Kevin Kit Parker (Harvard University)
7 March 2014. Biomedical engineers at Harvard University proposed a scheme for assessing the quality of stem cells used in drug testing to assure they transform into the cells and tissue they purport to represent. The team from Harvard’s Disease Biophysics Group, led by Kevin it Parker, published its findings online yesterday in the journal Stem Cell Reports.
Stem cells are quickly becoming a vital tool in medical research and practice, particularly for regenerative medicine and screening compounds for potential effects in humans. As their use has expanded, an industry has grown up to make stem cells commercially available for these purposes. So far, only the U.S. Food and Drug Administration proposed standards for stem cells, which are aimed at providing greater safety for patients receiving stem cell therapies.
Standards for stem cells used in drug screening, however, have not yet been proposed. Parker and colleagues note that screening drugs for potential adverse effects on the heart, a major use of commercial stem cells, brought more companies into the market. In a university statement, Parker says he and graduate student Sean Sheehy (also the first author of the paper) visited many of these companies, but “I’d never seen a dedicated quality-control department, never saw a separate effort for quality control.”
Parker adds when he ask the companies for samples of their stem cells, “Some we got were so bad we couldn’t even get a baseline curve on them; we couldn’t even do a calibration on them.” The quality of human stem cells varied to such an extent, the team had to rely on mouse stem cells to conduct a scientifically accurate study.
The company Axiogenesis AG in Cologne, Germany provided the mouse cardiac progenitor cells for their research. Axiogenesis donated both embryonic stem cells and heart muscle cells derived from induced pluripotent stem cells, adult cells that have been genetically reprogrammed to an embryonic stem cell-like state. While not human stem cells, the commercial mouse stem cells provided enough consistent quality to connect the stem cells to various types and functions of mouse heart tissue.
Sheehy, Parker, and colleagues started with more than 1,000 possible factors for evaluating stem cells and eventually winnowed them down to a core group of 64 variables. Based on these variables, the team constructed a quality index that made it possible to connect stem-cell properties to the form, structure, gene expression activity, electrical characteristics, and contraction behavior of different types of heart tissue.
The index offers a way, say the authors, for drug screeners to identify the best commercial stem-cell lines for their tests, as well as provide the industry with a quality system that provides customers with the assurance that they are getting the stem cells they need.
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Project leaders Kam Leang, left, and Ben Rogers (University of Nevada, Reno)
6 March 2014. University of Nevada in Reno and NevadaNano, a spin-off company from the university, are developing an aerial robotic device for environmental sensing and reporting over a large area. The project is funded by a $150,000 Small Business Technology Transfer grant from the U.S. Army.
The project combines the university’s expertise in autonomous robotic systems with NevadaNano’s work with microprocessor-based sensing devices. The university’s principal investigator on the project is Kam Leang, a professor of mechanical engineering, and director of the school’s Electroactive Autonomous Systems (Easy) Lab. The lab’s research includes mechanical airframe design, system identification and modeling, and position sensing and tracking.
NevadaNano was founded in 2004 to commercialize research conducted at Nevada-Reno on micro-electro-mechanical systems (MEMS)-based sensor modules. Much of its earlier work was funded by Defense Advanced Research Projects Agency to develop a prototype sensor system for measuring concentrations of unlawful or hazardous materials in ocean shipping containers.
The new project aims to design a self-powered flying robot with chemical sensors and the ability to communicate its readings. The project leaders — Leang and NevadaNano’s Ben Rogers — envision the vehicle being able to send and receive data with other flying robots deployed over a large area, and relay the data to controllers on the ground.
NevadaNano’s lead product is the molecular property spectrometer, a chip-based system with sensors that the company says can measure multiple thermodynamic and electrostatic molecular properties of sampled vapors, liquids, and particles. The system can analyze the various molecules picked up by the sensors and return an identification of the molecules detected.
For this project, the developers aim to integrate the molecular property spectrometer into a drone designed by Leang’s lab. In its current configuration, the molecular property spectrometer system fits into a shoebox-size housing for sensing potential threats in shipping containers. For the flying robotics project, the developers aim to shrink the system to about the size of a deck of cards.
The first (and funded) phase of the project runs through July and expects to determine the feasibility of the proposed vehicle. If the concept is adequately proven, the team plans to build and field-test a prototype in phase 2, with a final product developed in phase 3. The developers anticipate the robotic vehicle could be used in military reconnaissance, surveillance, law enforcement, hazardous waste inspection and removal, disaster search and rescue operations, and remote sensing and mapping.
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Bag of altered T-cells for infusion (University of Pennsylvania)
6 March 2014. Researchers from University of Pennsylvania, Albert Einstein College of Medicine, and the biotechnology company Sangamo BioSciences showed the company’s gene-editing technology could engineer the immune cells of HIV-positive patients to resist infection and decrease their viral loads. Results of the early-stage clinical trial led by Penn immunologist Carl June will be presented at this week’s Conference on Retroviruses and Opportunistic Infections in Boston and appears today in the New England Journal of Medicine (paid subscription required).
The trial tested the safety and potential efficacy of engineered T-cells, white blood cells in the immune system that defend against invading viruses, among 12 HIV-positive patients. The T-cells were taken from the patients themselves, then altered by blocking actions of the CCR5 gene, whose proteins enable the reception of HIV viruses. Removing the gene’s impact, in effect, simulates a mutation that creates a natural resistance to HIV infection.
The altering of the T-cell genomes used Sangamo BioSciences’ techniques for editing CCR5 genes the company code-names SB-728-T. The company’s platform creates zinc finger nucleases, enzymes that make it possible to modify DNA sequences. The modifications can include corrections and insertions into those sequences, or in this case, disruption of the sequence.
In this trial, some 10 billion T-cells were returned to the patients, with 11 to 28 percent of the cells genetically-altered with SB-728-T. The study looked primarily for safety issues, such as adverse reactions to the therapy, but also measured rebuilding of the patients’ immune systems and resistance to HIV. Six of the 12 patients also interrupted their antiretroviral therapy for up to 12 weeks, about a month after the infusion of T-cells.
The results following the first infusion showed a large spike in modified T-cells after one week. The number of those cells in the patients’ blood declined over several weeks, but decreases in the modified cells were less than those of unmodified T-cells during the interruption of antiretrovirals. The researchers also found modified T-cells in gut-associated lymphoid tissue, considered an important reservoir of immune cells and HIV infection, which indicates the modified T-cells function and move normally in the body.
June and colleagues also measured viral loads of patients in the trial that show amounts of HIV virus RNA in a blood sample. Four of the six patients who interrupted their antiretroviral treatments saw their viral loads decrease, in one case below standard detection levels, although that patient had an inherited genetic composition that favored the altered CCR5 gene.
The researchers say the SB-728-T infusions were safe and well-tolerated. They report one adverse effect, which they attribute to a reaction to the transfusion. The team plans further clinical trials to test larger infusions of T-cells and with larger numbers of patients.
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5 March 2014. Life science and engineering researchers at Harvard University developed a sponge-like gel material that when seeded with embryonic cells in lab tests shrinks and hardens into a predecessor of human tooth tissue. The team led by Donald Ingber, director of Harvard’s Wyss Institute for Biologically Inspired Engineering, published its findings online last month in the journal Advanced Materials (paid subscription required).
Ingber’s team, including colleagues from Boston Children’s Hospital, aimed to emulate a process used by human embryos to develop specialized tissue such as teeth and bone, where growth factor proteins combine with chemicals that activate genes and mechanical forces to differentiate stem cells into those specialized cells. Earlier research at the Wyss Institute and Boston Children’s Hospital examined the process and found loose, unorganized embryonic cells known as mesenchyme exchange signals with a covering layer of epithelial cells that cause the mesenchyme to compress into a small, tight formation.
The earlier research reported that in the lab, this tight collection of cells forms at the spot in the anatomy for the new tissue, activates genes, and develops into functioning tissue or organs. And those lab tests isolated tissues from the jaws of mouse embryos that differentiated into whole teeth, including enamel and dentin.
The new research, led by engineering Ph.D. candidate Basma Hashmi, sought to emulate the process, but with a bio-compatible material that could transform into artificial teeth when implanted in the body. With chemistry colleagues, the researchers started with a gel-forming polymer called poly-isopropylacrylamide or PNIPAAm that is biocompatible and used to deliver drugs into the body.
PNIPAAm is thermo-sensitive, and responds to heat by immediately contracting, but in its original state shrinks at too low a temperature to be useful. The researchers needed the gel to begin contracting precisely at body temperature, 37 degrees Celsius (98.6 F). Hashmi — the publication’s first author — and her chemistry colleagues spent a year modifying PNIPAAm to the point where, cells stuck to it and the material began contracting at 37 C.
In initial lab tests, the researchers seeded PNIPAAm gel with mesenchymal cells, and when warmed to 37 C, shrunk to form tight packs. The cells inside the tight packs stayed alive and activated three genes that form tooth tissue.
The researchers then, as a proof of concept, implanted the seeded PNIPAAm gel into mice beneath the kidney, an area that is well supplied with blood. The results show the implanted gel contracted inside the body, activated tooth-forming genes, and began forming calcium and minerals in preparation for making teeth. “They were in full-throttle tooth-development mode,” says Hashmi in a university statement.
In the next stage, the researchers plan to combine mesenchymal cells with epithelial cells in the polymer gel, which they expect to develop into fully functional teeth.
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RNA illustration (Research.gov)
5 March 2014. RXi Pharmaceuticals Corp., a biotechnology company in Westborough, Massachusetts, received a patent for its technology based on RNA-interference to treat skin scars, including surgical scars. Patent number 8,664,189 was awarded yesterday by the U.S. Patent and Trademark Office to seven inventors and assigned to RXi Pharmaceuticals.
RXi develops therapies with a technology harnessing RNA, the nucleic acid that sends genetic signals derived from an individual’s DNA to cells with instructions on their functions in the body. The technology uses a specific type of genetic instruction known as RNA-interference, a natural process that regulates the over-expression of proteins from a gene causing a disorder. The company’s therapeutics self-deliver interfering RNA to the affected cells, encouraging cells to take up the RNA, reducing obstacles from immune responses, and providing long-lasting cellular activity.
The patent covers self-delivered RNA-interference addressing connective tissue growth factor, a protein that encourages growth of fibroblasts and collagen, which are useful for healing wounds, but when overproduced, can lead to the formation of scar tissue. The company’s lead product, code-named RXI-109, is an RNA-interference therapy designed to treat surgical scars.
An early-stage clinical trial shows RXI-109 was well-tolerated at multiple dosage levels, and reduced production of connective tissue growth factor in treated areas. Two intermediate-stage clinical trials are now recruiting patients testing RXI-109 against a placebo with surgery to remove keloid scars resulting from earlier surgery or burns, and with abdominal scar revision surgery, following hysterectomy or Cesarean-section delivery.
RXi’s founder is Craig Mello, a professor of molecular medicine at University of Massachusetts medical school in Worcester, who still chairs the company’s scientific advisory board. Mello shares the 2006 Nobel Prize in medicine for his work on RNA-interference. RXI was spun-off from Galena Biopharma in 2012.
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4 March 2014. A study by public health researchers at Harvard University shows children eating lunch at school increased their consumption of fruit and vegetables after new school lunch standards took effect. The team led by nutrition research fellow Juliana Cohen published its results online today in American Journal of Preventive Medicine.
Cohen and colleagues conducted a before-and-after study of students at eight elementary and K-8 schools in Massachusetts to gauge changes in eating habits after passage of the Healthy, Hunger-Free Kids Act of 2010, with school meal standards authorized by the law and issued by U.S. Department of Agriculture in October 2011. Some 32 million students eat meals at schools. The new standards made whole grains, fruits, and vegetables more available, required a selection of a fruit or vegetable, increased the size of fruit and vegetable portions, removed trans-fats, and put limits on total calories and sodium in meals.
Harvard’s School of Public Health collaborated with the organization Project Bread, a not-for-profit group in Massachusetts to reduce hunger and promote better nutrition, in a project to implement the standards with meals planned by a professional chef to improve the nutrition and palatability of meals in schools. The researchers observed and measured food selections by students at all eight schools before the standards went into effect (fall of 2011), then after their implementation (fall of 2012) with four schools implementing the standards and the other four schools serving as controls. The team also measured food waste throughout the study.
Some 1,030 students participated, with the vast majority (85%) from low-income homes and eligible for free or reduced-price meals. The median age of the students was 11 years, with a little more than half (54%) girls. More than 8 in 10 students (83%) were Hispanic, with the remainder being white, Asian, and African-American.
The results showed 16 percent more students eating vegetables, and eating a higher volume of vegetables, after the new standards took effect. The amount of fruit consumed stayed about the same from before to after the standards, but the percentage of students selecting fruit as part of their meals increased 23 points from 53 to 75 percent. While all students selected an entree as part of their meals before and after the standards, the consumption of the entrees increased 16 points, from 72 to 88 percent.
Implementation of standards did not result in an increase in food waste, a concern from the increased serving sizes and requirement to include a fruit or vegetable selection. However, food waste at these schools was quite high both before and after the standards took effect. Students in the study discarded 60 to 75 percent of their vegetables and 40 percent of fruit on their lunch trays.
Critics of the standards questioned their need and cost when first proposed, with continuing attempts by critics to weaken the standards. “We hope the findings, which show that students are consuming more fruits and vegetables, will discourage those efforts,” says Cohen in a university statement.
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4 March 2014. Santen Pharmaceutical Co. in Osaka, Japan is licensing antibodies developed as a cancer therapy by Tracon Pharmaceuticals in San Diego as treatments for eye diseases. Tracon is expected to earn $10 million in an upfront payment from Santen, as well as undisclosed milestone payments and royalties.
Tracon develops biologic therapies for cancer, but also with potential for treating wet age-related macular degeneration. The agreement calls for Santen to develop and commercialize Tracon’s antibodies that target endoglin, a protein on the surface of cells that promotes development of blood vessels and a key contributor to angiogenesis, the process of growing blood vessels that can stimulate growth of cancerous tumors.
Tracon’s lead product, an endoglin antibody code-named TRC105, is in clinical trials in combination with other cancer drugs and inhibitors of vascular endothelial growth factor or VEGF, a chemical signal stimulating growth of new blood vessels. The overexpression of VEGF can also cause disorders in veins in the retina of the eye.
Wet macular degeneration is generally the result of abnormal blood vessels that leak fluid or blood into the region of the macula, found in the center of the retina, the layer of tissue on the back wall of the eyeball, causing loss in the center of your field of vision. The Macular Degeneration Association says the disorder in all forms is the leading cause of legal blindness in Americans age 65 and older, with wet macular degeneration accounting for about 10 percent of the cases, but 90 percent of all blindness from the disease.
Tracon says preclinical and some clinical findings show inhibiting both endoglin and VEGF has more potential to treat wet macular degeneration than VEGF alone. Santen develops treatments for a variety of eye disorders including glaucoma, diabetic macular edema, allergic and bacterial conjunctivitis (pink eye), and corneal abrasion. But up to now, the company has not addressed either wet or dry macular degeneration.
Under the agreement, Tracon grants Santen exclusive rights to develop and commercialize TRC105 and other endoglin antibodies as treatments for eye diseases. Santen will finance all development and commercialization activities, including studies leading to investigational new drug applications with the U.S. Food and Drug Administration. Tracon will continue to develop TRC105 as a cancer treatment.
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(National Institute on Aging, NIH)
Naurex Inc., a biotechnology company in Evanston, Illinois, says the U.S. Food and Drug Administration granted fast-track status for its drug candidate code-named GLYX-13 to treat depression. GLYX-13 is Naurex’s lead product for treatment of central nervous system disorders.
The company develops drugs for diseases of the central nervous system that stimulate N-Methyl-D-aspartate (NMDA) receptors, molecules found in synapses, a part of nerve cells that permit sending and receiving of signals. NMDA receptors help keep synapses flexible, which affects memory, learning, and development of the central nervous system. Naurex aims to use this platform to develop drugs to treat mood and anxiety disorders, cognitive disorders, neurodegenerative diseases, developmental disorders, neuropathic pain, and addiction.
GLYX-13 is in intermediate-stage clinical trials being tested as a back-up drug for patients with major depressive disorder not responding to earlier antidepressants. In one trial, a single dose of GLYX-13 is being tested against a placebo with 300 patients who did not respond to earlier antidepressants. The company says initial findings show the drug acted quickly, within 24 hours, to reduce depression scores on a standard rating scale, compared to patients receiving the placebo, with results lasting several days.
FDA’s fast-track designation, as the name implies, offers accelerated review to drugs with the potential to addres serious conditions or unmet medical needs. With fast-track status, FDA schedules more frequent meetings and provides more frequent correspondence. Fast-track status also provides for partial submissions and rolling review of a company’s new-drug or biological license applications, rather than waiting for the entire applications to be completed before submission.
Naurex is a spin-off company from Northwestern University, founded by biomedical engineering professor Joseph Moskal, who continues as the company’s chief scientist. Moskal is also director of the Northwestern’s Falk Center for Molecular Therapeutics that calls itself a “new organizational model … to translate discoveries with therapeutic potential into clinically useful compounds.” Part of that new model, says the Falk Center, is Naurex Inc., to which the center says is “tethered.”
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Lymphocyte (National Cancer Institute)
3 March 2014. Genocea Biosciences, a biotechnology company in Cambridge, Massachusetts, with Harvard Medical School and Dana-Farber Cancer Research Institute, are testing the company’s vaccine discovery platform to help target therapies for melanoma, an aggressive form of skin cancer. The collaboration is funded by Ludwig Institute for Cancer Research, but financial aspects of the partnership were not disclosed.
Melanoma is a form of skin cancer that occurs less often than the more common types, but is more dangerous and causes more deaths. National Cancer Institute says in 2013, the U.S. reported nearly 77,000 new melanoma cases and nearly 9,500 deaths from the disease.
Genocea develops vaccines and immunotherapies harnessing properties of immune-system T cells, lymphocytes (white blood cells) with receptors that target antigen fragments on infected or cancerous cells, and trigger a toxic response to the invaders. The company’s vaccine-discovery platform, called AnTigen Lead Acquisition System or Atlas, uses a high-throughput screening mechanism simulating the body’s natural immune system’s response to antigen proteins.
Atlas screens proteins from target antigens against T cells from human donors who generate either a successful immune response protecting against the invaders, or an ineffective immune response. This screening process makes it possible to quickly isolate a small number of proteins correlating with natural immunity, from which vaccines can be developed.
Genocea so far applied Atlas to several pathogens, including herpes simplex virus-2, pneumococcus bacteria, chlamydia, and malaria. In the new partnership, the company plans to apply the technology to melanoma, where a biologic drug ipilimumab, a monoclonal antibody already approved to treat metastatic melanoma, has mixed results in generating an immune response: some test subjects in an early stage clinical trial responded favorably, while other subjects did not. Ipilimumab is marketed by Bristol-Myers Squibb as Yervoy.
The collaboration includes Darren Higgins, an immunologist at Harvard Medical School on whose research Atlas is based, and Stephen Hodi and Glenn Dranoff at the Dana-Farber Cancer Institute, who studied the biologic and anti-tumor activities of ipilimumab. Higgins plans to create a cancer antigen protein library for screening in Atlas, while Hodi and Dranoff will isolate blood samples from test subjects who responded positively to ipilimumab.
Genocea will then screen with Atlas the protein library from Higgins’s lab against the cells derived from the test subjects. The aim is to generate a small number of relevant T-cell antigens for further testing and development. The company says the results of the partnership should help identify patients for clinical trials more likely to respond to immunotherapies, as well as better monitor the progress of melanoma patients after treatment.
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Kari Nadeau (Stanford University)
28 February 2014. Medical researchers at Stanford University in California and Johns Hopkins University in Baltimore found in an early-stage clinical trial that an asthma drug dramatically reduces the time needed for patients to lower their sensitivity to several food allergies at one time. The team led by Stanford’s Kari Nadeau and Johns Hopkins’s Robert Hamilton published its findings online yesterday in the journal Allergy, Asthma & Clinical Immunology.
Nadeau, Hamilton, and colleagues cite studies from the past three years showing 8 percent of children in the U.S. have a food allergy, with 30 percent of that group reporting allergies to more than one food. Food allergies in the U.S. are estimated to cost $25 billion, mainly from lost work time, changing careers, and emergency room visits, with that cost borne largely by families. People with food allergies are advised to avoid allergy triggers and always carry injectable epinephrine because of the risk of anaphylactic shock from accidental consumption.
This study is the second in a series of clinical trials on multiple food allergies. Many of the same Stanford/Johns Hopkins researchers published its earlier findings in the same journal on 15 January 2014. In that study, the researchers showed patients with several food allergies could be desensitized at once to several multiple foods causing an allergic reaction, rather than going through the process sequentially for each food.
In that process, called oral immunotherapy, patients with food allergies eat small amounts of the offending foods, gradually increasing the amounts they eat in a controlled setting and under a doctor’s supervision. In the earlier study, 25 patients allergic to peanuts and to at least one of other types of foods — sesame, other nuts, dairy, or egg — underwent oral immunotherapy. The researchers found the rates of allergic reactions to the multiple offending foods in this group of patients, was similar to a group of 15 patients with only a peanut allergy, also receiving oral immunotherapy.
In the later study, 25 children and adults with food allergies were first given the drug omalizumab, developed to reduce the number of allergic asthma attacks, those caused by environmental allergens, such as dander, pollen, and dust mites. Omalizumab, marketed as Xolair by Genentech and Novartis, reduces activity of imunoglobulin E (IgE), a type of antibody that binds to allergens and triggers the release of substances from mast cells — tiny cells with chemicals causing inflammation.
Eight weeks after omalizumab injections, the 25 patients underwent an oral immunotherapy regimen for multiple offending foods similar to the earlier trial group. The results show 19 of 25 patients receiving omalizumab injections were able to complete the six stage oral immunotherapy process, with little or no need for rescue therapy.
Patients receiving omalizumab were able to tolerate up to four grams each of the offending foods, in powdered protein form, in a median period of 18 weeks. Patients in the earlier trial of oral immunotherapy, without the omalizumab, needed a median of 85 weeks to become desensitized to the offending foods.
The trials’ main objective was to test for the safety of oral immunotherapy, both with and without omalizumab. In the earlier study, most reactions to the allergens were mild, although two severe reactions were reported each in the peanut-only and multiple-foods groups requiring epinephrine injections. In the later study, with omalizumab, 94 percent of reactions were considered mild, with one severe reaction reported.
Nadeau and colleagues are now planning for an intermediate-stage clinical trial at Stanford and four other sites.
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