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University Spin-Off Developing Sepsis Drug

Syringes for disposal

(alexroma, Pixabay)

23 August 2016. A spin-off enterprise from University of British Columbia is licensing a cholesterol-lowering drug from drug maker Novartis to develop a treatment for sepsis and other severe infections. Financial aspects of the agreement with Cyon Therapeutics Inc., a biotechnology company in Vancouver, were not disclosed.

The team of John Boyd, James Russell, and Keith Walley from UBC’s Centre for Heart Lung Innovation founded Cyon Therapeutics in May 2014 to commercialize discoveries from their joint research interest on organ failure from severe infections. Among the more serious infections is sepsis, which results from an immune-system reaction to chemicals released by the body to fight infection, including infections from medical equipment such as catheters. The inflammatory responses can occur anywhere in the body and generate a series of further reactions, including blood clots and leaking blood vessels, causing organ damage and failure.

The deal calls for Cyon to gain worldwide rights to a highly-specific engineered antibody code-named LGT-209, designed to block the actions of proprotein convertase subtilisin/kexin type 9, or PCSK9. Novartis developed LGT-209 to degrade receptors for low-density lipoprotein, or LDL cholesterol, the “bad” cholesterol that contributes to the build-up of plaque that clogs and hardens arteries. Novartis tested the safety of LGT-209 in two early-stage clinical trials, both on its own and with statins, another type of cholesterol-lowering drug.

Research at UBC by the founders discovered another property of antibodies like LGT-209. Degrading receptors for LDL cholesterol, the work of LGT-209, improves the liver’s ability to recycle these receptors, adding more receptors to the surfaces of liver cells, and thus removing more LDL cholesterol from the blood. Toxins generated by sepsis and related infections are fat soluble and accumulate in LDL cholesterol, which if not cleared quickly, can generate a severe immune reaction. Thus, the ability of LGT-209 to help the liver clear LDL cholesterol from the blood also helps the liver clear toxins from infections that build up in cholesterol.

The team expects to develop LGT-209 as a preventive drug and treatment for sepsis. Cyon is planning an intermediate-stage clinical trial for the first half of 2017, enrolling some 300 patients in emergency rooms at hospitals in Canada and the U.S. Participants will first be screened for genetic characteristics indicating those more or less likely to respond to the antibody. Single-injection doses are expected to range from 5 to 10 times higher than those given to lower cholesterol.

Cyon received its initial funds from Canadian and provincial science funding agencies including Centre for Drug Research and Development, Genome BC, and National Research Council of Canada. The company says the deal with Novartis clears the way for the company to initiate its first venture capital funding.

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Stem Cells, Engineered Protein Reverse Stroke Damage

Berislav Zlokovic

Berislav Zlokovic (University of Southern California)

23 August 2016. A combination of stem cells and synthetic human protein was shown in lab mice to repair damaged brain cells a week after an induced stroke. An international team, led by researchers at University of Southern California, published its findings in yesterday’s issue of the journal Nature Medicine (paid subscription required).

The researchers led by physiology professor Berislav Zlokovic, are seeking a treatment for damage to brain cells and normal sensory and motor functions caused by ischemic stroke, the type of stroke that results from clots that block the flow of blood and oxygen to the brain. Ischemic stroke accounts for 85 percent of all strokes and affects some 676,000 people in the U.S. each year. Strokes of all kinds kill almost 130,000 Americans annually, or about 1 in every 20 deaths.

Zlokovic, director of USC’s Zilkha Neurogenetic Institute in Los Angeles, and colleagues developed an engineered form of activated protein C, a natural compound in humans that protects the integrity of blood vessel walls, approved by FDA in 2001 as a therapy for sepsis infections. Because the protein in its natural form also inhibits blood clotting, the treatments caused severe bleeding problems, which sharply limited its use. The researchers since began investigating an engineered and safer form of activated protein C, code-named 3K3A-APC, as a potential treatment for stroke and other neurological disorders.

The team is studying 3K3A-APC as an immediate treatment for people diagnosed with ischemic stroke, given to patients within a few hours of the stroke, to prevent further damage from occurring. ZZ Biotech LLC, a company co-founded by Zlokovic, licenses 3K3A-APC from Scripps Research Institute, its initial developer, for commercial development. The Houston company is recruiting stroke patients for an intermediate-stage clinical trial of 3K3A-APC’s safety and effectiveness.

In the new study, however, the authors are investigating 3K3A-APC’s potential to repair damaged nerve cells in the brain some time after the stroke occurred. The team previously showed in lab cultures that 3K3A-APC could stimulate production of neurons from neural stem cells, and in the new study applied the technique to lab mice 1 week following induced ischemic stroke. The 1 week period in mice is equivalent to several months in humans.

The mice were treated with neural stem cells applied next to damaged brain regions, with 4 doses of 3K3A-APC and an immunosuppressant drug over 7 days. Compared to similar mice receiving a placebo, the treated mice developed 16 times the number of stem cells. After 5 weeks, the mice were also tested for sensory and motor functions, such as walking on a rotating pod and removing adhesive tape from a front paw, with the treated mice outperforming the placebo recipients.

“Functional deficit after 5 weeks of stroke were minimized, and the mice were almost back to normal in terms of motor and sensorimotor functions,” says Zlokovic in a university statement. “Synapses formed between transplanted cells and host cells, so there is functional activation and cooperation of transplanted cells in the host circuitry.”

The authors believe the technique can be applied to a number of other neurological disorders, such as spinal cord injuries. ZZ Biotech also acquired intellectual property for 3K3A-APC’s use in wound healing, and plans to test the protein as a treatment for diabetic foot ulcers.

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FDA Giving Fast-Track Review to Alzheimer’s Candidate

Nerve cells illustration

(commonfund.nih.gov)

22 August 2016. U.S. Food and Drug Administration is giving an accelerated review to a candidate drug designed to treat Alzheimer’s disease. The drug, code-named AZD3293, is being developed as a joint project by drug makers AstraZeneca and Eli Lilly and Company.

AZD3293 is a type of small-molecule or low molecular weight drug known as an oral beta secretase cleaving enzyme, or BACE, inhibitor that aims to prevent the build-up of amyloid plaque toxicity. In Alzheimer’s disease, amyloid plaque develops in the brain, breaking down the ability of neurons or nerve cells to function efficiently, leading to death of neurons and shrinkage of brain tissue. Cognitive and memory loss are common symptoms of Alzheimer’s disease, which is the leading form of dementia, and the 6th leading cause of death in the U.S.

The drug acts by cleaving an amyloid precursor protein that releases and activates peptides inhibiting BACE, which in turn reduces toxicity of amyloid beta proteins making up the accumulating plaque. AstraZeneca first developed AZD3293 and began early-stage trials in 2012, which show the drug can reduce levels of amyloid beta proteins in cerebro-spinal fluid of patients with Alzheimer’s disease.

The alliance of AstraZeneca and Lilly began in September 2014 to take AZD3293 into intermediate and late-stage trials. As reported in Science & Enterprise, Lilly, in Indianapolis, is leading clinical development of AZD3293 in intermediate and late-phase trials among patients in the early stages of Alzheimer’s disease. The two companies are sharing commercialization of the drug, while AstraZeneca will be responsible for manufacturing. Lilly is paying AstraZeneca, based in London, up to $500 million in development and regulatory payments.

The companies’ first joint clinical trial is enrolling some 2,200 individuals experiencing gradual and progressive memory loss for more than 6 months. The study tests 2 dosage levels of AZD3293 against a placebo, taken once a day for 2 years. The trial’s main efficacy measure is a standard rating scale of memory functions, but the study is also tracking a number of other variables through questionnaires and scales, as well as PET scans and tests of proteins associated with Alzheimer’s in cerebro-spinal fluid.

FDA’s fast-track designation, as the name implies, offers accelerated review to treatments with a potential to address 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.

In addition, Lilly and AstraZeneca are starting a new late-stage clinical trial of AZD3293, evaluating the drug among 1,900 individuals with probable or mild dementia caused by Alzheimer’s disease at 217 sites. The study is testing AZD3293 at 2 dosage levels against a placebo over 3 years. The randomly assigned placebo recipients, however, will start receiving AZD3293 at week 78, half-way through the study period.

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PhRMA: 258 Vaccines in Clinical Development

Vaccine syringe

(FirstResponder.gov)

19 August 2016. An industry group of American pharmaceutical makers says its companies have 258 vaccines, including immunotherapies, in clinical trials or awaiting FDA approval. The report, issued today by Pharmaceutical Research and Manufacturers of America, or PhRMA, covers preventive vaccines against infectious disorders, as well as disease treatments that harness the body’s immune system.

Vaccines are biological drugs derived from some form of living organisms, including weakened or parts of pathogens, inactivated microbes or toxins from bacteria, genetically engineered proteins or nucleic acids, and chains of sugar molecules known as polysaccharides derived from the cell walls of some bacteria or linked chemically to proteins. These substances are designed to induce an immune reaction, creating antibodies to protect against or neutralize disease-causing conditions.

Early vaccines, going back more than 200 years, were developed to prevent infectious diseases, beginning with smallpox. Since then, says PhRMA, vaccines have largely eliminated polio, measles, and rubella. More recently, vaccines against the human papillomavirus or HPV, reduced infections in teenage girls 64 percent, helping to prevent instances of cervical cancer. The organization notes that more than two-thirds of vaccines developed in the past 25 years were developed in the U.S.

While nearly half (48%) of the 258 vaccines in clinical development or regulatory review address infectious diseases, nearly as many (41%) are designed for cancer, and in many cases are cancer therapies. Among the vaccines listed in an appendix to the report is an immunotherapy code-named ADXS-HER2, made by Advaxis Inc. in Princeton, New Jersey for HER2-positive solid tumors. As reported recently in Science & Enterprise, the biopharmaceutical company Amgen is licensing the Advaxis technology for clinical development and commercialization.

The Advaxis technology derives its immunotherapies from weakened Listeria monocytogenes or Lm bacteria, associated by most people with food poisoning. The bacteria are engineered to include a form of listeriolysin O, a protein that enhances their ability to penetrate cell membranes, in this case tumor cells. Once inside the tumor cells, the listeriolysin O proteins make cancer cells, which normally hide from the immune system, look like bacteria and generate a response from T-cells in the immune system. In addition, the engineered proteins break down suppressor and regulatory T-cells that protect the immediate tumor environment.

Another immunotherapy in clinical trials listed by PhRMA is a treatment for gout, an autoimmune disorder and a complex form of arthritis, marked by sudden and severe episodes of pain, with tenderness and redness in the joints, particularly at the base of the big toe. Selecta Biosciences, in Watertown, Massachusetts, is developing a therapy code-named SEL-212 for severe gout that it says prevents the undesired immune reactions.

Selecta’s technology generates what it calls synthetic vaccine particles that direct the immune system to prevent and suppress immune responses to specific antigens. Thus specific immune responses are blocked without compromising an individual’s entire immune system. Science & Enterprise reported in June 2015 on the opening of Selecta’s early-stage clinical trial testing the safety of SEL-212 to treat gout.

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Genome Engineering Streamlines E. Coli DNA

E. coli bacteria

E. coli bacteria (National Institute of Allergy and Infectious Diseases)

19 August 2016. A genetics engineering team developed a technique for modifying the genome of E. coli bacteria to remove redundant DNA components, a step toward designing new organisms. The team led by Harvard Medical School geneticist George Church and University of Washington postdoctoral researcher Marc Lajoie published its findings yesterday in the journal Science (paid subscription required).

Church, Lajoie, and colleagues are seeking a technology for synthesizing substances not easily produced from nature, such as pharmaceuticals and chemicals, by harnessing processes in organisms, in this case E. coli, with genetic codes altered to produce those substances. Escherichia coli is best known as a bacteria causing intestinal infections, although most types of E. coli are harmless. Because E. coli is a well-studied bacteria, it is often used as a model for higher-order organisms.

The researchers at this stage looked for redundancies in the bacteria’s genetic code that could be eliminated without impairing its functionality. In earlier research, Church and Lajoie showed the feasibility of DNA components called codons to be replaced. Codons are sequences of three DNA molecules that correspond to specific amino acids in the production of proteins.

In their new study, the authors applied this technique to the overall E. coli genome. The task required the team to build many of their own tools from scratch, including rules-based software for testing the feasibility of identifying and replacing redundant codons in a way that still enables the organism to function. Because E. coli bacteria are a well-understood organism, a detailed template for the genome was available.

The researchers identified 7 of the 64 codons in the E. coli genome as replacement candidates. Algorithms in the software tested the presence of the 7 codons throughout the genome, identifying more than 62,000 instances where they occur, and replacing the codons with synonymous alternatives in all E. coli genes that produce proteins.

The authors called on 4 companies to synthesize E. coli DNA with the 57 rather than full 64 codons: Gen9 in Cambridge, Massachusetts, Twist Bioscience in San Francisco, Genewiz in South Plainfield, New Jersey, and Integrated DNA Technologies in Coralville, Iowa. The synthesized DNA was then amplified with polymerase chain reaction and assembled with a genetic assembly system from Life Technologies in Carlsbad, California.

The team so far tested and validated 63 percent of the recoded genes, and found 91 percent of the genes tested retain their functionality. The investigation also turned up 13 lethal exceptions in 2,229 genes.

The researchers say their findings show the feasibility of synthetic genome construction, which the authors estimate costs under $1 million, even with software development included. Harvard University applied for a patent on the processes developed for rules-based genome design.

In addition to his academic research, Church is a serial entrepreneur and a founder of Gen 9 Inc., one of the companies called on to produce synthetic DNA for the project. Gen9 provides customized gene synthesis and is developing a library of synthesized proteins and antibodies. Church is also a founder of Enevolv Inc. in Boston, a provider of synthesized microbes for production of pharmaceutical, nutrition, energy, and specialty chemical products.

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Safer Pain-Killing Drug Candidate Discovered

Fentanyl patch products

Fentanyl patch products (Alcibiades, Wikimedia Commons)

18 August 2016. A research team from the U.S. and Germany identified a chemical molecule with pain-killing properties of opioids, but apparently without the dangerous side effects. The new drug candidate and the process for its development are described in yesterday’s issue of the journal Nature (paid subscription required).

The researchers from University of California in San Francisco — with colleagues at Stanford University, University of North Carolina in Chapel Hill, and Friedrich-Alexander University Erlangen-Nürnberg in Germany — are seeking new treatments for pain without the adverse effects of today’s opioid-based prescription pain killers. Abuse of opioid pain killers is described by Centers for Disease Control and Prevention as a continuing and growing epidemic. CDC reports that in 2012, physicians in the U.S. wrote 259 million prescriptions for pain killers, enough for one bottle of pills for every adult in the country. As of July 2014, according to the CDC, 46 people die each day in the U.S. from an overdose of prescription pain killers.

The team took the approach of finding a completely new chemistry rather than working with existing drugs. Current opioid drugs target mu-opioid receptors to reduce the intensity of pain signals to the brain, particularly regions of the brain controlling emotion, which reduces effects of the pain stimulus. But these receptors are also found in other parts of the body, with opioid drugs causing release of proteins leading to unwanted side-effects including respiratory problems and gastrointestinal distress.

The lab of biochemistry professor and senior author Brian Shoichet at UC-San Francisco studies protein interactions, particularly molecular binding actions, using mathematical models and algorithms that reveal new drug targets. Co-senior author Brian Kobilka, a Nobel prize-winning biochemist, and colleagues at Stanford are studying the atomic structure of G protein-coupled receptors, found on cell surfaces, including nerve cells, and are targets for as many as half of today’s prescription drugs.

G protein-coupled receptors offer an alternative route to addressing pain signals, and first author Aashish Manglik, a graduate student in Kobilka’s lab, applied algorithms written by Shoichet’s group to simulate actions of G protein-coupled receptors. Manglik looked for signaling pathways that would generate the same pain-killing proteins of mu-opioid receptors, but would work only on nerve cells related to pain. The investigation took a massive effort, testing more than 3 million potential molecules against mu-opioid receptors, covering some 4 trillion separate chemical interactions.

The researchers recruited colleagues in medicinal chemistry and opioids at Friedrich-Alexander University and UNC-Chapel Hill to further evaluate the top molecular candidates from the screening process that only targeted nerve cells causing pain. This investigation yielded the molecule PZM21, a potent G-protein activator that addresses pain like mu-opioid receptors, but without triggering signals to respiratory and other functions. Tests in lab mice confirmed PZM21 relieved pain signals without affecting respiration, while the opioid morphine both relieved pain and caused breathing problems.

The paper identified PZM21 as a promising candidate for a new type of pain-killing drug, but extensive discovery, refinement, and testing lie ahead. Several of the authors, including Kobilka and Shoichet, filed a patent for PZM21. In addition, Shoichet and others founded Epiodyne Inc., a company in San Francisco, incorporated in April 2016 to develop new pain drugs. A regulatory filing in June shows the company already attracted $500,000 in debt and equity seed financing.

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Phone-Linked Glucose Meter Shows Health, Monetary Benefits

Livongo glucose meter

Livongo glucose meter (Livongo Health)

17 August 2017. The maker of a glucose meter that connects to cell-phone networks reports users of the device enjoy lower blood glucose readings and financial savings. Livongo Health in Mountain View, California issued a report of its findings today, which includes data presented earlier this summer at a meeting of American Diabetes Association.

The Livongo for Diabetes system is designed for people with either type 1 or type 2 diabetes. The system includes a smart blood glucose meter that connects to cellular networks, and transmits data from the meter to family members, clinicians monitoring the person’s condition, and third-party diabetes counselors certified by Livongo. The meter also collects other data related to the person’s health, such as physical activity.

People connected to the meter can provide feedback to the individual via voice telephone, e-mail, or text message. Data from the smart meter are sent as well to a database in the cloud, where a rules-based inference engine analyzes the data and offers personalized guidance to the individual with diabetes and his or her physician. Livongo users with the mobile app can receive coaching, with tips on nutrition and lifestyle changes, from licensed third-party counselors.

The Livongo report, citing data presented to American Diabetes Association, shows people with the connected glucose meters and taking part in the coaching program were able to decrease their average blood glucose levels, as measured by hemoglobin A1c, or HbA1c, from 8.0 percent at the start of the program to 7.1 percent after 90 days. In addition, glucose meter users maintained an average HbA1c score of 7.0 percent —  a target recommended by American Diabetes Association — for 180 days. These results were based on tracking 7,248 Livongo participants for 1 year.

The results also show participants are better able to keep their blood glucose levels in safe levels, between 80 and 180 milligrams per deciliter (mg/dL). When blood glucose levels go to low, a condition known as hypoglycemia with symptoms including dizziness or sweating, can occur. High blood sugar levels over time can lead to serious complications such as kidney failure, heart attack, and stroke. The company says that after 1 year Livongo participants reduced their likelihood of too-low blood glucose readings (less than 80 mg/dL) by up to 23 percent, and the chance of too-high readings (more than 180 mg/dL) by up to 21 percent.

The company cites data published in 2006 and 2013 to show the substantial economic cost of diabetes on people with the condition, with $7,900 per patient each year attributed to diabetes itself and total annual medical costs of up to $13,700. Using an existing cost model, Livongo estimates the 1 percent reduction in HbA1c over 180 days yields savings of $73 to $99 a month for each participant. In addition, the company estimates savings from lower costs for diabetes supplies more than offset the $75 per month Livongo subscription cost.

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Computer Models to Boost 3-D Print Designs in Mfring

3-D print stress failure

Supporting structures failed for these four fatigue test bars. Stress buildup in the longer length bars created an excessive curling force on the outer edges of the support structures, resulting in fracture. (Albert To, University of Pittsburgh)

17 August 2016. An academic-industry team is developing computer-based methods to improve the design for three-dimensional printing of complex manufactured items. The project by University of Pittsburgh and manufacturing enterprise Aerotech Inc. is funded by a 3-year $350,000 award from National Science Foundation.

The team led by Pittsburgh mechanical engineering professor Albert To is seeking faster and more effective ways to design complex pieces for additive manufacturing, the industrial application of 3-D printing. Many manufactured goods are subjected to failure from stresses and distortions, which when 3-D printed may not become apparent until after components are tested. Uncovering and correcting these weaknesses in the design stage can pay-off quickly in saved time and materials.

To’s computational mechanics lab studies structural properties of materials, including statistical models applied to the mechanical behavior of materials used in 3-D printing. In this project, the Pitt team will investigate computer models for optimizing 3-D printing of complex pieces, particularly in accounting for stresses manufactured pieces may face.

The project is expected to apply inherent strain concepts — sources of stress in an item without external forces being applied — to devise models for predicting residual stresses and distortions in manufactured pieces made with 3-D printing. The initiative also plans to develop design techniques that optimize complex geometries in additive manufacturing for freeform surfaces and those needing further machining.

“By utilizing advanced mechanic theory,” says To in a university statement, “we hope to reduce design optimization of additive manufactured parts to minutes, thereby reducing the time of design life cycle. This would lead to wider adoption of additive manufacturing by the U.S. manufacturing base and further improve the economic sustainability of the additive manufacturing process.”

The research team includes Stephen Ludwick, a design engineer at Aerotech and adjunct engineering professor at Pitt. Aerotech is an international company developing motion-control systems for manufacturing, health care, automotive, military, and semiconductor industries. In the project, Aerotech will give real-world tests to the models and design techniques produced in the university labs.

Ludwick adds that “the tools developed through this collaboration will allow us to produce the complex parts enabled by additive manufacturing with a minimum of trial-and-error and rework. This in turn allows us to design stiff and lightweight components in our high-speed motion systems which are also used by other companies engaged in advanced manufacturing.”

NSF is funding the project through its Grant Opportunities for Academic Liaison with Industry, or Goali, program that encourages collaborations between universities and businesses to undertake advanced research that the companies would likely not fund themselves.

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Leukemia Drug Shows Potential as Heart Attack Therapy

Heart in rib cage illustration

(CIRM.gov)

16 August 2016. A new drug being tested as a leukemia treatment was shown in lab mice to reduce inflammatory white blood cells that lead to a build-up of arterial plaques and heart disease. The study at Massachusetts General Hospital and Harvard Medical School tested the drug code-named GMI-1271 made by GlycoMimetics Inc. in Rockville, Maryland, with results reported recently in the journal Arteriosclerosis, Thrombosis, and Vascular Biology (paid subscription required).

GlycoMimetics is a biotechnology company that discovers and develops therapies acting on carbohydrates in cell processes. The company says carbohydrate structures account for much of the complexity and functions of proteins, with nearly all proteins expressed by human cells affected by complex carbohydrates on the surface of those proteins. The therapies discovered and developed by GlycoMimetics are synthesized compounds that mimic the structure and activity of carbohydrates, designed to function like traditional drugs, but also to enhance biological functions more than natural carbohydrates.

GMI-1271 is designed to limit effects of E-selectin, a protein found in cells lining blood vessels, and believed responsible for accumulations of white blood cells at inflammation sites that stick to blood vessel walls. GlycoMimetics is testing GMI-1271 in early and intermediate-stage clinical trials as a small molecule, or low molecular weight, supplemental treatment for blood-related cancers acute myeloid leukemia, or AML, and multiple myeloma.

The company, however, sees potential for GMI-1271 with cardiovascular disorders. In the paper, researchers tested effects in lab mice of GMI-1271 to limit the impact of E-selectin in producing inflammatory white blood cells in the spleen that then travel out through the blood stream, a condition occurring after myocardial infarction or heart attack. The drug was given to mice following induced atherosclerosis, or hardening of the arteries, and heart attack.

The results show mice in this condition given GMI-1271 reduced their production of inflammatory white blood cells and precursor cells in the spleen, as a result of blocking the actions of E-selectin. Because of lower inflammatory cell production, plaque build-ups in mice arteries stabilized, reducing the risk of a repeat heart attack.

“The results in this animal model of myocardial infarction and atherosclerosis demonstrate both the biological activity of GMI-1271 and the possible broader uses of an E-selectin antagonist,” says John Magnani,  chief scientist at GlycoMimetics in a company statement. “While GlycoMimetics is currently focused on developing GMI-1271 for treatment of AML, this drug candidate has shown activity in preclinical models of a number of diseases where E-selectin plays a key functional role.” Magnani is also a co-author of the paper.

GlycoMimetics is already pursuing other applications GMI-1271 as a cardiovascular drug. The company is recruiting participants in an early and intermediate-stage clinical trial testing the drug as a treatment for deep vein thrombosis.

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Robo-Bacteria Engineered for Cancer Drug Delivery

Sylvain Martel

Sylvain Martel (Polytechnique Montréa)

16 August 2016. A biomedical engineering team designed a technology for precise deployment of drugs to tumors with bacteria modified to deliver their cargoes. The system designed by researchers from Polytechnique Montréal, Université de Montréal, and McGill University in Quebec, Canada is described in yesterday’s issue of the journal Nature Nanotechnology (paid subscription required).

Computer engineering professor Sylvain Martel at Polytechnique Montréal and colleagues are seeking better delivery mechanisms for cancer drugs, which today are often given systemically, such as chemotherapy, causing adverse side effects in many patients. Even more targeted treatments, such as radiation, can harm nearby healthy tissue. Thus delivery of cancer-killing drugs directly to tumors is an unmet medial need.

One of the main obstacles to more precise delivery of drugs is the intense activity of cancer cells that depletes oxygen from the immediate tumor region, and makes tumors resistant to many therapies. The system designed and tested by the research team harnesses bacteria with an ability to penetrate these low-oxygen zones, and carry cancer-killing drugs directly to their targets.

The microbes in this case are a strain of Magnetococcus marinus bacteria with the unusual ability to respond to magnetic forces, a result of mineral crystals in their outer membranes that enable the organisms to naturally position along the Earth’s geomagnetic field. The team added chains of iron oxide nanocrystals to the bacteria to bolster their magnetic response. Another feature of these bacteria is their affinity for low-oxygen environments, which helps target the tumors.

In their paper, researchers engineered the bacteria further to carry cancer drugs in nanoscale lipid, or natural oil, containers, with some 70 of these tiny containers attached to each organism. The modified bacteria were then injected in lab mice grafted with human colon cancer cells near the site of the tumors, and guided by an external magnetic field. The results show 55 percent of the engineered bacteria penetrated inside the low-oxygen regions of the tumors.

“These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria,” says Martel in a Polytechnique Montréal statement, “and loaded with drugs that moved by taking the most direct path between the drug’s injection point and the area of the body to cure. The drug’s propelling force was enough to travel efficiently and enter deep inside the tumors.”

For Martel’s group, however, these findings are one step in the direction of a more advanced technology. “This innovative use of nanotransporters,” adds Martel, “will have an impact not only on creating more advanced engineering concepts and original intervention methods, but it also throws the door wide open to the synthesis of new vehicles for therapeutic, imaging and diagnostic agents.”

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