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MRSA Toxicity Predicted Through Genomic Sequencing

MRSA bacteria emerge from dead white blood cells (Frank DeLeo, NIH)

MRSA bacteria emerge from dead white blood cells (Frank DeLeo, NIH)

9 April 2014. Researchers in the U.K., U.S., Sweden, and Turkey developed a technique based on genomic sequencing to predict the pathogenic severity of methicillin resistant Staphylococcus aureus or MRSA bacteria, an antibiotic-resistant microbe often found in health care facilities. The team led by University of Bath biologist Ruth Massey published its findings today online in the journal Genome Research.

The Centers for Disease Control and Prevention says the number of cases of MRSA infections are declining in U.S. hospitals and clinics, but remains a serious problem. A CDC study published last year in the American Medical Association’s journal Internal Medicine reports life-threatening MRSA infections declined by more than half (54%) between 2005 and 2011. The same study reported nearly 31,000 fewer MRSA infections from 2005 to 2011, with 9,000 fewer hospital deaths.

Nonetheless, the study reported more than 80,000 cases of life-threatening MRSA infections in 2011, with more than three-quarters of these cases (78%) diagnosed either while in the hospital or soon after release. A 2007 study estimated the direct economic burden on hospitals of MRSA infections between 1999 and 2005 at more than $6 billion, which does not include indirect costs related to patient pain, illness, and time spent in the hospital.

The MRSA microbe is a complex organism, which the authors note, may require a more sophisticated and nuanced response than many current approaches. Massey and colleagues sequenced the genomes of 90 pure MRSA cultures and identified 125 genetic mutations that made each culture either high or low in toxicity.

The team was then able to find a common genetic signature for the high-toxicity cultures. Knowing this signature, say the authors, makes it possible to predict the cultures most likely to be toxic and cause severe cases of MRSA infection.

These findings, says Massey, make it possible to develop a diagnostic technique based on sequencing a swab sample from the patient and personalized to the individual’s infection. “Clinicians will then be able to tailor the treatment to the specific infection,” notes Massey in a university statement. “This technique can tell them which combination of antibiotics will be most effective, or tell them which drugs to administer to dampen the toxicity of the infection.”

The university says the researchers are extending this technique to other virulent MRSA strains as well as other bacterial pathogens.

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UC-San Francisco Launches Brain Disease Trial Registry

Brain visualization image

(Univ of California, San Francisco)

9 April 2014. University of California in San Francisco opened an online registry that aims to reduce the time and cost of recruiting participants in clinical trials for disorders of the brain, such as Alzheimer’s and Parkinson’s disease and traumatic brain injuries. The Brain Health Registry is led by UC-San Francisco radiology professor Michael Weiner, who founded the registry, and psychiatry professor Scott Macklin, with collaboration from a number of companies.

The pharmaceutical industry is increasing its use of online tools to reduce the costs of clinical trials, which account for a large proportion of the development cost of medications. Services like MyClinicalTrialLocator.com and TrialReach.com act as search engines for trials, while PatientsLikeMe uses the community/social media model to encourage people with disease to discuss their experiences and volunteer for clinical studies.

The registry asks volunteers to provide a brief personal medical history and take a few online neuro-psychological tests to provide an outline of visitors’ mental functions. From this first pool, some participants will be asked to provide saliva or blood samples, and take part in clinical trials. All data, says the university, will be protected according to federal privacy laws and the highest medical ethics standards.

Brain Health Registry is seeking volunteers initially from the San Francisco Bay area, and hopes to enroll some 100,000 participants by 2017; about 2,000 already enrolled during the site’s testing phase. The registry’s collections are expected to offer researchers data on brain capabilities through the aging process and help develop diagnostic tools, as well as provide a pool of potential clinical trial volunteers.

The registry is partnering with Lumiosity, a San Francisco company that offers online brain training games. Lumiosity is providing a series of assessments included in the registry’s brain performance tests, as well as recruiting volunteers. Other collaborating companies are Johnson & Johnson Innovation Center and Cogstate, an Australian company developing cognitive testing tools.

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University, Board Maker Partner on Point-of-Care Diagnostics

Microfluidic chip

Microfluidic chip (Sandia National Lab)

8 April 2014. Computer scientists in the U.K. at Southampton University and circuit board manufacturer Newbury Electronics Ltd. are designing a device to detect protein indicators for diagnosing diseases at a doctor’s office or clinic rather than sending out samples to a lab for analysis. The three-year project led by Southampton’s Themis Prodromakis, is funded by a £870,000 ($US 1.45 million) grant, from the Engineering and Physical Sciences Research Council, a science funding agency in the U.K.

The new device aims to perform the diagnostic and analytical functions of an enzyme-linked immunosorbent assay, or ELISA, now used to monitor cell-signaling proteins. But the device needs to be simple and inexpensive enough to perform its analysis at the point of care, return results within at least the same day, and at a much lower cost than today’s techniques that require a remote lab for analysis.

Prodromakis and colleagues plan to develop electronic components acting as chemical sensors, combined with microfluidic chips having tiny channels that capture fluid samples for analysis. The developers anticipate adapting current techniques for producing printed circuit boards to build the device, even if the boards have customized components and microfluidic channels and chambers.

Prodromakis’s lab, part of the university’s Nano Group, is working with Newbury Electronics to better understand processes used for making printed circuit boards. The Nano Group’s research includes work on hybrid biodevices for environmental sensing as well as medical diagnostics.

The project includes clinical trials of the new device at infection and immunity facilities of Imperial College Healthcare NHS, a health system of five hospitals in London. If the work proceeds according to plan, says the university, first prototypes should be available for testing by next year.

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U.S. Patent Granted for Simple Dry-Powder Drug Inhaler

XCaps dry-powder inhaler

XCaps dry-powder inhaler (Hovione International)

7 April 2014. Medical device manufacturer Hovione International in Lisbon, Portugal, received a patent for its inhaler for administering respiratory drugs in dry powder form. U.S. Patent and Trademark Office awarded patent 8,677,992 on 25 March to three inventors and assigned to Hovione International. Among the inventors is Peter Villax, the company’s vice-president for innovation.

Dry-powder inhalers are used by people with asthma, COPD, and other respiratory disorders that make it possible for them to take the drug compound directly into the lungs. The force needed to inhale the drugs is generated by the user who breathes in through the inhaler, which releases the fine powder into the lungs. Some dry-powder inhalers have the drugs preloaded, while others, like the design patented by Hovione, require the user to add the drugs.

The Hovione device, which it markets under the brand-name XCaps, can be configured for inhalation through the nose or mouth. The inhaler has two components: a sliding tray that holds a capsule with a pre-measured dose of the dry-powder medication, and an outer body with an attached inhalation tube.

Blades to cut open the powder capsule are fitted on the walls of the outer body. The user loads a capsule into the sliding tray, and pushes the tray into the inhaler body, where the blades open the capsule. The individual then breathes the medication through the inhalation passage. The tray slides out to dispose of the empty capsule.

Hovione says the XCaps device works with both lactose-based and engineered-particle powders. The company also provides formulation services to prepare medications for dry-powder inhalers. Patents for the device have already been awarded in Europe, Canada, South Africa, and three Asian countries.

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Clinical Trial to Test Advanced Lung Cancer Immunotherapy

Lung cancer X-ray

(National Cancer Institute)

7 April 2014. EMD Serono, a subsidiary of the pharmaceutical company Merck in Rockland, Massachusetts, is beginning a clinical trial to test a vaccine-type therapy for advanced cases of non-small cell lung cancer. The late-stage trial is assessing the ability of tecemotide, an experimental drug designed to trigger an immune response against cancer cells, to extend survival time of patients who already received concurrent chemo- and radiation therapy, but whose lung cancer cannot be removed by surgery.

Non-small cell lung cancer accounts for 85 to 90 percent of all lung cancer cases; the name refers to the size of the cancer cell when viewed under a microscope. This category of lung cancer has various sub-types, which are similar in treatment and prognosis.

Tecemotide is formulated as a vaccine to stimulate T-cells in the body’s immune system for controlling the growth and spread of cancer cells. It is made up of proteins that seek out the antigen MUC1, which appears on the surface of several types of cancer cells, including those of non-small cell lung cancer. Tecemotide was first developed by the biotechnology company Oncothyreon Inc. in Seattle, and licensed to Merck and EMD Serono for clinical trials and commercialization.

An earlier trial of tecemotide with patients having inoperable non-small cell lung cancer showed the therapy was about as successful in extending overall survival time as patients receiving a placebo. Patients in this first trial already received both chemo- and radiation therapy treatments, but the results showed longer survival times for those receiving tecemotide after concurrent chemo- and radiation therapy — median of 30.8 months — compared to the placebo (20.6 months). Patients receiving tecemotide after sequential chemo- and radiation therapies survived about as long as the patients receiving a placebo.

The new trial has a similar design as the earlier study, but in this case participants first receive only concurrent chemo- and radiation therapies, with the group of 1,000 non-small cell lung cancer patients divided about equally between those then receiving tecemotide or a placebo. Patients are being recruited in both the U.S. and Europe. A clinical study similar to the original trial is recruiting some 500 patients in China, Hong Kong, Taiwan, Singapore, and South Korea.

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Cancer Radiotherapy Company Lands $11.6M First Round Funds

PET scanner (DoE)

PET scanner (U.S. Department of Energy)

4 April 2014. RefleXion Medical, a company in Burlingame, California designing a more accurate form of radiation therapy to treat solid tumors, gained $11.6 million in its first round of venture financing. The financing was lead by venture capital company Sofinnova Partners, with participation by Pfizer Venture Investments and Venrock.

RefleXion Medical is developing a new form of radiation therapy for solid-tumor cancers, such as breast, prostate, and lung cancers. The company’s technology harnesses positron emission tomography (PET) scanning, where small amounts of radioactive tracers collect in organs and tissues, and emit signals that become visible when interacting with PET scans. Scans in a PET session are retrieved, assembled, and visualized by computer, providing a three-dimensional image of the target.

While PET scanning is used for cancer diagnosis, it has not been used up to now for treating cancer. Among the problems limiting PET scans for treatment with radiation therapy is the extended time — several minutes — needed to assemble a high-quality image and difficulty compensating for movement of organs and tumors, such as caused by breathing when trying to treat lung cancer.

RefleXion Medical’s solution tightly integrates PET scans with radiation therapy to sharply reduce the lag time between signal detection and radiation dosage. The system employs an algorithm that links light particles detected in PET scans to targeting of radiation therapy. This linkage, says the company, allows the signals detected in PET scans to guide the application of radiation therapy in real time directly to the tumor, delivering more radiation and avoiding healthy tissue nearby.

The company tested its technology in a simulation with lung and prostate tumors using a four-dimensional human model, conducted with engineering researchers at Georgia Tech, and published in 2012 in the journal Medical Physics. The simulation showed RefleXion Medical’s emission guided radiation therapy delivered between 19 and 41 percent more radiation to the tumors in doses aiming for 95 percent of the tumors’ gross volumes. When aiming the radiation to cover 50 percent of the tumors’ gross volumes, the technique delivered 52 to 55 percent more radiation.

RefleXion Medical’s technology was invented by company president Sam Mazin while a postdoctoral researcher in radiology at Stanford University. Also while a postdoc in 2009, Mazin was selected by the Ewing Marion Kauffman Foundation for a fellowship to commercialize the technology, and he went on the found the company soon thereafter.

Proceeds of the financing are expected to expand RefleXion Medical’s research organization and accelerate development of the technology. The company received a Small Business Innovation Research grant from National Cancer Institute in September 2011 to initially develop the technology.

Sofinnova Partners that led the financing is a Paris-based venture capital company specializing in life sciences enterprises. Pfizer Venture Investments is the venture capital arm of Pfizer Inc. Venrock was first established as the venture capital organization representing the Rockefeller family, but today focuses on technology and health care companies.

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Hat tip: Fortune/Term Sheet

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Daiichi Sankyo, UCSF Partner on Neurodegenerative Disorders

3-D brain wiring illustration

3-D brain wiring illustration (NIH)

4 April 2014. The pharmaceutical company Daiichi Sankyo in Tokyo and University of California in San Francisco (UCSF) are collaborating on discovering new drugs to treat neurodegenerative conditions such as Alzheimer’s, Parkinson’s, and Creutzfeldt-Jakob disease. While funding amounts were not disclosed, the deal gives Daiichi Sankyo the option to license compounds discovered through the partnership, in exchange for milestone payments and royalties to UC-San Francisco.

Neurodegenerative diseases cover a number of conditions where neurons or nerve cells in the brain or spinal cord are damaged or die. These disorders are today incurable, and treatments generally try to control symptoms affecting muscle movement and mental functioning. The EU’s Joint Programme on Neurodegenerative Disease says the breakdown of mental functions known as dementias cause the biggest burden of these disorders, with Alzheimer’s disease accounting for most (60 to 70%) of dementia cases.

The agreement calls for Daiichi Sankyo to provide its library of drug compounds to UC-San Francisco’s Institute for Neurodegenerative Diseases. Researchers from the company’s Venture Science Laboratories and the institute will perform high-throughput screening of the compounds to find promising biological connections among the compounds, genes, and molecular pathways that point to new targets for those compounds.

Much of recent research at the Institute for Neurodegenerative Diseases focuses on the role of prions in these disorders. Prions are pathogenic agents that propagate, are transmittable,  and cause abnormal folding of cellular proteins concentrated in the brain. Stanley Prusiner, director of the institute, conducted some of the early research connecting prions to “mad cow” and Creutzfeldt-Jakob disease. In an article published in the journal Science in June 2012, Prusiner outlined the potential role of prions in neurodegenerative disorders other than Creutzfeldt-Jakob disease.

“Alzheimer’s alone kills as many people every year as cancer does, but it only receives one-tenth of the funding that we dedicate to cancer research,” notes Prusiner in a university statement. “This collaboration won’t fill that funding gap, but it will offer the tremendous value of Daiichi Sankyo’s scientific expertise to make progress on these diseases.”

Neurodegenerative diseases represent a new direction for Daiichi Sankyo. The company’s current pipeline has drugs for chronic pain and spinal cord injury in clinical trials, but no programs underway for Alzheimer’s, Parkinson’s, or related diseases. Its Venture Science Laboratories taking part in the collaboration with UC-San Francisco operates as an internal entrepreneurial enterprise for the discovery of new therapeutic targets.

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Poplar Trees Engineered to Produce More Biofuels, Wood Pulp

Poplars

Poplars (Luciano/Flickr)

3 April 2014. Researchers at the Great Lakes Bioenergy Research Center, a consortium of University of Wisconsin in Madison and Michigan State University in East Lansing, created a genetically modified poplar tree variety with weakened lignin bonds, making it easier to process into commercial biofuels and wood pulp. The team from the labs of Wisconsin’s John Ralph and Michigan State’s Curtis Wilkerson, with University of British Columbia’s Shawn Mansfield, published its findings today in the journal Science (paid subscription required).

Lignin is a polymer material in trees and other plants that gives strength to the cell walls, but that same quality in lignin makes it difficult to break down, thus adding considerable effort and cost when processing poplar wood for commercial products, such as biofuels and pulp for making paper. Poplars are fast-growing trees used in packing boxes, industrial pallets, and musical instruments. Poplars also grow on marginal land, thus do not compete with food crops.

While popular wood can today be made into pulp for paper, the quantities of lignin in poplar require pretreatment with chemicals. Ralph’s lab at Wisconsin-Madison began investigating genetic modification of poplars in the mid-1990s, to make it a better feedstock for pulp and paper. Previous attempts to genetically engineer poplars reduced the amount of lignin, which resulted in smaller trees that could not stand up against wind and pests.

With Michigan State’s Wilkerson, the researchers sought a process for creating a variety of poplar with enough lignin to maintain the trees’ strength, but also with weaker esters, the organic bonds making lignin’s chemistry difficult to break down. The team sought out plants with lignin that digested more readily, and found a Chinese medicinal herb, dong quai (Angelica sinensis), where the genes in its root tissue expressed an enzyme that does not add ester bonds into the lignin.

Wilkerson’s lab isolated the key gene from dong quai needed to create a more processable form of lignin, and Mansfield’s lab created the modified form of poplar with the gene from dong quai added. The researchers then grew the modified poplars in a greenhouse. Their tests of the greenhouse plants showed the modified poplars exhibited no abnormalities compared to poplars grown in the wild, including similar total levels of lignin.

The team also submitted the lignin in the modified poplars to gas chromatography–mass spectrometry, a combination of analytical techniques that makes it possible to reveal and quantify the substance’s underlying components. Their analysis showed the lignin in the modified poplars contained the non-native enzymes, with the ability to produce the enzymes apparently transferred from dong quai. Further tests showed the lignin in the modified poplars to be more digestible with mild treatments, releasing more energy-generating glucose sugars than wild-type poplars.

“We can now move beyond tinkering with the known genes in the lignin pathway to using exotic genes to alter the lignin polymer in predesigned but plant-compatible ways,” says Ralph in a Great Lakes center statement. “This approach should pave the way to generating more valuable biomass that can be processed in a more energy efficient manner for biofuels and paper products.”

The research center says the technology is available for licensing through the Wisconsin Alumni Research Foundation.

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Baxter Acquiring Hemophilia Gene-Therapy Biotech Company

Adeno-associated virus

Adeno-associated virus (LBL.gov)

3 April 2014. Baxter International, a pharmaceutical and medical products company in Deerfield, Illinois is buying Chatham Therapeutics LLC, a developer of gene therapy to treat hemophilia. Under the agreement, Baxter will acquire outstanding LLC interests in Chatham for $70 million, but future milestone payments are also possible.

The acquisition gives Baxter access to all of Chatham’s research on gene therapy to treat hemophilia, an inherited disorder where blood is missing its normal ability to clot. Blood gets its clotting ability from proteins called clotting factors that work with platelets, which under normal conditions stick together when blood vessels are damaged and bleeding occurs. There are two types of hemophilia, A and B, depending on the type of absent clotting factors. Type A accounts for about 80 percent of all hemophilia cases.

Chatham Therapeutics, in Chapel Hill, North Carolina, is developing treatments for hemophilia A and B with a technology that harnesses benign viruses called adeno-associated viruses. These viruses are not pathogenic, thus do not cause disease and can serve as carriers for DNA strands. Chatham’s technology creates engineered adeno-associated viruses to carry healthy DNA to hemophilia sufferers. The technology was tested to treat hemophilia B in a small clinical study reported in the New England Journal of Medicine in December 2011.

Baxter agreed to license Chatham’s adeno-associated virus technology in June 2012 to develop a hemophilia B treatment. That program advanced to an early-stage clinical trial conducted in association with Asklepios BioPharmaceutical Inc., also in Chapel Hill, a company with which Chatham has a close relationship, including overlapping leadership. That trial is testing the safety and dosing levels of Chatham’s gene-therapy technology with 16 patients having hemophilia B.

The acquisition agreement calls for Baxter and Asklepios to continue their licensing and developmental ventures. Asklepios has gene-therapy programs for other conditions, including diseases of the heart, central nervous system, muscles, eyes, and liver.

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Hat tip: Fortune/Term Sheet

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Trial Shows Gene Test Improves Lung Cancer Diagnostics

Illustration of lungs (Mikael Häggström/Wikimedia Commons)

(Mikael Häggström/Wikimedia Commons)

2 April 2014. Allegro Diagnostics Corp. in Maynard, Massachusetts says results from a clinical trial testing its genomic technique for diagnosing lung cancer more accurately predicts development of the disease among former smokers than standard bronchoscopies working alone. The company plans to discuss the findings next month at an American Thoracic Society meeting in San Diego, as well as submit the results to a peer-reviewed scientific journal.

Allegro’s technology detects the gene expression of cells from the surface of airways to provide doctors with a much earlier diagnosis of the disease, when more treatment options are available. According to American Cancer Society, lung cancer is the leading cause of cancer death, with the majority of cases diagnosed after age 65, and the risk of contracting the disease much higher among smokers. The five-year survival rate for non-small cell lung cancer, which accounts for about 85 percent of cases, decreases sharply as initial diagnosis occurs later in the progress of the disease.

The BronchoGen test, as the company calls it, detects molecular changes in cells lining the airways, which are correlated with lung cancer. The test is designed to supplement standard bronchoscopy, where a tube is passed through the nose or mouth into the lungs to allow for visual examination with a small camera. Allegro says bronchoscopies alone result in a large percentage of inconclusive results or false negatives, leading to needless surgeries in some cases.

The clinical trial reported by the company tests the accuracy of BronchoGen to detect early molecular changes in cells lining the airways of former smokers. Preliminary results of the trial, reported in 2012 at a meeting of American College of Chest Physicians, gave results from 240 patients with confirmed lung cancer and 90 controls. The results showed BronchoGen combined with bronchoscopy improved the sensitivity of cancer diagnosis to 94 percent, compared to 74 percent for bronchoscopy alone. The BronchoGen alone, however, did not fare much better at 77 percent.

The new results report findings from a larger pool of patients of some 1,000 patients enrolled at 21 sites in the U.S., followed for as long as 12 months for signs of lung cancer.  Allegro says the combination of BronchoGen and bronchoscopy met all of the trial’s main objectives — sensitivity, specificity and negative predictive value for identifying patients with malignant lung cancer — and validate the preliminary findings.

Allegro Diagnostics was founded in 2006 by Jerome Brody and Avrum Spira, both faculty members at Boston University medical school. Spira continues as the company’s chief science and medical advisor.

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