://www.rxpgnews.com ) Researchers are using an innovative, multi-functional sensing tool to investigate adenosine triposphate (ATP) release and its role in cystic fibrosis. The ATP study marks the first application of a novel sensing system developed by a research team led by Christine Kranz at the Georgia Institute of Technology.

This patented technology adds recessed micro- and nano-electrodes to the tip of an atomic force microscope (AFM), creating a single tool that can simultaneously monitor topography along with electrochemical activity at the cell surface.

The new multi-functional imaging technique will advance the study of biological samples, said Boris Mizaikoff, an associate professor at Georgia Tech's School of Chemistry and Biochemistry and director of its Applied Sensors Lab. "Conventional AFM can image surfaces, but usually provides limited chemical information," he explained. "And though scanning electrochemical microscopy (SECM), another probing technique, provides laterally resolved electrochemical data, it has limited spatial resolution. By combining AFM and SECM functionality into a single scanning probe, our tool provides researchers with a more holistic view of activities at the cell surface."

In addition to Mizaikoff and Kranz, the team also includes post-doctoral scholar Jean-Francois Masson and graduate student Justyna Wiedemair.

In the ATP study, which is sponsored by the National Institutes of Health and done in collaboration with Douglas Eaton at Emory University's School of Physiology, the Georgia Tech team used the multi-scanning biosensors to study ATP release at the surface of live epithelial cells (cells that cover most glands and organs in the body). ATP, a chemical involved in energy transport, is of interest to medical researchers because elevated levels have been linked with cystic fibrosis, a disease that affects one out of every 2,500 people in the United States.

Using epithelial cell cultures from Emory, the Georgia Tech researchers have demonstrated that their multi-functional biosensors work at the live-cell surface during in vitro studies.

"Before you can identify what triggers the ATP release, we must be able to quantitatively measure the released species at the cell surface," Mizaikoff said, noting that many pathological events involve the disruption of chemical communication and molecular signaling between cells, especially in the nervous system, lungs and kidneys.

Improved understanding of cellular communication can lead to new strategies for treating diseases, Mizaikoff added: "Being able to operate sensors in an electrochemical imaging mode at the micro- and nanoscale is an exciting opportunity for complementing optical imaging techniques. There are many clinical research problems that these biosensors can help with."

During the same ACS session, the Georgia Tech team will also present findings of a related project.

A collaboration with Estelle Gauda at Johns Hopkins University and also supported by NIH grants, this project monitors ATP release at the carotid body. (The carotid body is a chemoreceptor that, among other functions, monitors oxygen content in the blood and helps control respiration.)

Chronic oxygen stress too much or too little oxygen during early postnatal development can lead to a deficiency in the amount of oxygen reaching body tissues in premature infants and newborn animals. But little is known about how oxygen stress affects regulatory networks and alters chemoreceptors. To gain insights, the Georgia Tech researchers will study ATP, which is among the signaling molecules released by the carotid body.

Researchers incorporate the same technology used for the multi-functional scanning probe. For this study, however, they have tailored the biosensor to work at a larger scale microelectrodes are about 25 micrometers in diameter as opposed to the sub-micrometer dimensions of the combined AFM-SECM approach.

"There are a lot of emerging sensor technologies, but few have been adapted for routine use in medical research, which is one of the development goals at the Applied Sensors Lab," Mizaikoff said. "As analytical chemists, we want to develop quantitative sensing devices that can answer important questions for clinical researchers."

Loss of CFTR-mediated fluid secretion is the culprit in cystic fibrosis

Sun, 19 Mar 2006 20:55:37 PST

( from http://www.rxpgnews.com ) Scientists at Stanford University have determined that the buildup of sticky mucus found in cystic fibrosis is caused by a loss in the epithelial cell's ability to secrete fluid. This research appears as the "Paper of the Week" in the March 17 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.

Cystic fibrosis is the most common, fatal genetic disease in the United States. It causes the body to produce thick, sticky mucus that builds up in the lungs and blocks the airways. This makes it easy for bacteria to grow and leads to repeated serious lung infections. The thick, sticky mucus can also block tubes in the pancreas, preventing digestive enzymes from reaching the small intestine.

The disorder results from mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR), a membrane channel regulator essential for proper salt and water movement across some epithelia. Currently, there are two essentially opposite explanations for the inability of the body to clear mucus from the airways in cystic fibrosis. The first is that the defective CFTR is unable to aid in fluid secretion in cystic fibrosis airway glands. The second explanation is that the glands still secrete fluid via non-CFTR pathways, but the fluid is reabsorbed by other channels. In fact, it has been proposed that one of CFTR's functions is to inhibit the activity of a channel called the epithelial Na+ channel (ENaC).

Nam Soo Joo and colleagues at Stanford University attempted to determine which hypothesis was correct by measuring the secretion from glands from patients with cystic fibrosis and from normal pigs. They added ENaC inhibitors to the glands to determine if the channel plays a role in mucus clearance. The researchers found no evidence that the inhibitors altered secretion rates in either normal or cystic fibrosis glands. This suggested that loss of CFTR-mediated fluid secretion is the culprit in cystic fibrosis.

"We previously showed that cystic fibrosis airway glands have defective gland secretion in response to certain drugs," explains Joo. "The results of our present study provide evidence that the defective cystic fibrosis gland secretion is not due to a potentially excessive fluid reabsorption pathway within glands but is due to most likely to a lack of fluid secretion from cystic fibrosis glands."

New treatment for cystic fibrosis patients

Thu, 19 Jan 2006 13:09:37 PST

( from http://www.rxpgnews.com ) Scientists have discovered a new therapy for lung problems associated with cystic fibrosis that they say may reduce the use of antibiotics.

Cystic fibrosis is a genetic disorder that causes chronic lung damage due to the build-up of excessive amounts of sticky mucus.

The treatment developed by researchers at the University of North Carolina and the University of Sydney involves inhaling a salt water aerosol solution almost twice as salty as the Atlantic Ocean, reported the online edition of BBC News.

This helps to cut damage by restoring a thin lubricant layer of water that normally coats airway surfaces, it said.

In healthy people, the water layer lining in the airways helps to clear away excess amounts of mucus by sweeping it up into the mouth where it can be swallowed.

But this water layer is missing in people with cystic fibrosis, so they are unable to prevent mucus from clogging up their lungs. Ultimately, this can lead to respiratory failure.

The new therapy works by using salt to suck water from the lung tissues out on to their surface, the researchers said.

The US team used the aerosol to treat a small group of cystic fibrosis patients. They found that it significantly improved mucus clearance, lung function and breathing symptoms.

The Australian team then applied it to another 164 patients for a longer period, almost a year. They found patients needed fewer antibiotics to treat lung infections and were more able to attend work or school.

"It gives us great hope that use of this therapy will reduce how often patients feel ill, will slow the decline of lung function over time and will help these people live longer," researcher Scott Donaldson said.

Genetic variations influence cystic fibrosis' severity

Sat, 08 Oct 2005 05:23:38 PST

( from http://www.rxpgnews.com ) Subtle differences in other genes -- besides the defective gene known to cause the illness cystic fibrosis -- can significantly modify the inherited disease's severity, a large new multi-center national study has concluded.

The study, led by University of North Carolina at Chapel Hill and Case Western Reserve University researchers, for the first time shows that particular versions of the transforming growth factor beta 1 (TGFb1) gene are largely responsible for how badly the illness affects patients' lungs.

A report on the findings appears in the Oct. 6 issue of the New England Journal of Medicine.

"As this gene is one of about 30,000 genes in our bodies, its identification as a modifier of the CF lung disease allows us a specific target to focus on for improving CF therapy," said Dr. Mitchell L. Drumm, associate professor of pediatrics and genetics at Case. "As we better understand its function in lung disease, we hope it will allow us to design better and more specific therapies. Because other researchers have found a similar effect of this gene in asthma, the implications likely extend to other disorders affecting the lungs as well."

More than 50 hospitals and medical centers and scores of physicians across the United States and Canada participated in the investigation, which was actually two closely related studies with separate groups of patients. Findings were essentially the same for both, according to principal investigator Dr. Michael R. Knowles, professor of medicine at the UNC School of Medicine.

"This study is especially important in the field of genetic modifiers, because we had enough patients -- over 1,300 -- and a robust study design to assure that our observation is likely correct," Knowles said. "That is in contrast to much of the previous work in this area where the number of subjects was usually too small to be conclusive.

"The observation has tremendous implications about the future for prognosis and potential new therapies in CF," he said. "We are on the verge in the next two or three years of being able to test for other such genetic variants across the entire human genome. Our hope is to be able to identify most of the important gene modifiers in CF so that they can be used for prognosis, the identification of novel therapeutic targets and perhaps even directing therapy in an individual patients toward different types of adverse gene modifiers."

Initially, the study involved 808 cystic fibrosis patients who had inherited an altered form of a gene known as delta F508 from both parents. The second study involved 498 people with the condition. By measuring the volume of air when patients' exhaled strongly into a machine, researchers determined how severe each subject's lung disease was.

Scientists then correlated patients' level of illness against various genetic mutations and found that variants of a gene known as TGFb1 were associated with worse disease. The findings appear to exonerate certain other previously suspected mutations.

Besides Drumm and Knowles, authors of the report include Drs. Fred A. Wright and Fei Zou, associate professor and assistant professor of biostatistics, respectively, at the UNC School of Public Health, and, at Case, Drs. Mark D. Schluchter and Michael Konstan, professors of pediatrics; and Dr. Katrina Goddard, associate professor of epidemiology and biostatistics. Thirteen other scientists and clinicians also contributed to the work and were listed as co-authors.

In an accompanying editorial, Drs. Christina K. Haston and Thomas J. Hudson of McGill University in Montreal praised the new study.

"There are many lessons about modifier genes to be extrapolated from this study, starting with recognition of the tremendous importance of the study design," Haston and Hudson wrote.

Among its strengths, they said, were its large size -- which is essential for such studies if they are to be useful -- that it focused on a single class of gene variation and that it took into account numerous possible confounders such as sex, other illnesses like asthmas, enrollment sites, associated diseases and infections.

"There are likely a number of gene modifiers in CF and other diseases, and this current paper describes one of the first robust examples," Knowles said. "Some CF patients may do worse because of 'severe inflammation' genes, whereas others may do worse because of differences in mucus genes. Still others might because of their growth and metabolism genes, etc... Thus, therapy might need to be targeted to a particular area or areas in individual patients. This is important not only for CF, but for other lung diseases as well because gene modifiers we discover in CF will be seen in other diseases, and there are already examples of that."

How to design a better drug to treat cystic fibrosis

Sun, 04 Sep 2005 08:29:38 PST

( from http://www.rxpgnews.com ) John Tomich, a Kansas State University professor of biochemistry, spends much of his day thinking about how to design a better drug to treat cystic fibrosis.

A chronic and progressive disease, cystic fibrosis is usually diagnosed in childhood. It causes mucus to become thick, dry and sticky. The mucus builds up and clogs passages in the lungs, pancreas and other organs in the body.

There is no cure for cystic fibrosis. Management of the disease varies from person to person and generally focuses on treating respiratory and digestive problems to prevent infection and other complications. Treatment usually involves a combination of medications and home treatment methods, such as respiratory and nutritional therapies.

Tomich, along with colleagues Takeo Iwamoto, a K-State research assistant professor, and Shawnalea J. Frazier, senior in biochemistry, Haysville, have been working to understand how ions travel across cell membranes, specifically the anion part of sodium chloride.

Tomich presented a paper on the trios' findings, "Assessing The Contributions of H-Bonding Donors to Permeation Rates and Selectivity in Self-Assembling Peptides that Form Chloride Selective Pores," Aug. 28 at the Membrane Active, Synthetic Organic Compounds Symposium of the American Chemical Society's national meeting and exposition in Washington, D.C.

"What's kind of an honor about this is we were one of the few, purely biochemical research groups who are presenting in this symposium," Tomich said. "This is a section organized by organic chemists."

Tomich and his collaborators have used a series of single and double amino acid substitutions to modulate the activity of a channel forming peptide derived from the second transmembrane segment of the alpha subunit of the human spinal cord glycine receptor.

Tomich said chloride ions are hydrogen bond acceptors; consequently, it is hypothesized the hydroxyl function contributes strongly to ion throughput across and/or ion selectivity within the channel structures. Residue replacements in the peptide involving the 13th and 17th positions were designed to correlate hydrogen-bonding strength with selectivity and permeation rates. The hydrogen bonding strengths of the amino acid side-chains correlate directly with anion selectivity and inversely with transport rates for the anion.

According to Tomich, these results will help in optimizing these two counteracting channel properties.

"Your body knows how to separate these things all by itself," Tomich said. "Sodium is usually higher outside the cell, potassium is higher inside the cell and chloride, depending on the cell type, can be the same or different.

"The chemical mechanisms directing chloride binding and transport are poorly understood," he said. "The mechanisms determining how sodium, potassium and calcium get across are much better known. We're trying to find out how chloride actually gets across so we will then be able to manipulate both the transport rates and selectivity."

Tomich began working on this many years ago. Over the past 15 years, his lab has developed more than 200 sequences that showed varied ion transport activity in synthetic membranes, as well as cultured epithelial cells and animals. From all of that they can change virtually the way this ion channel assembles. Some of the compounds that he has designed work at very low concentrations but lack some of the chloride specificity that it once had. Their presentation discussed how the researchers back-designed the channel pore so it can be more specified for chloride.

"Our goal is to make a drug that would work efficiently and effectively at low doses," Tomich said. "We have some early designs that are highly selective for chloride, but you'd have to give them a lot of the compound to see the effect."

FDA Gives Clearance to the First Cystic Fibrosis DNA test

Tue, 10 May 2005 09:17:38 PST

( from http://www.rxpgnews.com ) Tm Bioscience Corporation (Toronto, Ontario; TSX: TMC), a leader in the commercial genetic testing market, is pleased to announce that its Tag-It(TM) Cystic Fibrosis (CF) Kit is the first multiplexed human disease genotyping test to be cleared by the U.S. Food and Drug Administration (FDA) as an in vitro device (IVD) for diagnostic use in the United States.

This DNA based test is used to simultaneously detect and identify mutations and variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in human blood specimens in order to determine CF carrier status in adults, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children. Performance testing has established that the Tag-It(TM) CF Kit operates with 100% accuracy and greater than 99.9% reproducibility and precision.

"This clearance establishes Tm as a unique supplier of CF tests to our rapidly expanding customer base against such competitors as ABI (NYSE:ABI - News) and Third Wave (NASDAQ:TWTI - News)," said Greg Hines, President and CEO of Tm Bioscience. "The Tag-It(TM) Cystic Fibrosis Kit is the only CF testing system that has performance characteristics which have been established through extensive studies reviewed by the FDA. Having the first CF test and second multiplexed genetic test behind Roche's (RHHBF.PK) AmpliChip CYP450 to be cleared as an IVD, sets the regulatory pathway for other tests in our broad and growing pipeline and positions Tm as a leader in the commercial genetic testing market."

"Clearance by the FDA of a genetic assay for cystic fibrosis provides a highly standardized product for laboratories that offers tremendous benefits to the genetic testing industry, physicians and to patients." said Dr. Michael Watson, Executive Director, American College of Medical Genetics.

Cystic Fibrosis (CF) is the most common autosomal recessive disorder in the Caucasian population, with an incidence of approximately 1 in 3,200 live births. The Tag-It(TM) Cystic Fibrosis Kit simultaneously screens for the 23 cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations and 4 variants (polymorphisms), as recommended by the American College of Medical Genetics (ACMG) and the American College of Obstetricians and Gynecologists (ACOG) in 2004. In addition, the kit screens for 16 additional mutations prevalent in North America or the world.

Performance Results

The Tag-It(TM) Cystic Fibrosis Kit is sold with the following FDA cleared performance characteristics:

-Accuracy of the Tag-It(TM) CF Kit was established in a method comparison study using DNA sequencing as reference methods. Based on comparison of 2,924 genotyping calls for the 43 mutations and variants tested for by the Tag-It(TM) CF Kit, concordance between the Tag-It(TM) CF Kit and the reference tests was 100% (95% CI(equal sign)99.9% to 100%).

-Reproducibility was established as greater than 99.9% in a multi-site study by testing DNA samples obtained from the Coriell Institute for Medical Research (Camden, NJ) repository using three different lots and three operators.

-Precision was tested using synthetic positive controls representing all potential genotyping calls for all 43 mutations and variants tested for by the Tag-It(TM) CF Kit. Overall, study results showed that all genotyping calls that can be made by the Tag-It(TM) CF Kit were made correctly and reproducibly under the evaluated conditions with a precision of greater than 99.9%.

The kit is not indicated for fetal diagnostic, pre-implantation testing or for stand-alone diagnostic purposes.

About Tag-It(TM) reagents and genetic tests

Tm Bioscience's product menu is focused in the fields of human genetic disorders, pharmacogenetics and infectious disease. The Company has commercialized Analyte Specific Reagents(x) and a series of Tag-It(TM) tests(xx) for a variety of genetic disorders. All genetic tests from Tm Bioscience are based on the Tag-It(TM) Universal Array platform, which utilizes a proprietary universal tag system that allows for easy optimization, product development and expansion. Assays from Tm operate on the Luminex xMAP® system, a well-established bead based instrument. Combined, the Universal Array and Luminex instrument enable the rapid production of flexible, high-throughput, low-cost DNA-based tests.