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New Coating Material Stops Blood Clots, Bacterial Films

Coating test with glass slides

These glass slides were dipped in blood to demonstrate the effectiveness of the tethered–liquid perfluorocarbon or TLP coating. While blood sticks to the untreated slide on the left, the slide treated with TLP on the right emerges entirely clear. (Wyss Institute, Harvard University)

13 October 2014. Engineers and medical researchers at Harvard University developed a material to coat tubes in medical devices that repels blood, preventing clots from forming and reducing the need for blood-thinning drugs. The new material from Harvard’s Wyss Institute for Biologically Inspired Engineering and collaborators at affiliated labs and hospitals is described in an article published yesterday in the journal Nature Biotechnology (paid subscription required).

Blood clots and infections are concerns for people needing dialysis or catheter-based treatments, which can cause serious complications for people already with significant medical burdens. Preventing blood clots when using these devices often requires taking anticoagulants or blood-thinners, which can have adverse side-effects, such as excessive bleeding.

The Wyss team adapted a technology developed by Joanna Aizenberg, one its researchers and a senior author of the article, called Slippery Liquid-Infused Porous Surfaces or Slips, that creates a surface highly repellent to foreign matter. Slips is inspired in part by carnivorous pitcher plants that trap insects in a slippery inner chamber from which they cannot climb out. “Traditional Slips uses porous, textured surface substrates to immobilize the liquid layer,” says Aizenberg in a university statement,  “whereas medical surfaces are mostly flat and smooth. So we further adapted our approach by capitalizing on the natural roughness of chemically modified surfaces of medical devices.”

The researchers had another requirement for adapting Slips to medical devices, namely to use materials already approved by the U.S. Food and Drug Administration, to speed adoption by industry. Their solution binds two types of perfluorocarbons: a layer of perfluorocarbon similar to Teflon, with a liquid perfluorocarbon now used clinically to help infants with breathing difficulties. Perfluorocarbons are twice as dense as water and can dissolve gases like oxygen and carbon dioxide.

The team calls this new material tethered–liquid perfluorocarbon or TLP, which they tested in the lab on 20 different surfaces. The results show the super-slippery TLPs prevent the attachment of fibrins and platelets that cause blood clots, as well as the formation of biofilms, colonies of bacteria associated with medically-related infections.

In one of the tests, researchers tried to grow Pseudomonas aeruginosa bacteria in medical tubing coated with TLP for 6 weeks, and found less than 1 in a billion bacteria were able to adhere to the tube surface. An estimated 51,000 healthcare-associated P. aeruginosa infections occur in the U.S. each year, according to the CDC, with 13 percent of those infections involving antibiotic resistant bacteria.

In addition, the team implanted pigs with medical tubing similar to those in medical devices, and coated with TLP. The tests with pigs showed the coated tubing maintains high blood flow rates without the need for anticoagulant drugs.

The following video tells more about TLPs, including a test with a live gecko.

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Hepatitis C Combination Drug Approved by FDA

Microscopic view of the hepatitis C virus (VA.gov)

Microscopic view of the hepatitis C virus (VA.gov)

Updated 11 October 2014. The U.S. Food and Drug Administration approved a drug combining a new compound, ledipasvir, with the existing drug sofosbuvir to treat hepatitis C genotype 1, the most common form of the disease. The combination of ledipasvir and sofosbuvir is developed and marketed under the brand name Harvoni by Gilead Sciences Inc. in Foster City, California.

Hepatitis C is a viral infection affecting the liver, with some 3.2 million infected with the virus in the U.S., according to Centers for Disease Control and Prevention. The disease is transmitted through contact with infected blood; intravenous drug users sharing needles are among those at the highest risk. The virus causes inflammation of the liver and can lead to scarring and poor liver function (cirrhosis) over many years. Because there are no symptoms early on, many people with hepatitis C infections do not get treatment until more serious complications occur.

There are 6 known genetic types of hepatitis C, with genotype 1 accounting for 75 percent of all cases in the U.S. Genotype 1, however, is the least likely of the major types of the disease to respond to treatment.

Harvoni is the first drug to combine ledipasvir with sofosbuvir to treat hepatitis C, genotype 1. FDA approved sofosbuvir, also made by Gilead Sciences and marketed under the brand name Sovaldi in December 2013 to treat hepatitis C. Sovaldi, like Harvoni, is a once-a-day pill, and is taken with other drugs, such as ribavirin.

Harvoni, however, was tested in clinical trials, and found as effective when taken alone as with ribavirin. FDA cited three sets of late-stage clinical trials in its approval decision that show Harvoni enabled 94 percent of hepatitis C patients to be free of the virus in their blood after 8 weeks, and 96 to 99 percent virus-free after 12 weeks. Patients who underwent previous therapies required 24 weeks to be virus-free.

FDA reviewed Harvoni under its priority review program, which grants expedited review for treatments showing a substantial improvement over current drugs for serious or life-threatening conditions. The agency also called the drug a breakthrough therapy, thus also qualifying for expedited attention.

Forbes magazine reports today that Harvoni, like Sovaldi, will be an expensive drug, costing $94,500 for a 12-week course of treatment. Sovaldi costs $84,000 for a full treatment. The magazine says 35 states require prior authorization for Sovaldi, including a liver biopsy to determine severity of disease, before Medicaid authorities in those states will approve payments for the drug.

Update: 11 October 2014. The New York Times points out this morning that most people taking Harvoni will need only the 8-week course of treatment, making its cost over that time $63,000, less than the $84,000 needed for 12 weeks of Sovaldi. The cost per dose of Harvoni, $1,125, is still more than $1,000 for Sovaldi.

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Stem Cells Engineered to Produce Insulin-Making Cells

Human stem cell derived beta cells

Human stem cell derived beta cells in mice (Doug Melton, Harvard University)

9 October 2014. Researchers at Harvard University developed a technique that enables embryonic stem cells to transform into large quantities of insulin-producing beta cells found in the pancreas, a key step in developing a treatment for type 1 diabetes. The team led by biologist Douglas Melton, co-director of the university’s Stem Cell Institute, published its findings today in the journal Cell (paid subscription required).

Beta cells in the pancreas, when functioning properly, produce insulin, a hormone that helps the body store and process glucose provided by food in the diet. People with type 1 diabetes, a condition where the body’s immune system is tricked into destroying beta cells. Some 3 million people in the U.S. have type 1 diabetes, including many children and young adults, who need to replace their insulin supply daily through injections or devices such as insulin pumps.

Melton and colleagues designed a culturing protocol for transforming human embryonic stem cells into pancreatic and endocrine progenitor cells, and then into beta cells. Their techniques enabled the team to generate hundreds of millions of beta cells in the lab that perform the same insulin-secreting functions, responding to glucose as normal mature beta cells. Tests of the beta cells show their genes express similarly to normal beta cells.

The researchers then implanted the lab-produced beta cells in mice where the cells secreted insulin in response to glucose as they had done in lab cultures. In addition, the team induced a diabetic state in lab mice, and found transplants of the lab-produced beta cells relieved hyperglycemia, a high blood glucose condition, in the test mice. Harvard says Melton’s lab is also testing stem-cell derived beta cells in monkeys.

For Melton, the issue of type 1 diabetes is personal. The university says his son and daughter were diagnosed with the disorder as children, and he made finding a cure the goal of his career. Melton is collaborating as well with MIT biomedical engineer Daniel Anderson to develop a device that protects the 150 million implanted beta cells from immune-system attack. Preclinical tests of the device with lab mice indicate the device can protect the cells for months while they continue to produce insulin.

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Mind-Controlled Prosthetic Arm Given Long-Term Test

Prosthetic arm on truck driver

The recipient of the prosthetic arm works in a demanding job, as a truck driver (Chalmers University of Technology)

9 October 2014. Biomedical engineers in Sweden developed and tested for 18 months a prosthetic device connected to a man’s amputated arm that provides electrical signaling with his mind and body. The team of biomedical engineering Ph.D. candidate Max Ortiz-Catalan and professor Bo Håkansson from Chalmers University of Technology and orthopedist Rickard Brånemark of Sahlgrenska University Hospital, both in Gothenburg, published its findings in today’s issue of the journal Science Translational Medicine (paid subscription required).

Ortiz-Catalan and colleagues demonstrated a prosthetic arm connected with a titanium rod to the bone of a man whose arm was amputated between the elbow and shoulder. A surgical team led by Brånemark connected the prosthetic arm in January 2013 that offers mechanical stability and acts as an extension of the man’s amputated arm.

The device, made to look and feel like a real arm, has neuro-muscular electrodes woven under the skin to provide continuous sensory feedback that helps stimulate nerves and offer better control. In conventional socket prostheses, say the researchers, electrodes are placed on the skin rather than under it, and as a result can be disrupted by environmental factors such as changes in temperature and nearby electromagnetic interference (e.g., from heavy machinery), diminishing their reliability.

The electrodes connect to peripheral nerves and muscles, allowing the man to operate and control the device, over long periods during the day, as long as 18 hours at a time, with little physical fatigue. The device also provides sensory feedback in the hand that allows the man to fine-tune his gripping motion, to the point of handling fragile items. In addition, the sensors enable the man to sense touch in different parts of the hand to allow for complex hand movements, such as in tying shoelaces.

After tests in the lab, the patient took the prosthetic device on the road, literally. He works as a truck driver in northern Sweden, and according to the researchers, was able to function in the job, performing tasks such as clamping on trailer loads and operating machinery. He could also use the arm when unloading deliveries, including fragile items such as eggs.

“Reliable communication between the prosthesis and the body has been the missing link for the clinical implementation of neural control and sensory feedback,” says Ortiz-Catalan in  Chalmers statement, “and this is now in place.” The team plans to further develop the device-to-brain signaling to make the prosthetic arm’s electronic connections more bi-directional. The researchers also expect to expand the number of patients testing the device.

The man demonstrates capabilities of the prosthetic arm in the following video.

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Patent Awarded for Detailed Pandemic Flu Detection Test

U.S. Patent and Trademark Office

U.S. Patent and Trademark Office (A. Kotok)

8 October 2014. A genomics-based test to detect various types of pandemic influenza, including mutated forms resistant to antiviral drugs, is the recipient of a recent patent. The U.S. Patent and Trademark Office awarded patent number 8,808,993 — Methods and Kits to Detect New H1N1 “Swine Flu” Variants — to three inventors, and assigned it to Translational Genomics Research Institute (TGen) in Phoenix, Arizona and Northern Arizona University in Flagstaff.

The patent covers techniques devised by TGen’s Paul Keim, David Engelthaler and Elizabeth Driebe to detect the precise strain and properties of H1N1 or swine flu virus with genomic probes called oligonucleotides from a sample of genetic material that indicate specific genomic sequences. Keim is also a biology professor at Northern Arizona.

The H1N1 flu virus caused a global disease outbreak or pandemic in 2009, but has become a recurring seasonal flu virus, and in 2014 the predominant form of flu in the U.S. Tests are available to determine if someone with flu symptoms — fever, body aches, tiredness, and cough — is infected with a flu virus, but specialized equipment available in only a few labs, such as the U.S. Centers for Disease Control and Prevention, is needed to determine more details about the virus’s strain, including its resistance to current medications. Those detailed tests are normally conducted today only for patients requiring hospitalization or at high risk from a compromised immune system.

Techniques in the patent make it possible for tests to analyze a mucus sample or respiratory swab from the patient. The test is comprised of a series of oligonucleotides that determine the sequence of nucleic acid identifiers revealing the presence of H1N1, but also the precise strain, including properties likely to be resistant to current medications, such as Tamiflu.

The techniques are designed for packaging in a test kit administered in a doctor’s office, without sending it out to a separate lab. The results are expected to give physicians a precise identification of the H1N1 virus, to prescribe an appropriate treatment. “This new test puts the power in the hands of the clinician to determine if their drugs will work or not,” says Engelthaler in a TGen statement, adding, “This is really important moving forward as we discover new strains that are resistant to antivirals.”

TGen says it expects to license the technology for development of test kits or a flu testing service.

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Drug Screening Target Designed for All Ebola Types

Scanning electron micrograph of Ebola virus

Scanning electron micrograph of Ebola virus (National Institute of Allergy and Infectious Diseases)

8 October 2014. Researchers at University of Utah and Navigen Inc., both in Salt Lake City, designed a synthetic peptide acting like a protein found in all strains of the Ebola virus that can serve as a target when screening for potential drugs to treat patients with the deadly disease. The team led by Utah biochemist Debra Eckert published its findings online this week in the journal Protein Science (paid subscription required).

The Ebola epidemic now spreading in West Africa is caused by the Zaire species of the virus, one of five species identified so far. While current research and control efforts are focused on the Zaire species, Eckert and colleagues are seeking tools that can help develop therapies for all types of the virus, to prepare for future outbreaks, or a weaponized version of the disease.

“Although the current push of clinical trials will hopefully lead to an effective treatment for the Zaire species causing the present epidemic,” says Eckert in a university statement, “the same treatments are unlikely to be effective against future outbreaks of a different or new Ebola species. Development of a broadly acting therapy is an important long-term goal that would allow cost-effective stockpiling of a universal Ebola treatment.”

Previous research by the Utah lab looked at mechanisms of the HIV virus to enter human host cells, and the researchers in this paper used that same approach with Ebola. The team designed a synthetic peptide acting like a natural string of amino acids that forms part of the protein the Ebola virus uses to enter and start infecting human host cells. This protein is found in and acts similarly across all Ebola species.

The researchers tested the synthetic peptide as an marker for screening potential drugs to prevent entry of the Ebola protein into human host cells, with a phage display, a lab technique that identifies interactions among proteins, peptides, and DNA in a similar manner to natural processes. The tests show their synthetic peptide could act as a marker to find drugs that prevent the protein from entering human cells.

Navigen Inc. discovers and develops therapies from synthetic peptides called D-pepides that act like natural peptides, but are more stable in the body and less likely to cause an immune-system reaction. The company has a library of peptides that it says can screen billions of unique peptide sequences for binding to virtually any target. Navigen has an exclusive license to the Utah synthetic peptide technology and is currently screening D-peptide candidates to find Ebola treatments.

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Company Launched for Tissue Regrowth, Inflammation Drugs

Eva Turley

Eva Turley (London Health Sciences Centre)

7 October 2014. Novare Pharmaceuticals, an enterprise commercializing research on a protein that can treat inflammatory diseases and help create new cells for rebuilding tissue, such as after a mastectomy, began operations today under the auspices of Allied Minds, a company creating start-ups based on scientific discoveries at U.S. universities and national labs. The new company, based in Boston, expands on the work of ProGDerm, an earlier Allied Minds-supported start-up.

Novare aims to bring to market therapies that act on the Receptor for Hyaluronan Mediated Motility or RHAMM, a protein expressed in breast tissue, but also associated with spontaneous cell movement and stem cell differentiation. Regulation of this protein is believed to help moderate destructive inflammation, reduce scarring, and promote growth of adipose or fat tissue under the skin.

The company is expected to develop treatments based on RHAMM for disorders affecting the lungs, such as bronchopulmonary dysplasia in premature infants and idiopathic pulmonary fibrosis in older adults. RHAMM regulation is also associated with localized stimulation of adipose stem cells near the skin, that offers an opportunity to regenerate breast tissue for women who have undergone a mastectomy. In addition, RHAMM regulation is believed to help reduce fibrous scarring, which was the focus of ProGDerm, Novare’s predecessor.

Novare licensed research on RHAMM by Eva Turley at London Health Sciences Centre in Ontario, Canada in collaboration with Mina (M.J.) Bissell at Lawrence Berkeley National Laboratory in California. Turley, who serves as Novare’s chief scientist, found RHAMM regulation offers potentially safe and effective processes for regenerating breast tissue and treating disorders caused by inflammation and fibrosis. The company also licensed more RHAMM compounds from Turley’s London lab that increases Novare’s library of peptides that bind to RHAMM, thus adding more applications for this technology.

Allied Minds, also based in Boston, forms new companies based on research at universities in the U.S. as well as federally-sponsored labs, and provides financing and management to get their operations off the ground. Enterprises started by Allied Minds are founded as subsidiaries, then provided with management and financing to develop its products or services and revenues, leading to liquidity through acquisition or initial public offering. The company says it has formed 20 subsidiaries, including partnerships with federal research labs and the pharmaceutical company Bristol-Myers Squibb.

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Genes Identified to Boost Vitamin A in Corn

Orange corn

Orange corn, naturally high in carotenoids (Natalie van Hoose, Purdue University)

6 October 2014. Agricultural researchers at Purdue University identified a few key genes that can increase ingredients in corn for building vitamin A in humans. And because these genes are already found in some corn varieties, say the authors, new types of corn can be developed without transferring genes from other species. The team led by Purdue agronomist Torbert Rocheford — with colleagues from Purdue, Cornell, and Michigan State universities — published its findings last week in the journal Genetics.

Vitamin A deficiency is a condition that can lead to vision problems and according to World Health Organization is the main cause of preventable blindness, particularly in low income countries. It is considered a major public health problem in Africa and southeast Asia, affecting children and pregnant women, not only for vision problems, but also for increasing risks of severe infections. Lack of vitamin A can also contribute to macular degeneration among the elderly, a condition leading as well to blindness.

WHO estimates 250 million preschool children worldwide are deficient in vitamin A, and between 250,000 and 500,000 children become blind each year because of vitamin A deficiency. The source of vitamin A is a healthy diet rich in substances known as carotenoids used by humans to produce vitamin A, but in Sub-Saharan Africa, white corn is a staple food that has minimal amounts of carotenoids.

Rocheford and colleagues, therefore, sought to uncover genetic clues for producing corn varieties with higher quantities of carotenoids, known as orange corn since kernels on this corn turn a dark shade of orange. While orange corn is richer in carotenoids, it is not yet grown in Africa, but would likely be accepted by African corn growers, who can distinguish it from yellow corn that is fed to cattle.

The researchers conducted a genome-wide association study, a type of intensive genomic survey,of 201 lines of corn to reveal aspects of the corn genome most associated with carotenoid levels. Rocheford’s lab previously identified two genes linked to carotenoid production, but sought other genes associated with carotenoids, as well as to better understand the genetic pathways or processes for their production in corn.

The initial association study uncovered two genes not previously linked to carotenoid production. A further analysis of 58 gene candidates previously associated with nutrient processes revealed two more genes linked to carotenoid traits. In addition, the researchers analyzed a small number of quantitative trait loci, a statistical method connecting genomic characteristics to physical traits like carotenoid production, to identify genetic predictors of carotenoid production.

The genomic analysis and statistical models yielded data to outline a strategy for quickly developing new varieties of high-carotenoid corn that can be grown by farmers in Africa without introducing genes from other plant species. The Purdue team is already working with international agricultural groups including HarvestPlus and the International Wheat and Maize Improvement Center experimenting with some orange corn varieties.

“We now have the genetic information needed,” says Rocheford in a university statement, “to begin developing a major public-private sector collaboration with the goal of providing orange corn with high levels of provitamin A to farmers throughout Sub-Saharan Africa.”

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Drug Delivery, Rewards Companies Partner on Med. Adherence

Pills and drug bottles (FDA.gov)

(FDA.gov)

6 October 2014. West Pharmaceutical Services, a company producing devices for administering drugs, and HealthPrize Technologies that offers an online system for rewarding patients when they follow medication instructions, are collaborating on a platform that connects their products into a service to boost medication adherence. Financial details of the venture were not disclosed.

The companies plan to offer their service to drug manufacturers as an integrated system to improve the number of patients taking their medications as prescribed. Getting patients to take prescribed drugs is a particular problem with chronic diseases. A 2003 report by World Health Organization estimates half of patients are not taking medications as prescribed, with reasons attributed to behavior, activities, and incentives of the patients, physicians, and health care systems.

Not only does the health of patients suffer when they don’t take their prescribed drugs, the pharmaceutical companies worldwide lose an estimated $564 billion in revenue, according to a study for HealthPrize by CapGemini. HealthPrize Technologies, in Norwalk, Connecticut offers online services to encourage patients with chronic diseases to take their medications as prescribed, using games and other incentives. Its program aims to provide short-term rewards for patients who may receive long-term benefits from taking their drugs, but who need incentives in the interim to keep up with their medications.

West Pharmaceutical Services in Exton, Pennsylvania produces drug packaging, diagnostics, and delivery systems for the pharmaceutical industry. Among its products are hand-held and wearable devices for self-injected drugs or biologics, such as insulin. Under the deal, West and HealthPrize will develop drug delivery systems connected electronically to track adherence, engage and educate patients on the value of following medication instructions, and provide rewards for taking their drugs as prescribed.

While the collaboration is expected to focus first on West’s self-medication systems, the companies say they’re aiming for a comprehensive solution that can be applied to more types of devices. They anticipate employing technologies such as QR codes, near-field communications, and so-called smart labels with built-in radio-frequency ID tags, that can be extended to drug delivery systems made by companies other than West.

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Tissue Engineers, Biotech Firm Partner on Cartilage Repair

Engineered replacement cartilage

NeoCart engineered replacement cartilage (Histogenics Corporation)

3 October 2014. Histogenics Corp. that develops replacement cartilage is licensing technology from Intrexon Corp., a biotechnology company producing engineered genetics for commercial applications, for a new process to repair cartilage injuries with a patient’s own cells. The deal has a potential value of at least $44.5 million to Intrexon, but could also result in a return investment of up to $15 million in Histogenics.

Cartilage is the elastic connective tissue between joints that also acts as a cushion between the bones in the joint, but unlike bones, does not repair itself. While highly resilient, cartilage can wear down with age or tear under stress from trauma. The wear and tear of age, often compounded by obesity, can lead to a loss of joint cartilage, a condition known as osteoarthritis causing inflammation and pain. Various therapies are available from drugs to relieve the pain and inflammation to surgery.

One type of surgery takes a patients own cartilage cells, called chondrocytes, and cultures the cells in a lab, to grow replacement cartilage tissue. Histogenics, in Waltham, Massachusetts, offers a form of this therapy, which takes a piece of a patient’s cartilage from non-weight bearing surfaces in the body and grows new cartilage tissue on a collagen scaffold that can be implanted in the patient. The company is testing its implant therapy, called NeoCart, in a late-stage clinical trial.

Intrexon’s technology, known as UltraVector, combines DNA with cellular and protein engineering, but also applies computational models for the design and production of synthetic biological functions. UltraVector, says the company, acts as the operating system for the technology, with applications for the regulation of gene expression and precise targeting of engineered genetics built to work with UltraVector.

The deal calls for Histogenics to adapt genetic engineering techniques from Intrexon, in Germantown, Maryland, to develop a new kind of cartilage repair that starts with a patient’s own cells. The collaboration aims to create an off-the-shelf line of genetically modified chondrocyte cells that can control for immune system compatibility, and still work with Histogenics’ cellular scaffolds and manufacturing processes.

Under the deal, Histogenics pays Intrexon a one-time “technology access fee” of $10 million as a convertible promissory note, and will reimburse Intrexon for research and development costs, in two installments over the course of the collaboration. In addition, Histogenics will provide commercial and regulatory milestone payments to Intrexon of $34.5 million, as well as royalties on gross profits of products from the partnership. Intrexon, for its part, will have an option of investing up to $15 million in Histogenics.

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