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Clinical Trial Proposals Sought for ALS Treatments

3-D brain wiring illustration

3-D brain wiring illustration (NIH)

22 October 2014. A group of U.S. organizations promoting research on therapies for amyotrophic lateral sclerosis or ALS are seeking proposals from academic-industry research teams for intermediate stage clinical trials to test treatment candidates for the disease. The organizations — ALS Association, ALS Accelerated Therapeutics or ALS ACT, and Northeast ALS Consortium — plan to award up to $1.5 million in research support, with letters of intent due by 9 January 2015.

Amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease, is a progressive disorder that attacks nerve cells or neurons controlling voluntary muscle movements. In ALS, motor neurons in the brain stop sending signals to motor neurons in the spinal cord, and thus stop sending signals to muscles. Muscles begin to weaken and atrophy, eventually losing control over voluntary muscle movement. The result is disability and paralysis, including respiratory functions, leading to death. ALS affects 1 in about 30,000 people in the U.S., with 5,000 new cases each year.

At present there is no cure for ALS and only one approved drug — Riluzole, marketed as Rilutek by Sanofi — that slows the progress of the disease. The organizations say the research funded in this initiative can fill an urgent need for more treatments, particularly those beyond preclinical and early safety studies on humans.

Proposals should outline intermediate-stage studies of interventions that include markers to measure the therapy’s affect on the body, as well as a plan to collect samples for studies involving biomarkers. Intermediate-stage trials, sometimes called phase 2 trials, are studies involving larger numbers of patients than the small samples used in earlier safety studies, and test the effectiveness of the drug, as well as watch for safety or side-effects issues.

The organizations encourage teams comprised of academic and industry researchers, including those from pharmaceutical and biotechnology companies, to submit proposals. Letters of intent are due by 9 January 2015, with invitations to send in full proposals issued on 23 January. Full proposals are due by 2 March 2015, with evaluations conducted by a review panel from ALS ACT.

The winning proposal will be announced in May 2015. The successful bidder, say the organizations, will retain control of the study as well as intellectual property of the therapy being tested.

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Graphene Sensor Offers Clear Optical Access to Brain Cells

Blue light shines through brain sensor

Blue light shines through a clear sensor implanted in the brain of a lab animal. (Williams research group, Univ of Wisconsin – Madison)

22 October 2014. Engineers at University of Wisconsin in Madison developed an implanted transparent sensor made with graphene that allows for imaging and diagnostics in the brain requiring line-of-sight access. The team led by electrical engineering professor Zhenqiang Ma and biomedical engineering faculty Justin Williams published its findings this week in the journal Nature Communications.

A continuing problem with current implanted sensors to measure neural activity in the brain, say the researchers, is the composition of the devices, which blocks viewing by imaging and diagnostic technologies. “A traditional implant looks like a square of dots, and you can’t see anything under it,” says Williams in a university statement. “We wanted to make a transparent electronic device.”

Ma, Williams, and colleagues chose graphene as the main material for the electronics in their sensor. Graphene is a carbon material closely related to graphite like that used in pencils, but consists of only a single layer of atoms arrayed in a hexagonal mesh pattern. The material is very light, strong, chemically stable, and can conduct both heat and electricity, with applications in fields such as electronics, energy, and health care.

The Wisconsin device consists of 4 graphene circuits, each fabricated in a wafer, coated with Parylene C, a transparent and biocompatible polymer compound, using chemical vapor deposition. Graphene allows the device to remain extremely thin, even with 4 layers. “It’s got to be very thin and robust to survive in the body,” notes Ma.

The researchers tested the device, called carbon-layered electrode array, or Clear, for optical transparency over the spectrum from infrared to ultraviolet frequencies and found the sensor allows for transmission rates of 90 percent or more. The team also implanted devices in lab rats and mice, and found the devices allow for fluorescent microscope images and three-dimensional optical coherence tomography of the blood vessels in the brain immediately under the sensor. Optical coherence tomography is an imaging technology analogous to ultrasound, but using light rather than sound waves.

The researchers also conducted optogenetics tests in the focal cortical areas of the lab animals where the sensors were implanted. Optogenetics uses light to influence activities of genes sensitive to light. Focal cortical areas are parts of the cerebral cortex often causing seizures in children with epilepsy.

Lab mice with brain cells expressing a channelrhodopsin protein were fitted with Clear sensors in their brains and exposed to blue light, known to stimulate that protein. The results showed at some light intensity levels, nerve cells respond to the blue light exposure.

University of Wisconsin is in the process of patenting the technology. The team believes the Clear device can be a significant help to neuromodulation therapies involving electrical stimulation of brain cells, to treat disorders such as hypertension, epilepsy, and Parkinson’s disease. The device can assist in understanding precise effects of the stimulation, which at present are considered rudimentary.

The researchers are also working with colleagues at University of Illinois-Chicago developing contact lenses with built-in transparent sensors to detect damage to the retina and early stages of disorders such as glaucoma.

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Project Developing DNA Antibodies for Infectious Diseases

3-D image of MRSA bacteria

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

21 October 2014. The biotechnology company Inovio Pharmaceuticals Inc. and partners are developing synthetic antibodies based on DNA that generate an immune reaction to prevent infectious diseases, a project funded by Department of Defense Advanced Research Projects Agency or DARPA. The $12.2 million DARPA grant is supporting the work of Inovia, in Plymouth Meeting, Pennsylvania, with the MedImmune division of pharmaceutical company AstraZeneca, and University of Pennsylvania medical school.

The study aims to design and test monoclonal antibodies, proteins created to bind to the surface of specific antigen cells, lymphocytes or white blood cells in the immune system that generate an immune response attacking pathogen invaders, such as bacteria or viruses. The pathogens targeted in this project are Pseudomonas aeruginosa, Staphylococcus aureus, and influenza viruses.

Pseudomonas aeruginosa is a bacterium that can cause ear infections and skin rashes in healthy people, but poses a more serious risk to hospitalized patients and those with weakened immune systems, resulting in blood infections or pneumonia, often in health care settings. Staphylococcus aureus is bacterium responsible for staph infections on the skin, food poisoning, and serious disorders including toxic shock syndrome. One form of staph infection, Methicillin-resistant Staphylococcus aureus or MRSA is resistant to methicillin and other antibiotics, making it difficult to treat.

MedImmune, in Gaithersburg, Maryland, is a pioneer in the development of monoclonal antibodies, while Inovia is designing DNA-based monoclonal antibodies and vaccines, as well as a delivery system for these biologics. The delivery system, known as electroporation, sends millisecond-timed electrical impulses to create temporary pores in cell membranes, allowing for faster uptake of the payload.

While monoclonal antibodies are gaining more interest for their therapeutic potential, they remain time-consuming and expensive to produce, as well as having limited duration of potency in the body, requiring frequent repeated doses. In this project, the team plans to advance the technology, making it possible for monoclonal antibodies to be generated inside the body, thus simplifying their design.

The researchers aims to adapt a technology harnessing DNA, developed in the lab of David Weiner, a professor of pathology and immunology at Penn’s Perelman School of Medicine, and licensed by Inovio. Weiner and colleagues created some of the earliest DNA-based vaccines for HIV and cancer, and advanced them into clinical stages.

The companies and university plan to test encoding DNA sequences for monoclonal antibodies in DNA plasmids, circular DNA molecules found in nature, but can be used to transfer or manipulate genes. The plasmids then are delivered via electroporation directly into the target cells, where the DNA sequences produce the desired monoclonal antibodies inside the cells. Inovio says preclinical studies show monoclonal antibodies based on DNA generated immune responses against HIV in lab mice.

In this project, the team will demonstrate the ability of DNA plasmids with DNA sequences to generate monoclonal antibodies specific to the two targeted bacteria and influenza viruses, and in sufficient quantities to protect against those pathogens. While the grant funds preclinical studies, the researchers expect successful results will lead to commercial product candidates and clinical trials.

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Genomic Data Analysis Service Launches, Hosts Autism Data

DNA fragment (Wikimedia Commons)

(Wikimedia Commons)

20 October 2014. NextCode Health, a start-up informatics company in Cambridge, Massachusetts, unveiled its NextCode Exchange, a shared online genomics database and analysis service for diagnostics and research with sequencing data. The 1 year-old company also is hosting a genomics database of people with autism for online access to researchers.

NextCode Health says its databases have data from 350,000 whole genomes representing some 40 million known variants, which can be accessed from ordinary Web browsers. The company, begun in October 2013 as a spin-off from deCode Genetics in Iceland, licenses deCode’s genomics analysis platform, including IT infrastructure, for clinical diagnostics based on sequencing data. Hannes Smarason and Jeff Gulcher, CEO and chief scientist respectively of NextCode, are former executives of deCode Genetics, now a division of the U.S. biotechnology company Amgen.

The company says computational and analytical services in NextCode Exchange improve the ability of physicians and geneticists to diagnose diseases of unknown origin by identifying suspect genes and mutations faster and with greater accuracy. These services, says NextCode, can also be shared in real time with collaborators, or accessed privately and anonymously to validate findings relating genomic analysis to specific physical traits or conditions. The company also offers its own sequencing services, including for whole genomes, for clients lacking their own sequencing capability.

In addition, NextCode can host genomic databases for clients. In a partnership announced yesterday, NextCode is hosting the Simons Simplex Collection, a database of detailed genomics and related physical traits that aims to discover rare genetic events increasing the risk of developing autism spectrum disorders. Simons Simplex Collection consists of data from 2,600 so-called simplex families — those with one child diagnosed with autism, unaffected parents, and at least one unaffected sibling.

The collection is supported by the Simons Foundation Autism Research Initiative, and partners with 12 university-affiliated autism research clinics. Data in the collection were drawn from blood samples where DNA was extracted and analyzed by Rutgers University. Sequencing of Simons Simplex Collection data, says the foundation, has already yielded some 100 gene candidates for autism.

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FDA Exemption Sought for Ebola Blood Plasma Device

Scanning electron micrograph of Ebola virus

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

20 October 2014. Cerus Corp., a developer of blood safety devices, is asking the U.S. Food and Drug Administration to allow its system for removing pathogens from blood plasma be used to treat patients in the U.S. with Ebola, while the device is under review. The provision, called a Compassionate Use Investigational Device Exemption, allows physicians to allow the use of medical devices still under review in cases of serious or life-threatening conditions, and where no other alternatives are available.

Plasma is the part of blood containing proteins for blood clotting and antibodies to fight infections. Processes for donating plasma separate the plasma from blood, then return the remaining red blood cells to the donor’s blood stream. Plasma can be frozen and kept for up to a year.

The Concord, California company’s Intercept system for plasma synthesizes psoralen, a natural substance, into a compound known as amotosalen that penetrates DNA and RNA of targeted pathogens in plasma. When exposed to ultraviolet light, amotosalen forms a chemical cross-link with the genetic material, preventing it from replicating, thus deactivating the pathogen and preventing disease. Another Cerus system works the same way with blood platelets.

Because blood from Ebola victims contains antibodies against the disease, public health authorities are considering transfusions from Ebola patients who survived — now about half of those who contract the disease — as a therapy. Anecdotal evidence from previous Ebola outbreaks in Africa going back to 1976 show transfusions of whole blood or plasma help some patients recover. Kent Brantly, an American physician who contracted Ebola in Liberia and survived, received a whole-blood transfusion from another survivor, and in turn provided his plasma to three other patients.

One risk of blood or plasma transfusions is the presence of other pathogens that can cause other serious conditions, such as HIV or malaria, for Ebola patients. Cerus says its Intercept system can remove those pathogens, thus ensuring a safer supply of plasma for therapeutic transfusions.

The Intercept system is already approved for use in Europe and now under review by FDA. The company says a decision by FDA is expected in 2015.

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Better DNA Sample Prep Methods Sought in Challenge

DNA strand (NSF)

(James. J. Caras, National Science Foundation)

17 October 2014. A new challenge on InnoCentive is seeking methods that make it possible to prepare DNA samples in the field for sequencing, based on smaller quantities of microbial evidence. The challenge has an award of $25,000 and a deadline of 7 December 2014.

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 a theoretical challenge that requires a written proposal.

The sponsor of this challenge is seeking better ways of preparing DNA samples in the field — on-site, where samples are collected — for sequencing, which can be of considerable benefit to environmental and energy companies, as well as in forensic investigations. These methods would prepare samples for a type of DNA analysis called metagenomic sequencing that reveals genetic signatures of complex microbial communities.

DNA extraction kits today use technologies such as magnetic particles, known as functionalized magnetic beads, for isolation of nucleic acids, as well as purification and concentration of the samples for further analysis. With metagenomic sequencing, however, the amount of usable specimen material isolated for analysis can be extremely limited, , sometimes as little as 1 picogram, since only trace amounts of the total specimen material are often collected.

Today’s sequencing technologies require 50 nanograms of DNA to return high-quality and reproducible sequencing results. The challenge sponsor is looking for techniques with the sensitivity to process DNA samples as small as 1 to 10 nanograms, and return results of the analysis faster.

Participants in the competition will need to prepare and submit a written proposal with their solutions. To receive the full award, the winning entry will be required to transfer exclusive intellectual property rights to the sponsor. However, the sponsor will consider a partial award in cases where full intellectual property rights cannot be transferred.

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Simple 3-D Graphene Construction Process Devised

Porous graphene-based structure

Electron microscope image of porous graphene-based structure created by diffusion driven layer-by-layer assembly (Kyoto University)

17 October 2014. Materials scientists at Kyoto University in Japan developed a new process that simplifies the building of three-dimension structures with graphene, a light, strong, conductive material with many industrial and commercial applications. Franklin Kim and Jianli Zou from Kyoto’s Institute for Integrated Cell-Material Sciences  published their findings yesterday in the journal Nature Communications (paid subscription required).

Graphene is a material closely related to graphite like that used in pencils, but consists of only a single layer of carbon atoms arrayed in a hexagonal mesh pattern. The material is very light, strong, chemically stable, and can conduct both heat and electricity, with applications in fields such as electronics, energy, and health care.

The thin, single-atomic structure that makes graphene a desirable material also makes it difficult to piece together into 3-D structures needed for practical use, which hampers the advance of graphene into commercial applications. Stacking graphene layers, for example, causes the nanoscale sheets to lose their unique individual properties. Current methods for addressing this problem, say the authors, are costly and time consuming.

Kim and Zou sought a simple and scalable method for assembling graphene sheets that can be adapted to commercial and industrial enterprises. The researchers applied a chemical process known as interfacial complexation, where layers of negatively-charged graphene oxide sheets are interspersed with a positively-charged polymer. The polymer in this case is polyethylenimine, a compound used in detergents, adhesives, inks, dyes, and cosmetics, as well as a number of industrial processes.

Putting the opposite-charged layers of graphene oxide and polyethylenimine into contact forms a stable composite layer.  “Interestingly, the polymer could continuously diffuse through the interface, and induce additional reactions” says Zou in a university statement, “which allowed the graphene-based composite to develop into thick multi-layered structures.”

The multi-layered structures, say the authors are robust and can be designed with various porosity, from ultra-light to extremely dense, by adjusting the input properties and conditions. The process can be scaled easily for producing large-area films with patterns, or into free-standing shapes for energy generation or storage, such as in batteries or supercapacitors.

Kim adds that the process can be applied to more than just graphene, noting “we strongly believe that the new technique will be able to serve as a general method for the assembly of a much wider range of nanomaterials.”

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Personalized Leukemia Immunotherapy Gets 90 Pct Remission


T-cell (NIAID/NIH)

16 October 2014. Nine in 10 children and adults in early-stage clinical trials of a personalized therapy harnessing the patients’ immune systems achieved full remission of their acute lymphoblastic leukemia. The findings of the team from University of Pennsylvania and Children’s Hospital of Philadelphia are reported today in New England Journal of Medicine (paid subscription required).

The trials tested a personalized therapy code-named CTL019 with 30 patients having relapsed or unresponsive cases of acute lymphoblastic leukemia, a cancer of blood and bone marrow. The disease progresses quickly, making an overabundance of immature lymphocytes, a type of white blood cell. It is also the most common type of cancer among children, although it can also affect adults.

The process to make CTL019 starts with an individual’s blood cells and separates out T cells, white blood cells used by the immune system to fight invading pathogens, then reprograms the T cells with genetic engineering to find and kill cancer cells. The engineered T cells then become hunter cells, containing a protein known as chimeric antigen receptor that acts like an antibody. These hunter cells are infused back into the patient, seeking out and binding to a protein called CD19 found on the surface of B cells — another type of white blood cell — associated with several types of leukemia.

Among the properties programmed into CTL019 is the ability of hunter cells to quickly multiply and accumulate to battle the cancerous cells. The authors, led by pediatrics professor Stephan Grupp of Children’s Hospital, say their tests show some 10,000 hunter cells are produced for each engineered T cell received by patients.

The trials enrolled 25 patients, ages 5 to 22, at Children’s Hospital and 5 adult patients, ages 26 to 60, at University of Pennsylvania. “The patients who participated in these trials had relapsed as many as four times, including 60 percent whose cancers came back even after stem cell transplants,” says Grupp in a hospital statement. “Their cancers were so aggressive they had no treatment options left.”

The researchers began giving the CTL019 infusions two years ago. Of the 30 patients receiving these personalized infusions, 27 or 90 percent, achieved complete remission. Some 78 percent of the patients survived at least 6 months after the treatments. Of the original patients, 19 remain in remission, 15 of whom received only the CTL019 therapy, while 5 others sought out other therapies, including stem cell transplants. Also of the original patients, 7 relapsed between 6 weeks and 8.5 months after the infusions, although 3 of the relapsed patients developed a different form of leukemia, one where the CD19 protein is not expressed, thus it would not have been helped by the CTL019 therapy.

All of the patients receiving CTL019 experienced an adverse reaction a few days after the infusions called a cytokine release syndrome. While these reactions cause flu-like symptoms, they’re considered an indicator of hunter cells’ progress in fighting the cancer cells. However, nine patients developed severe cytokine release syndrome reactions requiring treatment with immunosuppressant drugs and steroids. All of the patients fully recovered from these reactions.

The pharmaceutical company Novartis is licensing the immunotherapy technology, under an agreement reached two years ago with University of Pennsylvania. In July 2014, CTL019 received breakthrough therapy status from the U.S. Food and Drug Administration, which provides expedited review for new therapies treating serious conditions and where the treatments are shown to be an improvement over current methods.

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Robot for MRI-Guided Epilepsy Surgery in Development

Mockup of surgical robot

Mockup of surgical robot designed to treat epilepsy (Vanderbilt University)

16 October 2014. Engineers at Vanderbilt University in Nashville are building a robot for epilepsy surgery guided by MRI scans and designed to be less invasive than current surgical methods. The team from Vanderbilt, with colleagues from Georgia Tech and Milwaukee School of Engineering, are demonstrating a prototype of the device this week at the Fluid Power Innovation and Research Conference in Nashville.

The project, from the lab of engineering professor Eric Barth, aims to provide a more precise surgical treatment for severe cases of epilepsy that now involve a risky procedure drilling a hole into the skull and going deep into the brain. Epilepsy is a neurological condition where nerve cell signals in the brain are disturbed, causing seizures that can range from blank stares to uncontrolled convulsions and loss of consciousness. The disorder can arise from genetic causes, as well as strokes — the leading cause of epilepsy for people over the age of 35 — and head trauma.

Surgery is a treatment option for difficult-to-control cases, and when the area of the brain causing the seizures is well defined and not interfering with vital functions. More complex types of surgery may be needed when the part of the brain causing seizures can’t be removed, and multiple incisions in the brain are needed to keep the disorder from spreading. Because a part of the brain often involved with epilepsy is the hippocampus, located in the temporal lobe at the base of the brain, surgeons must probe deep into the brain to get access to it.

The Vanderbilt device, designed with neurologists at the university, aims to make the surgery less invasive, by accessing the hippocampus through the cheek, rather than the skull, sharply reducing the distance to the target. Incisions are made with a small (1.14 millimeter), curved needle and guided by MRI scans. A curved needle is required since a straight needle cannot reach the target region.

The device is configured to work inside an MRI scanner, with the needle made of a nickel-titanium alloy that can operate in an MRI. The needle fits into a series of nested tubes, and can change shape and be steered through the brain, one millimeter at a time, powered by compressed air. An electrode in the device activates a radio-frequency signal for removing the targeted brain cells.

David Comber, a Vanderbilt graduate student who performed much of the design work and one the demonstrators at this week’s conference, says tests on models in the lab show the needle’s accuracy is within 1.18 millimeters, considered sufficient for this kind of surgery. Barth says the next step in the device’s development is testing with cadavers.

A continuing concern with medical advances is the cost of new therapies. The team developing the robotic device says it is designed to be built with three-dimensional printing, to keep its costs under control. Among the team members are experts in additive manufacturing, an industrial form of 3-D printing, at Milwaukee School of Engineering.

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Needleless Delivery Start-Up Lands $11M First-Round Funding

Ian Hunter

Ian Hunter (Mass. Institute of Technology)

15 October 2014. Portal Instruments Inc., a new enterprise developing needless injections for biologic therapies and other medications, raised $11 million in its first round of venture funding. Financing for the Cambridge, Massachusetts company was led by the Sunrise division of drug maker Sanofi, venture capital company PBJ Capital, and an unnamed medical device manufacturer in the U.S.

Portal Instruments is commercializing the research of MIT engineering professor Ian Hunter, who developed a needle-free injection technology. Hunter’s lab says the technology employs an electromagnetic actuator that allows for calibrating delivery of drugs based on the nature and volume of the payload and depth of the injection under the skin. Current needle-free injection techniques with springs or compressed gases use a single-jet delivery with no control over the pressure applied to the drug, which the lab says at high velocities can damage large-protein protein molecules.

The company has an exclusive license from MIT for Hunter’s drug delivery technology. The invention first delivers a high-speed pulse to break the skin and inject the drug to the desired depth, followed by a lower-speed and gentler delivery of the drug payload, which helps protect formulations sensitive to high pressure.

Hunter’s lab says it is conducting feasibility tests of the technology with vaccines and biologic therapies delivered in various kinds of tissue and organs.  Portal says the technology is suited for administering biologic therapies that can be viscous in consistency.

Sanofi’s Sunrise division, the funding round leader, seeks out partners to develop new kinds of life science products and co-invests in early stages rather than licensing technologies directly for internal development. Portal Instruments is the third investment for Sunrise, joining life-science start-ups WarpDrive Bio and MyoKardia.

“Portal Instruments provides us with a unique opportunity to deliver medicines in formulations that are currently not possible with needle-based devices in a highly controllable needle-free drug delivery system,” says Katherine Bowdish, who heads the Sunrise division, in a company statement. “For patients this may allow them to choose a way to take their medicines if they prefer not to have a needle-based device, or to choose needle-free self-administration at home of some medicines typically delivered in centralized health care facilities.”

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