New Life for Toxic Antibiotics?

Pills and a bottle
Researchers found that the antibiotic trovafloxacin cuts off a channel for communication between cells and interferes with a cell-death process. Credit: iStockphoto.

Many compounds that show promise as new antibiotics for treating bacterial infections never make it to the clinic because they turn out to be toxic to humans as well as to bacteria. A research team led by Kodi Ravichandran Exit icon of the University of Virginia recently gained insights into why one such antibiotic, trovafloxacin, harms human cells. They found that the compound cuts off a channel for communication between cells, which in turn interferes with how dying cells are broken down and recycled by the body. Roughly 200 billion cells in the human body die and are replaced every day as part of a routine cleanup process, and interference in this process by trovafloxacin may have contributed to the serious liver damage seen in some patients in clinical trials of the drug. Understanding how trovafloxacin causes toxicity in people may help researchers re-engineer this and related compounds to make them safe and effective for use in fighting bacterial infections.

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Study Comparing Sepsis Treatment Methods Shows Equivalent Survival Rates

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A 5-year, randomized clinical trial helped resolve a long-standing debate about how best to manage sepsis patients.

For years, doctors have debated the best ways to identify, predict and treat sepsis. The condition, which is usually triggered by infection, is marked by body-wide inflammation and can lead to a dangerous drop in blood pressure known as septic shock. Sepsis affects more than 800,000 people each year and kills about 20 to 30 percent of them. It’s the most expensive condition treated in U.S. hospitals, costing more than $20 billion a year.

Now, a nationwide, 5-year clinical trial that set out to compare three different treatment approaches has shown that survival of patients with septic shock was the same regardless of whether they received treatment based on structured, standardized medical plans (protocols) or the usual high-level standard of care. If patients were diagnosed shortly after the onset of sepsis and treated promptly with fluids and antibiotics, they did equally well whether they received treatment based on either of two specific protocols—one less invasive than the other—or got the usual, high-level care provided by the academic hospitals where the study was conducted.

According to the study’s leaders, the trial “helps resolve a long-standing clinical debate about how best to manage sepsis patients, particularly during the critical first few hours of treatment,” and shows that “there is not a mandated need for more invasive care in all patients.”

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Nanoparticles Developed to Stick to Damaged Blood Vessels, Deliver Drugs

Artery with fat deposits and a formed clot. Credit: Stock image.
Artery with fat deposits and a formed clot. Credit: Stock image. View larger image

Heart disease is the leading cause of death for both men and women in the United States, according to the Centers for Disease Control and Prevention. One treatment challenge is developing non-invasive ways to direct medication to damaged or clogged arteries, which can block blood flow and increase the risk for heart attack and stroke. A team led by Naren Vyavahare Exit icon at Clemson University has engineered extremely tiny particles—nanoparticles—that offer a promising step forward.

Healthy arteries have elastic fibers that make the arteries flexible. But, in most cardiovascular diseases, the fibers get damaged. The new nanoparticles, which can deliver drugs, attach only to damaged fibers and could enable site-specific drug delivery to minimize off-target side effects. The nanoparticles also allow drugs to be released over longer periods of time, potentially increasing the drugs’ effectiveness. The new biomaterial was tested in rodent models for studying vascular disease, so it is still in the early stages of development.

This work also was funded by NIH’s National Heart, Lung, and Blood Institute.

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Anti-Clotting Drugs: The Next Generation

Form of heparin
Scientists created a tailor-made form of the anti-clotting drug heparin that offers several advantages.
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The low molecular weight (LMW) form of the drug heparin is commonly used to prevent unwanted blood clots that can lead to heart attacks and strokes. It’s usually derived from pig intestines and normally cleared from the human body by the kidneys. In individuals with impaired kidney function, the drug can build up in the circulation and cause excessive bleeding. Impurities and the risk of contamination are also concerns with pig-derived heparin.

Now, Robert Linhardt of Rensselaer Polytechnic Institute and Jian Liu of the University of North Carolina at Chapel Hill have created a synthetic, tailor-made form of LMW heparin that offers several advantages over the animal-derived version, including alleviating the risk of contamination from natural sources. Studies in the test tube and in mice showed that the activity of this customized heparin molecule is easily reversible in cases of overdose or uncontrolled bleeding. And, since it is cleared from the body by the liver rather than the kidneys, this form of heparin would be safer for people with impaired kidney function. Additional research, including testing in humans, will be needed before this new version of LMW heparin can be considered for medical use.

This work also was funded by NIH’s National Heart, Lung, and Blood Institute.

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Epilepsy Drug Improves Health in Animal Model of Obesity

Liver cells of obese mice treated with valproic acid (right) and untreated obese mice (left).
Liver cells (magenta) of obese mice treated with valproic acid (right) had much less fat accumulation (white) than those of untreated obese mice (left). Credit: Lindsay B. Avery and Namandjé N. Bumpus, Johns Hopkins University. View larger image

With more than 90 million Americans affected by obesity, developing medications to help combat weight gain and its associated diseases has become a priority. In a study using obese mice, a team led by Namandjé Bumpus of Johns Hopkins University recently showed that a commonly prescribed epilepsy drug, valproic acid, reduced fat accumulation in the liver and lowered elevated blood sugar levels like those associated with type 2 diabetes. Body weight also stabilized in mice given the drug, whereas untreated mice continued to gain weight. Additional experiments in mouse and human liver cells suggested that the byproducts of valproic acid produced as the body breaks down the drug, rather than valproic acid itself, were responsible for the observed effects. These byproducts achieved the same effects in cells at one-fortieth the concentration of valproic acid, making them promising candidates for further drug development.

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An Experimental Contact Lens to Prevent Glaucoma-Induced Blindness

Contact lens. Credit: Peter Mallen, Massachusetts Eye and Ear Laboratory/Kohane Laboratory, Boston Children's Hospital.
An experimental contact lens design releases a glaucoma medicine at a steady rate for up to a month. Credit: Peter Mallen, Massachusetts Eye and Ear Laboratory/Kohane Laboratory, Boston Children’s Hospital.

Like a miniature donut stuffed inside a tiny pita pocket, a common glaucoma medicine held within a biomaterial ring is sandwiched inside this contact lens. In laboratory experiments, the lens, which can also correct vision, releases the eyesight-saving medication at a steady rate for up to a month. Its construction offers numerous potential clinical advantages over the standard glaucoma treatment and may have additional applications, such as delivering anti-inflammatory drugs or antibiotics to the eye. Led by Daniel Kohane and Joseph Ciolino at Harvard Medical School, the researchers who developed the lens are now gearing up to test its effectiveness in additional laboratory studies. They hope a Phase I clinical trial to evaluate the safety and ability of the lens to reduce pressure in the human eye could begin in about a year.

This work also was funded by NIH’s National Eye Institute.

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Targeting Toxic RNA Molecules in Muscular Dystrophy

Genetic defect that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University.
Scientists revealed a detailed image of the genetic defect that causes myotonic dystrophy type 2 and used that information to design drug candidates to counteract the disease. Credit: Ilyas Yildirim, Northwestern University. View larger image

Myotonic dystrophy type 2 (DM2) is a relatively rare, inherited form of adult-onset muscular dystrophy that has no cure. It’s caused by a genetic defect in which a short series of nucleotides—the chemical units that spell out our genetic code—is repeated more times than normal. When the defective gene is transcribed, the resulting RNA repeat forms a hairpin-like structure that binds to and disables a protein called MBNL1.

Now, research led by Matthew Disney of The Scripps Research Institute (TSRI), Florida Campus, has revealed the detailed, three-dimensional structure of the RNA defect in DM2 and used this information to design small molecules that bind to the aberrant RNA. These designer molecules, even in small amounts, significantly improved disease-associated defects in a cellular model of DM2, and thus hold potential for reversing the disorder.

Drugs that target toxic RNA molecules associated with diseases such as DM2 are few and far between, as developing such compounds is technically challenging. The “bottom-up” approach that the scientists used to design potent new drug candidates, by first studying in detail how the RNA structure interacts with small molecules, is unconventional, noted Jessica Childs-Disney of TSRI, who was lead author of the paper with Ilyas Yildirim of Northwestern University. But it may serve as an effective strategy for pioneering the use of small molecules to manipulate disease-causing RNAs—a central focus of the Disney lab.

This work also was funded by NIH’s National Cancer Institute.

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Genetic Discovery Could Enable More Precise Prescriptions

Prescription pad with DNA illustration on it. Credit: Jane Ades, NIH’s National Human Genome Research Institute.
New insight into the genes that affect drug responses may help doctors prescribe the medications and doses best suited for each individual. Credit: Jane Ades, NIH’s National Human Genome Research Institute.

Scientists know that variations in certain genes can affect the way a person responds to medications. New research by Wolfgang Sadee Exit icon at Ohio State University shows that drug responses also depend on previously overlooked parts of DNA—sections that regulate genes, but are not considered genes themselves. This study focused on an important enzyme abbreviated CYP2D6 that processes about one-fourth of all prescription drugs. Differences in the enzyme’s performance, which range from zilch to ultra-rapid, can dramatically alter the effectiveness and safety of certain medications. Researchers discovered two new genetic variants that impact CYP2D6 performance. One of these, located in a non-gene, regulatory region of DNA, doubles or even quadruples enzyme activity. Coupling these findings with genetic tests could help doctors better identify each patient’s CYP2D6 activity level, enabling more precise prescriptions. The findings also open up a whole new area of investigation into genetic factors that impact drug response.

This work also was funded by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development.

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NIH Director Blogs About Value of Model Organisms in Drug Discovery Research

(Left) Untreated yeast cells, (Right) Treated yeast cells. Credit: Daniel Tardiff, Whitehead Institute.
Treating yeast cells with the NAB compound reverses the toxic effects of elevated levels of alpha synuclein protein. Credit: Daniel Tardiff, Whitehead Institute. View larger image

These eye-catching images and the NIGMS-funded research that yielded them were recently featured by NIH Director Francis Collins on his blog. Scientists led by a team at the Whitehead Institute for Biomedical Research engineered yeast to produce too much of a protein, alpha synuclein. In Parkinson’s disease, elevated levels or mutated forms of this protein wreak havoc on the cell. Using the model system, the researchers tested tens of thousands of compounds to identify any that reversed the toxic effects. One did. The compound, abbreviated NAB, worked similarly in an animal model and in rat neurons grown in a lab dish. Collins described the approach as “an innovative strategy for drug hunting that will likely be extended to other conditions.”

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Using Model Organisms to Study Health and Disease Fact Sheet
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New Approach Subtypes Cancers by Shared Genetic Effects

Cancer

Cancer tumors are like snowflakes—no two ever share the same genetic mutations. Their unique characteristics make them difficult to categorize and treat. A new approach proposed by Trey Ideker and his team at the University of California, San Diego, might offer a solution. Their approach, called network-based stratification (NBS), identifies cancer subtypes by how different mutations in different cancer patients affect the same biological networks, such as genetic pathways. As proof of principle, they applied the method to ovarian, uterine and lung cancer data to obtain biological and clinical information about mutation profiles. Such cancer subtyping shows promise in helping to develop more effective, personalized treatments.

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