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Computer Model Predicts Bacteria Mutations, Aids Drug Design

3-D image of MRSA bacteria

3-D image of MRSA bacteria (Melissa Brower, CDC)

2 January 2014. Researchers at Duke University and University of Connecticut wrote a mathematical model with open-source software that predicts mutations in bacteria to help design treatments for bacteria resistant to antibiotics. A team of computer scientists and biochemists from the two universities published their findings on 31 December 2014 in Proceedings of the National Academy of Sciences (paid subscription required).

The researchers, led by Duke’s Bruce Donald and UConn’s Amy Anderson, are seeking better drug design tools to test the potential effectiveness of new treatments for infections. While antibiotics greatly reduce illnesses and deaths from infections, the wide use of these drugs contibutes to microbes developing resistance to current drugs. Centers for Disease Control and Prevention estimates at least 2 million in the U.S. people develop infections resistant to antibiotics each year, leading to some 23,000 deaths.

Donald, Anderson, and colleagues adapted software from the open source protein-design package Osprey, short for Open Source Protein REdesign for You. The software offers algorithms for modeling proteins to capture changes in chemistry from mutations in corresponding genomes, and test bindings of proteins with their ligands or chemical connectors. Osprey is available as a free download from Donald’s lab.

The researchers used a routine in Osprey, called the K algorithm, that mathematically tests combinations of proteins and ligands for the most likely ensembles to result from a mutation. In this case, the algorithm modeled genomic variations, called single-nucleotide polymorphisms or SNPs, in methicillin-resistant Staphylococcus aureus (MRSA) bacteria. CDC estimates more than 80,000 annual cases of MRSA infection occur in the U.S., leading to more than 11,000 deaths.

The team specifically tested SNPs that provide resistance to a new class of experimental antibiotic drugs known as propargyl-linked antifolates. These compounds, still in preclinical testing, block activity of an enzyme called dihydrofolate reductase that feeds and recycles carbon atoms in the mutated DNA, thus stopping the development of a mutated bacteria. Anderson’s lab at UConn studies the role of propargyl-linked antifolates in fighting antibiotic resistance.

The Osprey model returned four SNPs with the ability to become resistant to propargyl-linked antifolates, which the researchers say were not previously known to have this potential. The researchers then treated a sample of MRSA bacteria in the lab with propargyl-linked antifolates that killed some, but not all, of the bacteria. By sequencing the DNA of the surviving MRSA, the team found more than half of the survivors’ DNA carried two of the four mutations predicted by the model.

The Duke-UConn authors believe applying mathematical models to predict “drug resistance mutations early in the discovery phase would be an important breakthrough in drug development.” Current methods require look-ups on databases reporting known mutations, but the new study shows not all mutations are always known, giving an advantage to computational methods.

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Happy New Year

1 January 2015. Science and Enterprise wishes all of our visitors a joyous holiday and successful 2015, in any way you define that term. To celebrate the holiday and begin 2015, we offer the new year anthem Auld Lang Syne, sung by Mexican singer and composer Malukah. Science and Enterprise will return to regular posting on Monday.

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Project Aims to Boost Ebola Drug Production

Karen McDonald

Karen McDonald (University of California, Davis)

31 December 2014. A research team at University of California in Davis aims to find new ways of boosting production capacity of the experimental Ebola drug ZMapp. The 1-year project, led by UC-Davis chemical engineering and materials science professor Karen McDonald, is funded by a $200,000 rapid-response grant from National Science Foundation.

The current Ebola outbreak has taken an enormous toll on West Africa and put public health authorities worldwide on alert. World Heath Organization reports as of 24 December nearly 19,500 cases of Ebola reported in the region with 7,588 deaths since the oubreak began. While the outbreak spurned increased R&D activity by academic and industrial labs, no treatments or vaccines are yet available for Ebola.

One promising therapy is a cocktail of engineered antibodies engineered for use in humans called ZMapp, made by the biotechnology company Mapp Biopharmaceutical in San Diego. Mapp Bio derived ZMapp from Nicotiana, a flowering tobacco plant. A test with monkeys reported in August 2013 showed 43 percent of the animals recovered when treated with the antibodies after showing Ebola symptoms. Earlier studies showed all of the test animals were protected against infection when treated with the antibodies an hour after exposure.

The company identified ZMapp as a therapy candidate in January 2014. Mapp Bio, and its commercialization partner LeafBio, produce the treatments using whole tobacco leaves. The company’s process transfers the antibodies into live tobacco leaf DNA with a bacteria, where the antibodies incubate and grow. The plants are then ground up, from which the cultured antibodies are derived and captured as an Ebola therapy.

That process however, is slow and produces only small amounts of usable treatments. As the West Africa Ebola outbreak spread, Mapp Bio made its small stock of ZMapp available for humanitarian purposes, and in August 2014 reported its supply was exhausted.

McDonald and colleagues expect to apply more industrial-scale techniques to quickly expand production of ZMapp. The UC-Davis team plans to adapt the same transfer of enginereed antibodies with bacteria used by Mapp Bio, but culture the antibodies in plant cells in the lab, rather than whole tobacco leaves. If the researchers can grow small quantities of cultured plant cells in the lab, they then expect to expand quantities eventually to a 100-liter bioreactor. Biotechnology companies use these methods to produce medications from microbes, plant, and animal cells.

“Whereas if we can produce it in a bioreactor” says McDonald in a university statement, “a lot of biotech companies and contract manufacturers can do that, and it would allow for much more rapid production.” Global HealthShare Initiative that develops health and economic solutions for low-resource regions, also at UC-Davis, is collaborating with McDonald’s lab on the project.

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Pump Device Shown to Deliver Parkinson’s Drug

3-D brain wiring illustration

3-D brain wiring illustration (NIH)

30 December 2014. A clinical trial testing a pump worn by Parkinson’s disease patients shows the device can continuously deliver drugs under the skin to treat severe forms of the disorder, which today requires a surgical implant. The pump made by NeuroDerm Ltd. in Rehovot, Israel is designed to overcome shortcomings of oral forms of the drugs levodopa and carbidopa to treat symptoms of Parkinson’s disease.

Parkinson’s disease occurs when the brain produces less and less of the substance dopamine, a neurotransmitter that sends sends signals from one nerve cell to another. As the level of dopamine lowers, individuals become less able to control their bodily movements and emotions. Symptoms include tremors, i.e. shaking, slowness and rigidity in movements, loss of facial expression, decreased ability to control blinking and swallowing, and in some cases, depression and anxiety. According to National Parkinson Foundation, some 50,000 to 60,000 new cases of Parkinson’s disease are diagnosed each year.

Among treatments for Parkinson’s symptoms is levodopa, a nervous system agent that converts to dopamine in the brain. Levodopa is often given with carbidopa that gives levodopa more stability and prevents it from breaking down before it reaches the brain, allowing for lower doses. The lower doses of levodopa help reduce nausea sometimes caused by the drug.

Even with carbidopa, however, levodopa taken as a pill still has a short activity life and low absorption, which requires patients to take the drug every 3 to 4 hours, and with only about 30 percent entering the blood stream. To deliver levodopa and carbidopa continuously today, for some patients with severe forms of Parkinson’s disease, requires a pump that infuses the drugs in gel form directly into the small intestine with a tube that must be surgically implanted.

The device developed by NeuroDerm aims to provide continuous delivery of levodopa and carbidopa without surgery. The device code-named ND0612 is a small pump worn on the belt, with 1 or 2  tubes inserted under the skin to deliver a liquid form of the drugs. The ND0612H version is designed to deliver higher doses of the levodopa and carbidopa with 2 tubes, while ND0612L delivers lower doses using 1 tube.

The intermediate-stage clinical trial tested the safety and tolerability of the pump device with a small sample of Parkinson’s disease patients, against a placebo and earlier baseline readings for oral forms of the drugs. The trial also tested the ability of the device to deliver the drugs in maximum concentrations sufficient to treat Parkinson’s symptoms. Of the patients in the trial, 7 were fitted with the higher-dose pump, while 9 had the lower-dose version, with the drugs administered for 8 hours a day over 3 days. All of the patients also took entacapone, an oral drug that helps extend the effects of levodopa and carbidopa.

The results reported by the company show the NeuroDerm devices delivered higher and lower doses of levodopa and carbidopa, as designed, over the treatment periods. In addition, says the company, the devices markedly reduced fluctuations in levodopa and carbidopa levels in the patients’ blood streams, compared to earlier baseline levels for oral forms of the drugs. The company reports as well that all patients completed the trial, with the only adverse effects being minor reactions at the infusion sites.

Oded Lieberman, NeuroDerm’s CEO, says in a company statement that based on the results, “we will proceed with the clinical development of ND0612H and ND0612L in the United States and the European Union in 2015.”

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Vaccine Combo Produces Ricin, Anthrax Antibodies

Anthrax spores (U.S. Food and Drug Administration)

Anthrax spores (U.S. Food and Drug Administration)

29 December 2014.  Tests of a vaccine to prevent ricin and anthrax poisoning shows it produces long-lasting antibodies against both toxins, making a single vaccine against both bioterror agents more feasible. Results of a study by biotechnology company Soligenix Inc. in Princeton, New Jersey are reported in the January 2015 issue of the journal Vaccine (paid subscription required).

Soligenix develops therapies and vaccines with engineered proteins, including vaccines to prevent contracting diseases caused by biological agents. Among vaccines in the company’s pipeline are RiVax to protect against illness from ricin exposure and VeloThrax for anthrax protection. The company’s technology includes processes to produce vaccines in freeze-dried form, making them easier and less expensive to store and distribute than conventional methods requiring continuous refrigeration through the supply chain.

While both ricin and anthrax are considered bioterror threats, they come from very different sources. Ricin is a naturally-occurring substance found in castor beans. Because it is easily produced and stable, ricin can be made into powder or pellets, dissolved in water, and sprayed as a mist. In 2013, ricin-laced letters were sent to the President and members of the U.S. Senate, resulting in an FBI investigation and arrests.

Anthrax is an infectious disease from Bacillus anthracis bacteria, found in soil and in its natural form can infect farm and wild animals. Infections from this natural source of anthrax are rare among humans, and found most often among people working with infected animals. When purified and made into a fine powder or aerosol, however, it can be distributed and spread easily through the air. Letters with anthrax powder sent through the mail in 2001 caused 22 people to become ill, including 12 mail handlers, leading to 5 deaths.

The journal article reports on a study by Soligenix, with colleagues from New York State Department of Health and University at Albany in New York, that evaluated a vaccine formulated with engineered proteins used in the company’s RiVax and VeloThrax. The researchers found the combination vaccine produced antibodies in lab mice to protect against both ricin and anthrax. In addition, mice given the combination vaccine were protected against disease when subsequently exposed to both ricin and the anthrax toxin for as long as 6 months after 2 immunizations of the combination vaccine.

Research by the company for a combination vaccine is funded by a $9.4 million grant from the National Institute of Allergy and Infectious Diseases, part of National Institutes of Health. “The demonstration of simultaneous immunity to ricin and anthrax toxin is a step towards vaccines that can be used in the event of a national emergency,” says Christopher Schaber, Soligenix’s president and CEO.

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Merry Christmas/Feliz Navidad

Science and Enterprise is taking a break tomorrow and Friday for Christmas. In the spirit of the season, here is a video from a group of talented, yet little-known musicians taking part of an initiative called Playing for Change. That organization finds unknown, talented musicians worldwide, many of whom are playing on the street or in open-mike sessions, and gives them a worldwide forum. We’ll be back on Monday, 29 December.

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Early Trial Underway Testing Brain Cancer Drug

Brain silhouettes (Research.gov)

(Research.gov)

24 December 2014. Kinex Pharmaceuticals, a developer of cancer therapies, began an early-stage clinical trial of an experimental treatment for tumors of support cells in the brain. The Buffalo, New York biotechnology company says the first patient received the drug code-named KX2-361 in the trial taking place at Roswell Park Cancer Institute, also in Buffalo, and the Cleveland Clinic, as well as a third site to be named.

The trial is testing KX2-361 in patients with glioma, cancers affecting glial cells that surround and support the brain’s nerve cells. Cancers of this type, including glioblastoma, can be aggressive and highly malignant. Glioma accounts for about a third of all brain cancers, including the kind contracted by the late Ted Kennedy, U.S. senator from Massachusetts.

KX2-361 acts by inhibiting growth of structural elements in tumor cells and signaling enzymes supporting tumor growth. Kinex developed the small molecule drug with its Memetica platform for designing enzyme inhibitors that the company says produces compounds with qualities similar to drugs and a framework for creating drugs taken orally.

Kinex says in preclinical tests KX2-361 clears a wide range of brain tumor cells, including tumor cells resistant to common chemotherapy drugs, in 30 to 60 percent lab animals after 4 weeks of treatments. In these tests, KX2-361 induces more cancer cell death than chemotherapy drugs, and also generates an immune response to glioblastoma. In addition, the tests indicate the drug is absorbed when taken orally and achieves 75 percent penetration into brain tissue.

The company licensed KX2-361 to XiangXue Pharmaceuticals in Guangzhou, China for commercialization in China. XiangXue says it expects to begin an early-stage trial of KX2-361 in China following approval from regulatory authorities.

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FDA Approves New Influenza Treatment

Influenza ultrastructure illustration (Dan Higgins, CDC)

Influenza ultrastructure illustration (Dan Higgins, CDC)

23 December 2014. The U.S. Food and Drug Administration approved yesterday a drug to treat influenza infections in adults. The treatment, Rapivab, is a small molecule drug made by BioCryst Pharmaceuticals in Durham, North Carolina.

BioCryst designs and develops therapies that block enzymes involved in infectious and inflammatory diseases, with a technology that creates synthetic compounds using x-ray crystallography and computer modeling of molecular structures. The company says its use of crystallography allows for analyzing the three-dimensional structure of molecules, resulting in more precise targeting by its drug compounds.

Centers for Disease Control and Prevention reports the 2014-15 flu season is already underway with the proprtion of outpatients visits for flu-like symptoms at 3.7 percent, well above the national baseline of 2 percent. CDC expects between 5 to 20 percent of the U.S. population to get the flu, with more than 200,000 hospitalizations.

Rapivab is designed by BioCryst to block the activity of neuraminidase, an enzyme that releases virus particles from the surface of infected cells. The drug is given as an intravenous infusion in doses of 600 milligrams. FDA approved the drug for adults age 18 and over, who have influenza without complications and experience symptoms for no more than 2 days.

BioCryst developed Rapivab under contract to the Biomedical Advanced Research and Development Authority, a division of the U.S. Department of Health and Human Services. The company says Rapivab was tested in 27 clinical trials, and more than 1 million patients received the drug in Japan and Korea, where it was earlier approved. FDA says there are two other neuraminidase inhibitors, but Rapivab is the first of its kind approved for intravenous infusion.

FDA’s approval was based on a clinical trial with nearly 300 flu patients receving Rapivab in doses of 600 or 300 milligrams, or a placebo. The results show patients receiving 600 milligrams of Rapivab had their flu symptoms relieved 21 hours earlier and reducing fever to normal temperature 12 hours earlier than the placebo. The drug’s effectiveness could not be established, however, in patients with serious cases of flu requiring hospitalization.

The most common adverse effects is diarrhea, although in the clinical trial it occurred at about the same rate (8%) as the placebo (7%). Rare skin infections also occurred.

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Trial Testing Biologic Treatment for Hepatitis D

Liver

Liver (National Library of Medicine)

22 December 2014. An intermediate-stage clinical trial testing a biologic treatment made by Eiger BioPharmaceuticals Inc. shows lower hepatitis D virus levels among patients taking the treatment compared to a placebo. The San Carlos, California company says the treatment, called lonafarnib, also received orphan drug status by regulatory authorities in the U.S. and Europe.

Hepatitis D, also known as delta hepatitis, is a rare type of liver disease caused by defective RNA that requires help from hepatitis B to replicate. Thus, hepatitis D only infects people already infected with hepatitis B. The disease is spread through sexual contact, infected blood products, or shared syringes. People not immunized against hepatitis B are at risk for hepatitis D. If left untreated, hepatitis D can lead to cirrhosis, liver cancer, and liver failure.

Lonafarnib inhibits the activity of enzymes that modify proteins encouraging replication of hepatitis D viruses in the liver, and as a result, blocks the ability of viruses to multiply. Eiger is also developing a similar biologic, code-named EBP921, that inhibits the same protein-modifying enzymes, but in preclinical tests blocks formation of hepatitis D virus particles.

The clinical trial, conducted by National Institutes of Health at its facilities in Bethesda, Maryland, is enrolling 14 patients with chronic hepatitis D. Patients are randomly assigned to receive lonafarnib or a placebo twice a day for 28 days, in doses of 100 or 200 milligrams. The main effectiveness measure in the trial is level of hepatitis D virus RNA in the blood, but the trial is also tracking levels of an enzyme indicator of liver damage and side effects from treatments.

The results of the trial, reported at a meeting of American Association for the Study of Liver Diseases, shows patients taking lonafarnib had lower levels of hepatitis D virus RNA compared to patients receiving a placebo. The researchers also report lower levels of hepatitis D virus RNA when patients take higher doses of lonafarnib. In addition, patients reported lonafarnib was well tolerated with the most common adverse effects being gastrointestinal in nature.

Eiger reports as well that lonafarnib received orphan drug designation from the U.S. Food and Drug Administration and European Medicines Agency. Orphan drug designation from FDA is granted to treatments being developed for diseases affecting fewer than 200,000 people in the U.S. Therapies, both drugs and biologics, designated as orphan drugs qualify for incentives such as tax credits for clinical trials and exemptions from marketing application fees.

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3-D Tissue Assembly System Designed

Jeffrey Morgan

Jeffrey Morgan (Brown University)

22 December 2014. Medical and engineering researchers at Brown University in Providence developed a system that puts together synthetic tissue components into larger tissue assemblies, a step in the creation of synthetic organs. A description of the system from the lab of Brown bioengineering professor Jeffrey Morgan was published on Saturday in the journal Tissue Engineering Part C (paid subscription required).

The university says it filed for a patent on the process, and Morgan recently founded the company Microtissues Inc. in Providence to take inventions from his lab to market.

Morgan and first author Andrew Blakely, now a surgeon at Rhode Island Hospital, developed the system to apply advances in electronic semiconductor assembly to tissue engineering, namely selection, placement, and connection of pre-made components into microchip devices. The technique they call bio-pick, place, and perfuse or Bio-P3 is an extension of the lab’s research creating small tissue parts in standard rod, sphere, and ring shapes, then inducing their self-assembly into more complex shapes, such as honeycombs. These parts are grown in molds without a scaffold or matrix, simplifying their design.

In their paper, Morgan, Blakely, and colleagues demonstrate a prototype system that picks and places the tissue parts into larger pieces of live tissue, while keeping the assembled piece infused with fluid. The system has a clear plastic box with two chambers, one for storing the tissue components and the other for building the new piece of tissue. A nozzle uses gentle suction to pick up and release the tissue components, as well as provide fluid and nutrients for the new tissue assembly.

With the prototype, an operator uses the nozzle pump to manually move a component from the parts chamber to the assembly chamber. The team says later versions will have an automated system for picking, moving, and placing the parts.

In the paper, the researchers report creating a tissue tube by stacking 16 doughnut-like rings around a post. In about 2 days, the rings fused together to create the tube. The team reports as well that they stacked and fused four honeycomb pieces, each with about 250,000 cells, into a single slab about 2 millimeters thick. The structures use cells from liver and ovarian tissue, as well as breast cancer cells.

Morgan says in a university statement, Bio-P3 is an advance over 3-D printing to create engineered tissue. “In contrast to 3-D bioprinting that prints one small drop at a time,” notes Morgan, “our approach is much faster because it uses pre-assembled living building parts with functional shapes and a thousand times more cells per part.”

In August 2014, Morgan’s lab received a 3-year $1.4 million grant from National Science Foundation to build an automated Bio-P3 system for tissue and organ engineering.

Blakely demonstrates and tells more about Bio-P3 in the following video.

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