An engineered protein can disrupt tumor-promoting ‘messages’ in human cells

Over a century of research has shined light on the once-murky innards of our cells, from the genes that serve as our “blueprints” to the proteins and other molecules that are our cellular taskmasters.

Building on this basic knowledge, the search is underway for cellular mechanisms that could serve as gateways for new therapies. These could lead to precise treatments for disease — targeting a specific cellular function or gene with fewer unintended side effects. Ideally, these effects would also be temporary, returning cells to normal operation once the underlying condition has been treated.

A team of researchers from the University of Washington and the University of Trento in Italy announced findings that could pave the way for these therapies. In a paper published July 18 in Nature Chemical Biology, they unveiled an engineered protein that they designed to repress a specific cancer-promoting message within cells.

And that approach to protein design could be modified to target other cellular messages and functions, said senior author and UW chemistry professor Gabriele Varani.

“What we show here is a proving ground — a process to determine how to make the correct changes to proteins,” he said.

For their approach, Varani and his team modified a human protein called Rbfox2, which occurs naturally in cells and binds to microRNAs. These aptly named small RNA molecules adjust gene expression levels in cells like a dimmer switch. Varani’s group sought to engineer Rbfox2 to bind itself to a specific microRNA called miR-21, which is present in high levels in many tumors, increases the expression of cancer-promoting genes and decreases cancer suppressors. If a protein like Rbfox2 could bind to miR-21, the researchers hypothesized, it could repress miR-21’s tumor growth effects.

But for this approach to be successful, the protein must bind to miR-21 and no other microRNA. Luckily, all RNA molecules, including microRNAs, have an inherent property that imbues them with specificity. They consist of a chain of chemical “letters,” each with a unique order or sequence. To date, no other research team had ever successfully altered a protein to bind to microRNAs.

“That is because our knowledge of protein structure is much better than our knowledge of RNA structure,” said Varani. “We historically lacked key information about how RNA folds up and how proteins bind RNA at the atomic level.”

UW researchers relied on high-quality data on Rbfox2’s structure to understand, down to single atoms, how it binds to the unique sequence of “letters” in its natural RNA targets. Then they predicted how Rbfox2’s sequence would have to change to make it bind to miR-21 instead. Elegantly, altering just four carefully selected amino acids made Rbfox2 shift its attachment preference to miR-21, preventing the microRNA from passing along its tumor-promoting message.

The UW team spent several years proving this, since they had to test each change individually and in combination. They also had to make sure that the modified Rbfox2 protein would bind strongly to miR-21 but not other microRNAs. Since microRNAs have many functions in cells, it would be counterproductive to repress miR-21 while disrupting other normal microRNA-mediated functions.

The researchers also engineered a second protein that should clear miR-21 from cells entirely. They did this by grafting the regions of Rbfox2 that bound to miR-21 onto a separate protein called Dicer. Dicer normally chops RNAs into small chunks and generates functional microRNAs. But the hybrid Rbfox2-Dicer protein displayed a specific affinity to slice miR-21 into oblivion.

Varani and his team believe that Rbfox2 could be redesigned to bind to microRNA targets other than miR-21. There are thousands of microRNAs to choose from, and many have been implicated in diseases. The key to realizing this potential would be in streamlining and automating the painstaking methods the team used to model Rbfox2’s atomic-level interactions with RNA.

“This method relies on knowledge of high-quality structures,” said Varani. “That allowed us to see which alterations would change binding to the microRNA target.”

Not only would these be useful laboratory tools to study microRNA functions, but they could — in time — form the basis of new therapies to treat disease.

Lead author on the paper is former UW researcher Yu Chen, who is now at the Seattle Children’s Research Institute. Other UW chemistry co-authors were Fang Yang, Tom Pavelitz, Wen Yang, Katherine Godin, Matthew Walker and Suxin Zheng. Co-authors from the University of Trento include Lorena Zubovic and Paolo Macchi. The research was funded by the National Institutes of Health, the University of Trento and the government of Trento province.

Full story can be found from University of Washington website.

Penumbra Launches Newest Stroke Thrombectomy Technology Device

Penumbra announced U.S. commercial availability of its most advanced thrombectomy device, the ACE™68 Reperfusion Catheter, part of the fully integrated Penumbra System®, at the Society of NeuroInterventional Surgery (SNIS) 13th Annual Meeting in Boston, Massachusetts.

The ACE68 Reperfusion Catheter leverages the latest advancements in tracking technology to deliver maximum aspiration power easily and safely for extracting thrombus in acute ischemic stroke patients.

Clinical experience with the ACE68 will be shared today from 1:30-1:45 p.m. ET in the Industry Technology Luncheon Symposium by Blaise Baxter, M.D., chief of radiology at Erlanger Hospital in Tennessee and chairman of radiology for the University of Tennessee College of Medicine Chattanooga.

“The tracking technology of the ACE68 Reperfusion Catheter is the most advanced,” said Baxter. “In my clinical experience with the ACE68, I saw the device easily navigate difficult tortuosity that would have challenged other devices. ACE68’s tracking performance, combined with a large aspiration lumen to enable efficient clot removal, make ACE68 the most compelling frontline device in stroke intervention.”

The ACE68 Reperfusion Catheter was engineered on a new, innovative tracking platform from hub to tip. Featuring a unique coil winding geometry along 16 transitions to create the optimal tracking profile, ACE68 is designed to ensure easy tracking through tortuosity that is typical in acute ischemic stroke patients. ACE68 is powered to extract clot en masse quickly and effectively as part of the fully integrated Penumbra System.

“With the ACE68 Reperfusion Catheter, I can easily deliver full aspiration power to the occlusion,” said Johanna Fifi, M.D., assistant professor of neurology, neurosurgery and radiology at The Mount Sinai Hospital and director of the Endovascular Stroke Program at the Mount Sinai Health System in New York. “The ACE68’s large lumen increases the likelihood of capturing the clot fully within the catheter or the canister, potentially reducing the number of passes to achieve complete revascularization and minimize ENT (embolization to new territory).”

“The ACE68 provides an opportunity to reverse strokes faster and with less expense,” said Adam Arthur, M.D., MPH, FACS, professor, Department of Neurosurgery, UTHSC, Semmes-Murphey Neurologic & Spine Institute. “The larger lumen seems to allow better clot capture, which may reduce the need for adjunctive devices, simplify the procedure and reduce procedure cost — important considerations as hospitals look to expand stroke services.”

The ACE68 represents the latest advances in tracking technology to deliver a large bore reperfusion catheter easily and reliably through tortuosity that is typical in acute ischemic stroke patients.

“We designed the ACE68 with the intent to make real improvement on stroke procedure time, outcome and cost. The early reports from physicians on the performance of ACE68 confirm that this is the most impactful stroke product we have ever developed,” said Adam Elsesser, chairman and chief executive officer of Penumbra.

A press release can be found from Penumbra website.

Novocure Receives FDA Approval for Second Generation Optune System

Novocure announced that the U.S. Food and Drug Administration (FDA) approved its premarket approval (PMA) supplement application for Novocure’s second generation Optune system. The new smaller, lighter Tumor Treating Fields (TTFields) delivery system is now available to glioblastoma (GBM) patients in the United States.

Novocure designed the second generation Optune system to make treatment with TTFields more convenient and manageable for GBM patients. The new model features a TTFields generator that is less than half the weight and half the size of the generator in the first generation Optune system. Including its battery, the second generation Optune system weighs 2.7 pounds, compared to the first generation system that weighs 6 pounds. Novocure reduced the size and weight of Optune by utilizing novel digital signal generation technology. Additional improvements include: easy-grip texture that allows for better handling; a battery indicator that displays power and alerts patients when to change the battery; a light-detecting sensor that auto-dims the device and charger in the dark; and a “No-Stop Swap” feature that enables patients to change batteries or power source without disrupting delivery of TTFields therapy.

Novocure started offering the second generation Optune system to patients in Germany in October 2015 and has since made it available to all new patients in Europe.

“From the start, Novocure’s mission has been to improve the lives of cancer patients,” said Mike Ambrogi, Novocure’s Chief Operating Officer. “The second generation Optune system was designed to be more convenient and to make it even easier for patients to incorporate treatment with TTFields into their lives. We have received positive feedback from our second generation Optune patients in Europe, and we are excited to roll out our new device to patients in the United States.”

Novocure will offer existing Optune patients in the United States the opportunity to convert to the second generation Optune system over the next several weeks. All new patients will receive the second generation Optune system.

“We are happy to receive FDA approval of our second generation Optune system,” said Asaf Danziger, Novocure’s Chief Executive Officer. “We believe the improvements incorporated into the second generation Optune system will make a big difference to the patients and families who face this devastating disease every day. We will continue to work to improve our technology and patient experience.”

A press release can be found from Novocure website.

Chocolate Heart, a novel drug-coated coronary balloon, received CE approval

QT Vascular Ltd announced that it has received CE mark clearance for the sale and distribution of the Chocolate Heart™ drug-coated PTCA balloon for dilatation of the stenotic portion of coronary arteries for the purpose of improving myocardial perfusion in Europe.

      

Chocolate Heart™ is the drug-coated version of the Company’s Chocolate® PTCA balloon that has been commercially available in the United States (“US”) since late 2014. Chocolate® PTCA features a unique nitinol constraining structure that causes the balloon to open in a controlled uniform fashion, thus is designed to reduce acute trauma, dissections, and unplanned stenting compared to conventional balloons. Initial evidence of this has previously been demonstrated in a trial of the peripheral version of Chocolate® known as Chocolate® PTA (“Chocolate BAR”)1. The Company has added a proprietary coating containing the proven drug, paclitaxel, to the Chocolate® PTCA platform in order to reduce the incidence of repeat procedures. This combination of an atraumatic balloon platform and a proven therapeutic agent is intended to allow certain patients to be treated with Chocolate Heart™ while avoiding the need for a permanent implant such as a metallic stent.

Drug-coated balloons represent a rapidly growing new category of device that combines the mechanical dilatation of a balloon catheter with the biological effect of a drug to treat occluded arteries in the leg. These devices have been available for several years in Europe and were recently approved in the United States. Since their approval in the U.S., adoption has been increasing and CMS (Centers for Medicare and Medicaid Services) has granted additional reimbursement for these devices. According to some analyst estimates3, revenues for drug-coated peripheral balloons are expected to reach $1 billion by 2020. The Company believes that drugcoated balloons may also play an important role in the future in the treatment of patients with disease in their coronary arteries.

More information can be found from QT Vascular Ltd website.

Liver tissue model accurately replicates hepatocyte metabolism, response to toxins

A team of researchers from the Massachusetts General Hospital (MGH) Center for Engineering in Medicine (MGH-CEM) have created a “liver on a chip,” a model of liver tissue that replicates the metabolic variations found throughout the organ and more accurately reflects the distinctive patterns of liver damage caused by exposure to environmental toxins, including pharmaceutical overdose. Their report has been published online in the journal Scientific Reports.

“Our goal with this project was to create a liver tissue construct that responds to toxins the same way the liver in your body does,” says William McCarty, PhD, a postdoctoral fellow at MGH-CEM and the paper’s lead author. “The liver is a chemical processing plant, but it’s not a single vat; different locations within the liver react differently to drugs and toxins. Here, we exploited microfluidics to control the metabolism of liver cells down to a resolution of a few cells, allowing us to create liver tissue that shows the same patterns of toxicity caused by differences in drug metabolism as the liver in your body.”

When blood passes through the liver, it travels from arteries to veins through channels called sinusoids, lined with the liver cells called hepatocytes. From one end of the sinusoid to another, the hepatocytes have different metabolic functions, often controlled by external factors and gene expression. For example, the cells closest to the arterial end of the sinusoid are most efficient at releasing glucose that has been stored in the form of glycogen, while cells at the venous end are most efficient at taking up and storing glucose. Similar differences for other liver functions are well known, with metabolic changes occurring across the 25-cell length of the sinusoid.

In order to develop a system that more closely replicates the metabolic differences among hepatocytes, the research team developed a microfluidic device that distributes hormones or other chemical agents across a 20- to 40-cell-wide sample of hepatocytes in such a way that the effects on the liver cells vary from one side to the other. For example, if blood-sugar-lowering insulin is fed into one of the device’s two inlets while glucagon, which raises blood sugar, is added through the other, the metabolism of the hepatocytes is changed so that those on one side release glucose while those on the other take it up. The use of other agents produced similar results across the field of hepatocytes regarding nitrogen metabolism or alcohol degradation, and use of a molecule that induces the expression of drug metabolism enzymes resulted in varied zones of susceptibility to the toxic effects of acetaminophen.

“Investigators have been developing in-vitro liver models for 40 years, but all of those systems ignore the distinct patterns of metabolically active hepatocytes that exist within the liver sinusoid” says Martin Yarmush, MD, PhD, director of the MGH-CEM and the paper’s senior author. “We hope this tool, which displays zonation of carbohydrate and nitrogen metabolism, in addition to drug detoxification and alcohol degradation, will improve our ability to understand and predict the effects of toxins and new drugs on the liver.”

More information can be found from Massachusetts General Hospital website.

FDA Approves Extended Depth of Focus Lenses for People with Cataracts

Abbott announced today that the U.S. Food and Drug Administration (FDA) has approved the Tecnis Symfony® Intraocular Lenses for the treatment of cataracts. The first in a new category of intraocular lenses (IOLs), the Tecnis Symfony lenses are the only lenses in the United States that provide a full range of continuous high-quality vision following cataract surgery, while also mitigating the effects of presbyopia by helping people focus on near objects. The FDA approval includes a version of the lens for people with astigmatism, the Tecnis Symfony Toric IOL.

Cataracts are a common condition, with almost 4 million cataract surgeries performed each year, and that number is expected to increase.1 By age 80, more than half of all Americans either have a cataract or have had cataract surgery.2 However, cataracts do not just impact seniors. In 2016 it is estimated that nearly one in four cataract surgeries will be performed on people younger than 65.1 Many people who have cataracts experience other problems with their vision, such as presbyopia and astigmatism, which the Symfony lenses also address. Presbyopia, which affects most people over age 40, means people have lost the ability to focus on objects up close and often require glasses to perform near visual tasks. Astigmatism is when the cornea is misshapen, which causes blurry or distorted vision.

“The Symfony intraocular lens is a new option I can offer my patients to improve their vision following cataract surgery, especially those who have difficulty focusing on objects at near distances because of presbyopia,” said Eric D. Donnenfeld, M.D., of Ophthalmic Consultants of Long Island, New York. “Many of my patients live very active lifestyles and want to see clearly at all distances, and without glasses if possible. With the Symfony lens, I can give patients the freedom to enjoy the activities that matter to them, while wearing glasses less.”

During cataract surgery, the natural lens of the eye is removed, and an artificial lens, called an intraocular lens, or IOL, is inserted into the eye. The IOL most commonly used in cataract surgery is a monofocal lens, which only allows the person to see at a distance, with closer objects being out of focus. In contrast, the Symfony lens was specifically developed with features to improve both the range and quality of vision.

“Abbott is focused on improving people’s vision and their lives by helping them stay healthy and active. Symfony offers patients, including those with astigmatism, an option for crisp, clear vision at all distances,” said Thomas Frinzi, senior vice president of Abbott’s vision business. “This is an important addition to our portfolio of lenses, as we expect many patients to choose a Symfony lens over a standard monofocal lens, given its benefits. We are happy that we can offer more people around the world this new category of lenses.”

The approval was based on results of a U.S. pivotal study that compared the Tecnis Symfony lens to a Tecnis aspheric monofocal lens in 298 patients. Compared with patients in the monofocal group, those who received a Tecnis Symfony IOL achieved greater improvements in intermediate and near vision while maintaining similar distance vision. Patients in the Symfony group were also more likely to achieve reduced overall spectacle wear and high overall visual performance in any lighting condition. Rates of adverse events did not differ between the Symfony and monofocal groups.

The Symfony lens is approved in more than 50 countries around the world, and has been widely studied, with data from numerous clinical studies involving over 2,000 eyes. In clinical studies, the Symfony lens:
Provided seamless, day-to-night vision. Patients could see objects sharply and clearly at near, intermediate and far away distances, and points in between.
Provided high-quality vision. Some IOLs may leave patients with an inability to focus clearly due to competing wavelengths of light passing through the lens at different angles (known as chromatic aberration), or with vision that is not completely focused because of the shape of the lens (known as spherical aberration). The Symfony lens has been engineered to correct these issues.
Demonstrated a low incidence of halo and glare, which may be perceived as rings or blurring around bright lights. Glare and halo can sometimes affect an individual’s ability to drive at night or to perform other visual tasks.

More information can be found from Abbott website.