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Nanoneedles Deliver Therapeutic DNA, Grow Blood Vessels

Microscopic view of cell on nanoneedles

Electron microscope image of cell, in brown, on blue nanoneedles (Imperial College London)

31 March 2015. A device made of tiny nanoscale needles successfully delivered genetic material that encourages growth of blood vessels in lab animals, in tests of its therapeutic potential. Researchers from Imperial College London in the U.K. and Houston Methodist Research Institute in Texas reported their findings yesterday in the journal Nature Materials (paid subscription required).

The team led by Imperial biomaterials professor Molly Stevens and professor of nanomedicine Ennio Tasciotti at Houston Methodist is seeking a more efficient, safe, and reliable method to deliver nucleic acids as treatments for disease and regenerative medicine. Nucleic acids are the genetic building blocks that make up DNA containing an individual’s unique genetic code and related RNA molecules giving instructions for the functioning of cells in the body.

In their study, the team tested a device made of tiny nanoscale needles — where 1 nanometer equals 1 billionth of a meter — to deliver nucleic acids directly to affected tissue. The device is made of chemically-etched nanoneedles in biodegradable silicon, arrayed on a spongy base that can hold larger volumes of nucleic acids than solids. The researchers designed the device to deliver their payloads directly into cells, with the needles penetrating the outer cell membrane, that then degrade into a harmless substance.

Stevens, Tasciotti, and colleagues tested their device first with human cells in lab cultures, where they report the nanoneedles delivered DNA and a form of RNA with an efficiency greater than 90 percent. The team then applied the device to muscles in the backs of lab mice, delivering  vascular endothelial growth factor 165 gene that expresses a protein encouraging growth of blood vessels. The researchers report the implanted nanoneedles induced a 6-fold increase in blood vessel formation in back muscles of the mice.

The authors believe the nanoneedle device could be used with natural or artificial organ transplants to encourage blood vessel growth that helps the implanted organ connect faster with the recipient’s body. “There are a number of hurdles to overcome and we haven’t yet trialled the nanoneedles in humans,” says Stevens in a university statement, “but we think they have enormous potential for helping the body to repair itself.”

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Novartis, Aduro Biotech Partner on Cancer Immunotherapy


T-cell (NIAID/NIH)

30 March 2015. The pharmaceutical company Novartis is licensing cancer immunotherapy technology from Aduro Biotech in Berkeley, California. The collaboration could earn Aduro as much as $750 million, including an equity stake, for access to its work on cyclic dinucleotides, still in preclinical study, but considered promising as a cancer treatment.

Cyclic dinucleotides are naturally occurring molecules, found in both bacteria and mammals, but in mammals activate a signaling mechanism in immune-system cells. When stimulated, this pathway, known as Stimulator of interferon genes or Sting, induces production of cells and proteins that support and amplify the immune system.

Aduro says its technology develops engineered cyclic dinucleotides that are more potent in stimulating the Sting pathway than the naturally-produced variety, to encourage a response in T cells, key immune system cells. In tests with lab animals, the company reports injections of its cyclic dinucleotides directly into tumors, sharply inhibited growth of melanoma, colon, and breast tumors, and protected against regrowth of those tumors as well as spreading of cancer cells.

Under the deal Novartis receives rights to commercialize Aduro’s cyclic dinucleotide technology outside the United States, where Aduro retains commercialization rights including sales. The companies will share profits in the U.S., Japan, and major European countries. In addition, Aduro will qualify for royalties on sales of products from the collaboration in other parts of the world.

Novartis is paying Aduro an initial $200 million, with the potential for another $500 million if all development milestones are met. Novartis is also investing $25 million for a 2.7 percent equity stake in Aduro, with a commitment for another $25 million investment in the future.

Cyclic dinucleotides are a relatively new addition to Aduro’s pipeline. The company’s lead technology is based on engineered listeria bacteria that produce cancer immunotherapies, where two genes in the listeria genome making the bacteria infectious are deleted. The technology then modifies the genome to allow addition of tumor-specific antigens. Aduro has a product from this platform in an intermediate-stage clinical trial as a treatment for pancreatic cancer.

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Hat tip: FirstWord Pharma

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New Processes to Manufacture Food Sought in Challenge

Jam jars

(Jarmoluk, Pixabay)

27 March 2015.  Sponsors of a new challenge on InnoCentive are seeking new manufacturing processes for making food and snacks. The competition has a total prize purse of $10,000 and a deadline of 23 April 2015 for submissions.

InnoCentive in Waltham, Massachusetts conducts open-innovation, crowdsourcing competitions for corporate and organization sponsors. The sponsor, in this case, is not disclosed. Innocentive calls this type of competition an ideation challenge that requires a brief written proposal. Free registration is required to see details of the competition.

The sponsor of this challenge is looking for novel techniques for creating and manufacturing food and snacks. One approach to this problem is to design methods for adjusting properties of food products, such as color, texture, and flavor. By offering methods for controlling these properties, food companies would be able to better control ingredients in food products, and thus enhance their flavors, or even create entirely new kinds of food or snacks.

Because of the desire for new methods and processes, the sponsor is eager to attract entrants to the challenge from outside the traditional food and beverage industry, with ideas on manufacturing processes for controlling and adjusting food properties. Competitors working in paints, inks, bulk and fine chemicals, pharmaceuticals, cosmetics, aerospace, or electronics are invited to submit entries.

This ideation challenge requires a brief (two-page) proposal. Ideation proposals can contain ideas originating from the participants, ideas from the public domain where no restrictions are applied, or ideas from third-parties where participants have the rights to propose solutions with those ideas. Participants are asked not to submit confidential information in their proposals.

The competition has a total prize fund of $10,000, with at least one award no smaller than $5,000 and no award smaller than $2,000. The sponsor guarantees at least one prize will be awarded. The sponsor also indicates that submitting a proposal grants the sponsor a non-exclusive, perpetual, and royalty-free license to use any information in the proposal, including for promotional purposes. An exclusive transfer of intellectual property rights to the sponsor, however, is not required.

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Intermediate Trial Shows Ebola Vaccines Safe

Scanning electron micrograph of Ebola virus

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

27 March 2015. An intermediate-stage clinical trial in Liberia testing two new vaccines to prevent Ebola infections, shows the vaccines appear to be safe, allowing for larger-scale assessments. Initial results of the trial were reported yesterday by National Institute of Allergy and Infectious Diseases (NIAID), part of National Institutes of Health.

The 2014-15 Ebola virus disease outbreak is one of the largest ever recorded and affects mainly three countries in Africa: Guinea, Liberia, and Sierra Leone. The disease is caused by a virus spread through direct contact, often through broken skin or mucous membranes, with a sick person’s blood or bodily fluids, contaminated objects such as needles, and infected animals. The latest case counts reported by WHO and CDC show nearly 25,000 confirmed or suspected cases, and more than 10,000 deaths. Liberia recorded some 9,600 total cases and 4,300 deaths

The clinical trial with more than 600 volunteers in Liberia is testing two experimental vaccines:

– cAd3-EBOZ, developed by NIAID and GlaxoSmithKline

– VSV-ZEBOV, made by Public Health Agency of Canada and licensed to NewLink Genetics Corporation and Merck

Participants are randomly assigned to receive either an injection of a test vaccine or a saline solution placebo. Blood tests are taken immediately after, as well as 1 week and 1 month later, with follow-up blood tests 6 and 12 months following the injection. Participants will also be contacted monthly with inquiries about their health for up to 12 months.

The intermediate-stage trial, begun in early February, aims to enroll about 1,500 participants, with the primary goals to test the vaccines’ safety — evidenced by adverse reactions — and their ability to generate an immune response. NIH says the initial safety results, confirmed by an independent review board, will make it possible to complete enrollment at a hospital in Monrovia, Liberia’s capital, with completion scheduled for the end of April. With the added participants, the team is aiming to increase enrollment of women, who make up only 16 percent of the first participants.

The results also enable the research team to plan a larger late-stage trial of the vaccines with 27,000 participants testing their effectiveness in protecting against Ebola infections. Since only one new Ebola case is reported in Liberia since mid-February, however, the researchers are seeking to expand the study outside Liberia to sites in other West African countries.

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Sharp Rise in Livestock Antimicrobial Use Expected

Cattle (ARS)

(Agricultural Research Service, USDA)

26 March 2015. An international research consortium estimates that global use of antibiotics in livestock is expected to jump by two-thirds by the year 2030, imperiling attempts to overcome antibiotic resistance and posing a threat to public health. The team led by Princeton University environmental researcher Ramanan Laxminarayan published its findings last week in Proceedings of the National Academy of Sciences (paid subscription required).

Laxminarayan — with colleagues from research institutes in Europe, Kenya, India, and the U.S. — sought to develop a technique for measuring worldwide consumption of antibiotics by livestock, which is becoming an increasing concern as global demand for animal protein increases. Antibiotics provide ranchers with better animal health and growth, as well as fewer foodborne pathogens. But more antibiotics fed to livestock also contribute to increased occurrence of antibiotic resistant bacteria.

A report last year from World Health Organization highlighted the need to reduce inappropriate use of antibiotics in livestock production and noted …

More data are needed on antibiotic consumption in food-producing animals worldwide, and on the occurrence of antimicrobial resistance in different countries and different production systems, in order to make comparisons between countries and identify priority areas for intervention.

The researchers developed statistical techniques known as Bayesian models using methods that allow for projections based on limited data at hand combined with previous quantitative knowledge. Their models incorporated economic projections for demand of meat products and maps of livestock densities, with estimates of consumption based on sales of veterinary antimicrobials in 32 mainly developed countries. In the U.S. for example,  say the researchers, antibiotic consumption in animals represents as much as 80 percent of total antimicrobial sales.

Laxminarayan and colleagues estimate total worldwide consumption of antimicrobials for livestock will increase from about 63,200 tons in 2010 to 105,600 tons in 2030, a jump of 67 percent. Gains in antibiotic use among livestock are expected to be larger in BRICS countries — Brazil, Russia, India, China, and South Africa — where rates are projected to rise by 99 percent, nearly doubling in that 20 year period.

Many of the increases are attributed to changes in livestock production to large-scale intensive practices where antimicrobials are routinely used in sub-therapeutic doses. This trend to more intensive production practices is expected to account for up to one-third of antimicrobials consumed between 2010 and 2030. The remaining two-thirds of total global consumption is expected to result from the larger number of animals raised for food.

The researchers point out policy makers need to make difficult choices in confronting this problem, calling for initiatives to preserve antibiotic effectiveness, while still ensuring food security in low- and middle-income countries. Nonetheless says Laxminarayan in a Princeton University statement, “Antibiotic resistance is a dangerous and growing global public health threat that isn’t showing any signs of slowing down.”

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Hand-Held DNA Sequencer IDs Bacteria, Viruses

MinIon device

MinIon device (Biomed Central)

26 March 2015. A palm-sized DNA sequencing device was able to identify a number of bacteria and viruses, and discriminate between closely related species in about 6 hours. Tests of the MinIon device, made by Oxford Nanopore Technologies in Oxford, U.K., were reported today in the journal GigaScience.

Oxford Nanopore is developing the MinIon as a portable disease surveillance system that analyzes DNA from blood samples in the field, and operates as a plug-in peripheral on a laptop computer. The company makes early versions of the system available to researchers for hands-on testing, and the GigaScience article reports on results by testers at the U.S. Army’s Edgewood Chemical Biological Center in Aberdeen, Maryland and the company Signature Science LLC in Austin, Texas.

Oxford Nanopore is a spin-off from University of Oxford, founded in 2005 and licensing technology from research by biochemistry professor Hagan Bayley. The company’s technology is based on straining and isolating individual DNA strands through nanoscale pores in a membrane that allows for electronic sequencing processes to identify the base components of DNA passing through the pore. These nanopores were originally formed in proteins in a lipid membrane, but the company since introduced synthetic materials for nanopores, including graphene.

The team from Edgewood and Signature Science analyzed lab samples of E. coli bacteria and 3 types of pox viruses: cowpox and 2 closely related strains of vaccinia, used to develop smallpox vaccines. Data generated by the MinIon were then analyzed with software performing polymerase chain reactions that amplify single copies of DNA into amplicons, providing multiple copies of sequences.

The use of amplicons makes it possible, say the authors, to overcome a limitation of the MinIon, namely a high read error rate of 30 percent. The multiple sequences provide a more robust analytical pool after about 6 hours that the researchers could then compare to known reference sequences for E. coli and the 3 pox viruses. The results show the system was able to successfully identify the 4 samples, including the individual strain of E. coli and distinguish between the 2 closely related vaccinia samples.

Oxford Nanopore says additional analyses of MinIon data from can be performed through cloud-based software. The following 4 minute video tells more about the MinIon.

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FDA Approves Inhalational Anthrax Treatment

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

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

25 March 2015. The U.S. Food and Drug Administration today approved a treatment for inhalational anthrax, a rare but dangerous respiratory condition that can result from a bioterrorist attack. The drug is marketed as Anthrasil by Emergent BioSolutions Inc. in Gaithersburg, Maryland.

Anthrax is caused by Bacillus anthracis, bacteria found naturally in soil and commonly affecting domestic and wild animals. Humans can become ill when exposed to contaminated animals or if anthrax spores are released intentionally. When inhaled, anthrax spores reproduce in the body, producing toxins that can cause widespread and irreversible tissue damage, often leading to death.

The U.S. in recent history experienced a terrorist attack from anthrax spores, making it far from a hypothetical issue. When purified and made into a fine powder or aerosol, anthrax 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.

Anthrasil, previously called Aigiv, is a solution of purified human immune globulin G with antibodies that target the toxins produced by anthrax bacterial spores. The drug is made from plasma collected from healthy donors who were immunized with BioThrax, also produced by Emergent, an FDA-approved vaccine to prevent anthrax.

Emergent tested the drug’s safety and chemical activity in the body in an early-stage clinical trial, but relied on animal studies to test for efficacy. FDA allows for animal studies when human clinical trials are not feasible or ethical. Tests with lethal aerosol doses of anthrax spores on rabbits and monkeys showed much higher survival of animals receiving the drug compared to a placebo, with higher survival rates among animals receiving larger doses.

Anthrasil was developed under a $160 million contract to contract to Biomedical Advanced Research and Development Authority, or Barda, a division of the Department of Health and Human Services. Barda previously stockpiled Anthrasil as an experimental drug, but would have required an emergency authorization from FDA to use the drug before today’s approval. The company says approval by FDA makes it eligible for a $7 million milestone payment from the agency.

The drug also received Orphan Drug designation, and as a result of its approval by FDA, Anthrasil qualifies for 7 years of market exclusivity. In addition, Emergent is collecting anti-anthrax human plasma needed to produce Anthrasil under a $63 million Barda contract awarded in 2013.

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University Breeds Genome-Edited Pigs



25 March 2014. Veterinary researchers at University of Maryland successfully bred 18 pigs with their genomes edited by a technique that prominent geneticists recently called for strict guidelines. The university today announced birth of the baby pigs bred by animal sciences professor Bhanu Telugu and faculty research assistant Ki-Eun Park.

Telugu and Park applied the technique known as CRISPR, short for  clustered, regularly interspaced short palindromic repeats. CRISPR is adapted from a natural process used by bacteria to protect against attack by viruses, where a protein that deactivates or replaces genes binds to targeted RNA molecules generated by the human genome. The RNA molecules then guide the editing protein to specific genes needing repair.

The Maryland team is using a different approach to CRISPR. Instead of sending a protein to edit the genome, Telugu and Park are modifying nucleotides — biochemical building blocks in DNA and RNA — in the pigs’ genomes. The university says Telugu and Park and are pursuing a patent on this CRISPR technique.

Last week, in a statement published in Science, a group of leading genomics researchers, including some working directly in CRISPR, called for scientists, companies, and physicians to develop ethics guidelines for the use of CRISPR, particularly in research on human diseases. “Assuming the safety and efficacy of the technology can be ensured” said the statement, “a key point of discussion is whether the treatment or cure of severe diseases in humans would be a responsible use of genome engineering, and if so, under what circumstances.” A concern of the writers is that without a responsible road map for CRISPR, a public backlash against the technique could put a halt to the work done so far and prevent further applications in medicine.

Telugu and Park say their research is aimed for improving the welfare of animals, not humans. In September 2014, Telugu’s team received a $1.6 million grant from National Institute of Food and Agriculture, part of U.S. Department of Agriculture, to apply genome editing to improving the resistance of pigs to influenza. The Maryland researchers are studying ways of deactivating genetic receptors in pigs for the flu virus that in the past damaged herds, and led to swine flu pandemics among humans.

But research in pig genomes may still have implications for humans, since pigs have some organs and functions, such as in the digestive system that are similar to humans. Telugu and Park hope to extend their research beyond influenza to other conditions faced by humans, such as obesity and diabetes.

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Stem Cell Biotech Gains $44M in First Venture Round

Human stem cell derived beta cells

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

24 March 2015. A biotechnology start-up developing a stem-cell technology to replace missing beta cells that produce insulin for patients with type 1 diabetes, secured $44 million in its first venture funding round. Funding for Semma Therapeutics in Cambridge, Massachusetts was led by MPM Capital, with participation by Fidelity Biosciences, ARCH Venture Partners, and Medtronic.

Details about a separate agreement with the pharmaceutical company Novartis were not disclosed.

Semma Therapeutics is licensing research findings by its scientific founder biologist Douglas Melton, co-director of Harvard University’s Stem Cell Institute. Melton studies beta cells, which when functioning properly, produce insulin in the pancreas. Insulin is a hormone that helps the body store and process glucose provided by food in the diet.

Type 1 diabetes is 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’s interest in type 1 diabetes goes beyond business and science. As reported in Science & Enterprise in October 2014, his son and daughter were diagnosed with type 1 diabetes as children, and he made finding a cure the goal of his career. Researchers in Melton’s lab 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 in animals show their genes express similarly to normal beta cells, and enable control of blood glucose levels.

Semma Therapeutics is extending Melton’s discoveries into processes for implanting the engineered beta cells in people with type 1 diabetes so they function similar to people without the disorder, and that protects the recipients from an immune-system reaction.

The funds raised in this first venture round, plus the agreement with Novartis are expected to fund development of Semma Therapeutics’ technology through early clinical development that shows the solution is feasible. While the nature of the Novartis agreement was not disclosed, Novartis’s research labs are concentrating on autoimmune disorders as one of their key targets.

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Hat tip: Fortune/Term Sheet

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Clinical Trial to Test Ketamine to Treat Rett Syndrome

Ketamine vials

Ketamine vials (Licensed under Public Domain via Wikimedia Commons)

23 March 2015. A clinical trial is planned to test an anesthetic used in surgery as a treatment for Rett syndrome, a rare developmental disorder affecting girls. The trial testing the anesthetic ketamine will be conducted by Case Western Reserve University medical school in Cleveland, funded by a $1.3 million grant from Rett Syndrome Research Trust.

Rett syndrome is a genetic disorder affecting 1 in 10,000 to 15,000 female births, and while it is caused by a mutation in the MECP2 gene, the disease is not inherited. Symptoms of Rett syndrome are similar to autism, reflected in problems with communication, learning, and coordination, as well as breathing difficulties such as hyperventilation, beginning at about 6 months of age. Treatments for Rett syndrome generally involve management of symptoms and occupational skill therapy.

The clinical trial will test the ability of ketamine to reverse symptoms of Rett syndrome. Neuroscience professor David Katz at Case Western Reserve tested ketamine as a therapy for Rett syndrome in lab mice genetically engineered to exhibit the disease. Katz reports that low doses of ketamine were able to rebalance characteristic neurological activity of Rett syndrome in the mice and show improved neurological functions.

While ketamine is widely used a sedative and anesthetic in surgery, it also has a checkered history. Ketamine was a 1990s-era party drug known on the street as Special K, but is showing promise recently as a treatment for depression, working as quickly as 6 hours and with the capability of reducing suicidal thoughts. Due to ketamine’s potential for abuse and ability to cause adverse effects, such as nausea and hallucinations, clinicians are moving ahead cautiously with the drug.

“Because ketamine was initially developed for use in surgical anesthesia, it has never been used to treat a chronic illness,” says Katz in a university statement. “So one of the next questions will be whether we can develop a chronic dosing paradigm with this or similar drugs that would be safe and effective for patients with Rett syndrome.”

The trial led by Katz, and with colleagues at the Cleveland Clinic, plans answer those questions by enrolling 35 individuals with Rett  syndrome. Participants will receive ketamine in various low doses or a placebo, in random order, in multiple 2-day sessions, with each session about a month apart. The researchers will look particularly at changes in breathing and behavioral symptoms.

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