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Infographic – Partisan Split Remains on Research Spending

Party differences on research spending

Click on image for full size view (Pew Research Center)

21 Sept. 2019. While public support overall in the U.S. for federal spending on science is increasing, a sharp and continuing difference between the political parties emerged as well. More Democrats say they’re in favor of increased federal spending on scientific research than Republicans, a gap that began in 2010, according to the Pew Research Center, and continues today.

Pew Research Center reported the data earlier this month, and are shown in this weekend’s infographic on Science & Enterprise. Overall, about half of Americans polled in March 2019 (52%) favor more federal spending for scientific research, while 31 percent want to keep spending at current levels and 14 percent favor less spending on science. Since 2010, percentages of Americans in favor of more federal dollars going to scientific research are growing, while those preferring the same or fewer dollars spent on science are generally in decline.

When examining these opinions broken down by political preferences, however, sharp differences emerge. Beginning in 2001, about four in 10 Americans favored increased federal spending on scientific research, with barely any difference between Republicans and Democrats. By 2013, however, nearly half of Democrats, and independents leaning toward Democrats (46%), wanted more spending on science, while only a quarter of Republicans and like-minded independents (25%) favored increased research spending.

By this year, percentages of people favoring more spending on science increased in both parties, and among their independent allies. Now, more than six in 10 Democrats (62%) want more federal scientific research spending, as do four in 10 Republicans (40%), but the sizable decade-long partisan gap remains.

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Logistics Innovations All Businesses Need to Know

– Contributed content –

Warehouse

(Flickr)

20 Sept. 2019. If your business makes money by selling physical products to customers, then it’s a good bet that logistics is a priority. In fact, making sure your product gets to the customer safe and promptly is crucial. Of course, that means you must stay ahead of the curve with what is happening in logistics. If you want to keep your commercial edge, that is? Luckily, you can find out all about the latest developments in the post below.

Next / same-day delivery 

Customer expectations are very different from what they once were. Well, actually their not because back in the 19th-century people used to order things from shops and then get them delivered the same day. Which is basically what is happening now for at least some of the prominent providers.

Of course, what I actually mean is that 20 years ago we would think nothing of waiting for a week or more for something that we order via telephone or post. However, to wait so long seems to most people interminable!

What this means is that you will always have a competitive edge if you can offer fast delivery. Next day is good, same day is even better where possible. You can even add the cost of this expedited delivery onto the product in many cases. The reason being that customers would still prefer to pay the extra and get their item sooner than wait.

Digital stock management 

If you aren’t already using a digital stock managing system to monitor and ship goods, then it’s high time you do. Of course, most businesses already have these in place.

However, the real innovation here is linking them up to your website, thereby showing your customers exactly how many you have left in stock. In fact, doing so can really help to encourage customers to buy and manage their expectations in terms of delivery as well. Something thing that can help you get good feedback on every sale.

Automatic driverless trucks 

There is so much talk about automated driverless cars at the moment which of course begs the question: ‘Are we about to see fully automated logistics fleets on the road?’ However, in this issue, it’s essential not to get too caught up in the hype.

After all, we are only just starting to fully electric cars becoming available. Therefore it is likely that the tech for fully automated truck is still a significant time away.

What does this mean for your business? Well, it means that investing and vehicles and cdl training should still be high on your list of priorities. If you want to be able to meet your deliveries and please your customers.

Automation with robots

Everyone has seen the little orange robots that Amazon is starting to use in their warehouses now. However, whether it is worth investing in them for your operation really depends on the costs involved.

After all, Amazon has a vast multinational logistics infrastructure, so it makes sense for them to invest in the tech. Something that it may not be sensible for smaller businesses to do until the price of each robotic unit comes down.

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Trial Underway Testing Brain-Computer Implant

Stentrode implant

Stentrode implant (Synchron Inc.)

20 Sept. 2019. The first participant in a clinical trial received an experimental minimally-invasive brain implant to record brain signals, testing the implant’s feasibility for assistive technology. The trial is conducted in Australia by Synchon Inc., based in Melbourne and Campbell, California, developer of the Stentrode device being assessed.

The Stentrode is a small metallic wire mesh tube, similar to a stent. The device has electrodes on tiny disks inside the tube, placed in a blood vessel adjacent to the primary motor cortex that controls voluntary muscular movements in the body. However, instead of drilling a hole in the skull to implant the device, the electrode travels from a vein in the neck into the selected brain blood vessel. When the Stentrode reaches its destination, it expands to fill the blood vessel.

Once implanted, the Stentrode captures electric signals directed to the motor cortex to stimulate specific muscles in the body. Those same signals are sent from the Stentrode to a device implanted in the person’s chest called the brainPort that relays the signals to a nearby receiver. From the receiver, says Synchron, the signals are translated into computer-readable commands by another system component called brainOS for communication and to restore limb functions.

“By using veins as a naturally-existing highway into the brain,” says Thomas Oxley, Synchon’s founder and CEO in a company statement, “we have been able to reach the clinical stage significantly earlier than other more invasive approaches.” Oxley is also a neurology professor at University of Melbourne.

Synchron tested the system in preclinical studies with colleagues at University of Melbourne. Science & Enterprise reported on one of those studies in December 2018, published in the journal Nature Biomedical Engineering. In that report, researchers inserted Stentrodes in brains of sheep and directed the electrodes to stimulate facial and limb muscles in the animals. The results show the appropriate sheep muscles responded on demand, similar to electrodes implanted surgically.

The early-stage clinical trial is recruiting five individuals in Melbourne with loss of motor function due to limb loss or paralysis from spinal cord injury, motor neuron diseases such as ALS, stroke, or muscular dystrophy. Participants will be followed for 12 months, looking primarily for signs of adverse effects. However, the study is also tracking the quality and stability of the signals transmitted from the Stentrodes.

“What we learn from the first-in-human clinical trial will be highly valuable in guiding our device design and clinical protocol for a pivotal trial in the U.S.,” notes Oxley.

Synchron is developing brainOS into a collection of apps to help patients restore lost speech and limb functions, strictly by channeling their thoughts captured on Stentrodes to direct movement of specific muscles, without a mouse or keyboard. “By reimagining the concept of the operating system,” adds Oxley, “we have designed our technology platform to enable a completely hands-free user experience.”

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Opioid Abuse Treatment Medications Underused

Head in hands

(Photo by Cristian Newman on Unsplash)

20 Sept. 2019. While three medications for opioid abuse are approved by the Food and Drug Administration, the treatments are used sparingly in therapy according to a new review of data. Findings from a team at the Mayo Clinic in Rochester, Minnesota and Washington University in St. Louis appear in yesterday’s issue of the journal Mayo Clinic Proceedings.

The number of drug overdose deaths from opioid abuse continues to grow in the U.S. According to Centers for Disease Control and Prevention, or CDC, more than 702,000 Americans died from a drug overdose between 1999 and 2017, with more than 70,000 deaths occurring in 2017 alone. About two-thirds of those deaths (68%) involved a prescription or illicit opioid.

Researchers led by Tyler Oesterle, medical director of the Mayo Clinic Fountain Centers — the Clinic’s provider of substance abuse and addiction treatments — reviewed the extent to which practitioners are making use of medication-assisted therapies in treating opioid addiction. In fact, three federal agencies in the U.S. — CDC, National Institute of Drug Abuse, and Substance Abuse and Mental Health Services Administration — recommend adding medication therapies to psychotherapy and counseling-based treatment programs.

For its part, FDA so far approved three medications for opioid-abuse therapy programs: naltrexone, buprenorphine, and methadone. Yet, according to estimates by the authors, only about 11 percent of individuals with opioid use disorder are prescribed these medications.

Oesterle and colleagues note that no single medication is ideal for all opioid-abuse patients, and discuss the pros and cons of each drug. Naltrexone works by blocking opioid receptors and acts as a deterrent to further opioid use. If taken as intended, naltrexone can increase the chance for sobriety and reduce the risk of overdose. The problem with naltrexone is that it requires complete abstinence from opioids, and any reduction in compliance with treatments or break in abstinence can trigger a relapse.

Buprenorphine is a semi-synthetic opioid that satisfies the addiction cravings from opioids without creating the pleasurable intoxication. Users of this treatment report high compliance, as well as fewer overdoses and reduced crime. But it requires dosing in a doctor’s office or therapy site, and close monitoring, which reduces its utility for some patients. Abuse of buprenorphine is also a risk, thus its modest use and need for close scrutiny.

Methadone is a maintenance drug approved for heroin addiction treatment programs, and in liquid form is relatively low in cost. Results show methadone maintenance reduces overdose deaths, criminality, and spread of infectious diseases, including HIV, when sharing needles. Methadone compounds last longer in the body, and as a result increase the risk of accidental overdose. In addition, diversion of methadone to street use is a continuing risk.

To encourage more use of mediation-assisted treatments for opioid use disorder, the authors provide a structured decision flowchart for guiding clinicians to recommend an appropriate medication-assisted treatment for patients, after the initial screening. The researchers also call attention to special considerations, including pregnancy, age of the individual, and if the patient needs surgery or is in pain.

The authors conclude that the U.S. and other countries continue to face problems of opioid abuse because of overzealous prescription of the drugs, their wide availability, and the expectation that all pain can be eliminated. “We clearly cannot medicate our way out of the problem,” says Oesterle in a Mayo Clinic statement, “but we have the opportunity to mediate the problem through more judicious use of prescription opioids.”

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First Therapies Selected for Multi-Drug ALS Trial

Brain cell networks

(Gerd Altmann, Pixabay)

19 Sept. 2019. A clinical trial is getting underway to test five treatment candidates for amyotrophic lateral sclerosis, or ALS, beginning with the first three therapies. The study, known as a platform trial, is being conducted by the Healy Center for ALS at Massachusetts General Hospital in Boston.

ALS, also known as Lou Gehrig’s disease, is a progressive neurodegenerative disorder where neurons or nerve cells controlling muscles in the body begin to waste away, and can no longer send or receive signals from the brain or spinal cord. As the nerve cells stop functioning, muscles in the limbs, and later speech and breathing muscles, begin weakening and eventually stop functioning. Most people with the disease die of respiratory failure. There are currently no cures for ALS, and few effective treatments for slowing progression of the disease.

A platform clinical trial, also called an adaptive trial, is designed to test multiple treatments at a time. The studies use a common master plan or protocol that allow for adding new therapies or changing the study’s characteristics as conditions require. These trials also use Bayesian statistics, a branch of statistics using models built to accommodate adding new data and adjusting the model’s calculations as new data are added. Platform or adaptive trials are now used to test cancer therapies, with results from one of those trials reported by Science & Enterprise in September 2018.

Merit Cudkowicz, director of the ALS Center at Mass. General, says in a hospital statement, “This approach cuts the time to find an effective treatment in half, decreases costs by a third or more, and is supported by our patients, the FDA, ALS clinicians and scientists, and our pharma colleagues.”

In March 2019, the ALS Center issued an open call for new ALS therapies for testing in the trial. From 30 responses, the trial’s evaluation and advisory committee’s selected five drugs for assessment. The study is expected to start with testing three drugs:

Pridopidine, developed by Prilenia, a start-up enterprise in Herzliya, Israel. Pridopidine is a Sigma-1-receptor agonist that the company says regulates cellular processes important to neurodegenerative diseases. Prilenia says Pridopidine is being tested in preclinical studies and clinical trials for several neurodegenerative disorders, including ALS.

Zilucoplan, made by Ra Pharmaceuticals in Boston, a synthetic peptide developed to treat the autoimmune disorders generalized myasthenia gravis and  immune-mediated necrotizing myopathy, as well as ALS. The drug candidate is now in early- and mid-stage clinical trials for the two autoimmune diseases.

Verdiperstat, developed by Biohaven Pharmaceutical in New Haven, Connecticut. Verdiperstat, says Biohaven, inhibits the myeloperoxidase or MPO enzyme, considered a a key driver of oxidative and inflammatory processes. Higher MPO levels, says the company, are found in a number of brain disorders, and verdiperstat is found to reduce oxidative stress and inflammation, also implicated in the onset of ALS.

The trial plans to soon add two more therapy candidates for testing, CNM-Au8 nanocrystalline gold being developed by Clene Nanomedicine in Salt Lake City, and IC14 immunotherapy, developed by Implicit Bioscience in Seattle.

The trial is expected to evaluate promising biomarkers of ALS and incorporate new types of outcome measures. “This design,” adds Cudkowicz, “optimizes chances for people to receive active treatment, provides answers faster, and ensures we keep learning about the disease.”

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Start-Up Targets Extra DNA in Cancer, Raises $46.4M

Paul Mischel

Paul Mischel (Ludwig Institute for Cancer Research)

19 Sept. 2019. A new biotechnology enterprise is developing treatments for aggressive solid tumor cancers that block the effects of DNA residing outside of chromosomes. Boundless Bio Inc. in San Diego formed earlier this year and raised more than $46 million in its first venture financing.

Boundless Bio says it’s designing a new type of cancer therapy addressing extrachromosomal DNA, strands of DNA that are not part of normal chromosomes in the genome or found in typical cells. Instead, the circular pieces of DNA reside within the nucleus of oncogenes, mutated genes responsible for cancer. These extrachromosomal DNA occurrences are associated with nearly half of all solid tumor cancers, says Boundless Bio, particularly aggressive, fast-growing cancers.

The biotechnology company is founded by six researchers from the fields of cancer biology, but also computer science and biomedical engineering. The scientific founders are led by Paul Mischel, a researcher in cancer genetics at the Ludwig Institute for Cancer Research, affiliated with University of California in San Diego. Mischel studies extrachromosomal DNA in oncogene amplification, a process where genes make multiple extra copies that contribute to cancer cell multiplication. These copy number variations code for proteins that evade normal regulatory functions and encourage tumor growth.

Boundless Bio says its technology aims to address the role of extrachromosomal DNA, or ecDNA, in cancer, leading to new cancer treatments. “Guided by our developing understanding of ecDNA,” says Mischel in a company statement released through BusinessWire, “our scientific founders have created a new architectural map of the cancer genome to demonstrate why some cancers aggressively evolve and resist existing treatment approaches. We have developed technology capable of identifying, characterizing, and ultimately, drugging, ecDNA-driven tumors.”

The company formed earlier this year and began operations in stealth mode. Zachary Hornby, who became Boundless Bio’s president and CEO in May 2019 notes, “Boundless Bio aims to improve cancer care by bringing a whole new class of weapons to the cancer-fighting armamentarium that exploit the emerging field of ecDNA biology.” He adds, “We are creating powerful medicines that counterattack this ecDNA phenomenon by eliminating cancer cells’ ability to employ ecDNA to survive.”

Boundless Bio is raising $46.4 million in its first venture funding round, led by health care and life science venture investors ARCH Venture Partners in Chicago and City Hill Ventures in San Diego. Taking part in the financing are Vertex Ventures, GT Healthcare Capital Partners, Boxer Capital of the Tavistock Group, Alexandria Venture Investments, and other undisclosed investors.

The company expects to apply the funds to building its technology to identify and describe tumors that result from extrachromosomal DNA. The first treatments will aim for solid tumor cancers caused by high copy number mutations.

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Smart Solar Powered Crop Dryer Receives Grant Funds

Klein Illeji, left, and Reiko Habuto Illeji, with a solar-powered crop drying device. (Jua Technologies International)

18 Sept. 2019. An Indiana company is receiving U.S. government and private grants to develop a solar-powered algorithm-controlled crop dehydrator for small farms. Jua Technologies International in Carmel, Indiana, a spin-off enterprise from Purdue University, is the recipient of a $100,000 award from National Institute of Food and Agriculture, part of the U.S. Department of Agriculture, and a supplemental $50,000 from Elevate Ventures, a venture development organization supporting new enterprises in Indiana.

Jua Technologies is the creation of Purdue agricultural engineering professor Klein Ileleji and his wife Reiko Habuto Ileleji, a Ph.D. graduate in education from Purdue. The founders started the company in 2016 to develop crop drying and dehydrating equipment for small farmers. Quick, inexpensive drying methods, says the company, can reduce crop losses and waste, a continuing problem for small and mid-size growers. The company cites estimates of global crop losses after harvest totaling $20 billion per year. Using solar energy also reduces greenhouse gas emissions from natural gas or fuel oil.

Dehydration of fruit, spices, and herbs now often takes place either on open-air mats or energy-intensive commercial dehydrators. Open-air drying, while energy efficient says Jua Technologies, degrades nutrients in the crops and reduces food quality. And while solar-powered dehydrators are being designed, few are yet commercialized.

With the new funding, Jua Technologies is developing a high-efficiency crop dehydration system called the Dehymeleon using solar energy that operates both day and night. The system will include a drying chamber controlled by an algorithm to maximize control of the dehydration process, and a heat recovery module using zeolite minerals to absorb moisture during evening hours. The system is expected to have a thermal collector using copper tubes for heat exchange, and employ heat transfer with fans controlled by the system’s algorithm. The systems will also be able to generate supplemental solar electric power for the farm or home.

The project calls for developing simulation models to optimize performance of the Dehymeleon, and to predict performance of the system in the field with a range of fruits, vegetables, spices, and herbs. The end-result of the project is two or three prototype Dehymeleon crop dehydrators for testing on farms and orchards in Indiana and California. The company signed a a cooperative research and development agreement — a shared-cost arrangement — with a USDA research center in California to test its prototype systems with the state’s local produce.

While the system will be developed mainly for low-resource regions of the world, Ileleji expects to market the device to growers serving farmers markets in the U.S. “The Dehymeleon will be used by small and mid-size growers of specialty crops that have added value through drying,” says Klein Ileleji in a Purdue University statement. “You will be able to use the Dehymeleon to preserve essential nutrients in medicinal plants, tea, coffee and cocoa, which are very sensitive to temperature and ultraviolet light.”

The National Institute of Food and Agriculture award is made under the agency’s Small Business Innovation Research, or SBIR, program that sets-aside a portion of its research funds for small businesses in the U.S.

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Trial Shows Radio Waves Safe for Alzheimer’s Therapy

brain stimulationgraphic

(Media News, Flickr)

18 Sept. 2019. Results from a small clinical trial show a treatment for Alzheimer’s disease using radio waves is safe and offers early evidence it can reverse memory loss. Findings from the trial conducted by NeuroEM Therapeutics Inc. in Phoenix appear in the 3 September issue of the Journal of Alzheimer’s Disease.

Alzheimer’s disease is a progressive neurodegenerative disease affecting growing numbers of older people worldwide. People with Alzheimer’s disease often have deposits of abnormal substances in spaces between brain cells, known as amyloid-beta peptides, as well as misfolded tangles of proteins inside brain cells known as tau. The Alzheimer’s Association says some 5.8 million individuals in the U.S. have the disorder, and by 2050 that number is expected to increase to 14 million.

The clinical trial tested the NeuroEM system called Transcranial Electromagnetic Treatment, or TEMT, mainly for safety with Alzheimer’s patients, but also for signs of efficacy. The device uses eight radio wave antennas woven into a cap worn over the patient’s head, with the antennas emitting radio wave pulses in frequencies similar to cell phones. The individual wears the cap for two sessions of one hour each during the day, separated by at least a seven-hour interval. The head cap is wired to battery-powered control panel worn on the upper arm.

As reported by Science & Enterprise in December 2016, preclinical studies show transcranial treatments can prevent cognitive impairment of younger mice, before amyloid-beta peptides began accumulating into plaques. With older genetically-engineered mice, the treatments reversed accumulations of amyloid-beta peptides, as well as cognitive impairment displayed by the animals. Further preclinical studies indicate the treatments can prevent and reverse proteins from penetrating and accumulating inside neurons, causing further damage, as well as enhance the mitochondrial, or cellular energy components in neurons.

The early-stage clinical trial recruited eight participants with mild to moderate Alzheimer’s disease at University of South Florida’s Byrd Alzheimer’s Center in Tampa. Participants wore the TEMT device for twice-daily sessions at home for 60 days, with the study team conducting a follow-up evaluation two weeks after the last treatment.

The researchers looked primarily for signs of adverse effects from the treatments. The team also assessed participants with a standard Alzheimer’s Disease Assessment Scale–Cognitive Subscale, or ADAS-Cog, that measures the level of cognitive dysfunction in Alzheimer’s disease and the Rey Auditory Verbal Learning Test measuring short-term auditory-verbal memory and related functions. In addition, the team measured changes in brain and central nervous system chemistry indicating changes in toxic protein levels.

The study team found no evidence of physiological or behavioral harm from the treatments, including signs of bleeding in the brain or evidence of tumor formation from MRI scans. The findings show seven of the eight participants recorded higher scores of memory retention on the ADAS-Cog scale at the end of the 60-day treatments compared to before the treatments that continued in the 14-day follow-up test. The eighth participant showing decreases in memory function typical of people with Alzheimer’s disease.

Scores on forgetfulness measures in the Rey Auditory Verbal Learning Test from before to after treatments also declined, but other cognitive indicators in the small sample were not large enough for statistical reliability. In addition, tests of cerebrospinal fluid, blood, and glucose in the brain from PET scans show at least modest improvement in indicators of amyloid-beta and tau proteins, as well as brain connectivity, which correlate with participants’ ADAS-Cog scores.

Amanda Smith, medical director of the Byrd Institute at USF and a co-author of the paper, says in a NeuroEM statement, “These results provide preliminary evidence that TEMT administration we assessed in this small AD study may have the capacity to enhance cognitive performance in patients with mild to moderate disease.”

NeuroEM is extending the study to document effects over an average of 17 months following treatment. And the company is planning a larger-scale clinical study recruiting 150 patients to test the TEMT treatments.

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Clinical Research Sites Open in Canadian Walmart Stores

Walmart entrance

Entrance to Walmart store in Pincourt, Quebec, Canada (Bull-Doser, Wikimedia Commons)

17 Sept. 2019. A collaboration between a research company and local health clinic chain is enabling customers at Walmart stores across Canada to take part in clinical research studies. Financial aspects of the partnership between Elligo Health Research in Austin, Texas and Jack Nathan Health in Georgetown, Ontario are not disclosed.

Jack Nathan Health operates a chain of self-contained medical and dental clinics located at some 70 Walmart retail stores in six Canadian provinces: Quebec, Ontario, Manitoba, Saskatchewan, Alberta, and British Columbia. The clinics, operated under contract to Walmart, provide family health services by appointment, as well as walk-in services. In addition, Jack Nathan Health can provide an annual health assessment that includes physical exam, lab tests, and fitness and diet assessments.

Elligo Health Research is offers clinical research capabilities as a service for physicians’ offices and clinics. The company cites data showing only 3 percent of physicians and their patients take part in clinical trials. To make it easier for medical practices to participate in trials, Elligo Health Research offers a technology package that accesses a physician’s electronic health records, enabling medical practices to take part in clinical studies with little up-front investment. The company says participating practices that meet its standards are designated as research-ready sites.

For clinical trial study teams, Elligo offers a service called GoesDirect that connects study sponsors and commercial research companies to research-ready sites. Elligo says it queries electronic health records at its participating sites for criteria matching patient recruitment needs for clinical trials, and matches patients to study teams. The company cites its own study showing this approach recruits and randomizes three times the number of trial participants as conventional methods. This approach, Elligo adds, also increases diversity of clinical trial samples.

The agreement gives Elligo Health Research exclusive access to Walmart’s health clinics in Canada operated by Jack Nathan Health. The Walmart clinics will offer clinical research participation to their patients as a health care option. Jack Nathan Health clinics will be designated as research-ready sites by Elligo, and participating patients will be eligible for enrollment in clinical trials through GoesDirect.

“Partnering with Elligo,” says Jack Nathan Health co-founder and  CEO George Barakat in an Elligo company statement, “gives us the opportunity to stay informed of the newest advancements, improve our cutting-edge facilities, and continue to meet our patients’ health care challenges.”

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Gel, Crispr Help Defeat Cancer Drug Obstacles

Crispr-Cas9 illustration

Crispr-Cas9 illustration (LBL.gov)

17 Sept. 2019. A high-powered binding protein, formulated as a gel and targeted by Crispr gene editing is shown in lab mice to precisely deliver drugs and kill cancer cells. A description of the technology and test results by a team from Duke University in Durham, North Carolina appear in the 4 September issue of the journal Science Advances.

Researchers from the biomedical engineering lab of Ashutosh Chilkoti and pharmacology lab of Kris Wood at Duke seek to overcome continuing obstacles in developing effective treatments for cancer. A promising class of small-molecule drugs known as tumor necrosis factor–related apoptosis-inducing ligand, or Trail, is shown in lab tests over the years to kill a range of solid tumor cells in breast, lung, colon, melanoma, lymphoma, pancreatic, and prostate cancer. In real-world tests, however, Trail drugs repeatedly fail due to lack of binding ability to targeted tumor cells, short effective potency times, and resistance built-up to Trail drugs by the tumors.

The team led by graduate student Mandana Manzari, now a postdoctoral researcher at Memorial Sloan Kettering Cancer Center in New York, designed a strategy to address these limitations. Trail drugs promote cell apoptosis or death by sending chemical signals to receptor proteins that kill the cells from inside. Manzari and colleagues designed a six-part death-receptor agonist that binds to a site called DR5, sensitizes target cells to the drug, and sends more intense chemical signals, making it extremely toxic. Tests with human cancer cell lines in lab cultures confirmed this cancer-cell killing power.

The researchers then created a delivery method for longer-term release of this death-receptor agonist. For extending the release time of the drug, the team designed a gel material made from elastin-like polypeptides, short chains of biocompatible polymers used previously for drug delivery and tissue engineering. Elastin-like polypeptides are temperature-sensitive and can fuse with the delivered drug. In this case, the elastin-like polypeptides are formulated as a liquid for easier injection at room temperature, but when subjected to body temperature, they form into a gel that adheres for longer periods to the tumor.

To help overcome resistance to Trail drugs developed by tumors, the researchers assessed the genetics of tumor cells with the gene-editing technology Crispr, short for clustered, regularly interspaced short palindromic repeats. Using the editing enzyme Cas9, the team systematically knocked-out genes in the target tumor cells until they found the genes contributing to resistance to death-receptor agonists, or DRAs.

“When we figured out the genes that drive resistance,” says Manzari in a Duke University statement, “we were able to map them to commercially-available drugs that could specifically target the proteins that come from those genes. It basically gave us a platform to figure out what drugs we can combine with the DRA in cases where this drug or other protein drugs don’t work well to nip that resistance in the bud.”

The researchers tested their death-receptor agonist, formulated into a liquid that transforms into a gel, targeted to overcome tumor resistance. The test subjects were lab mice grafted with human colon cancer tumor tissue, receiving combinations of two or three small-molecule Trail drugs and death-receptor agonist, against the death-receptor agonist alone. The results show mice receiving the gel-delivered death-receptor agonist and three cancer drugs have less tumor growth and longer survival times than the two-drug combinations or death-receptor agonist alone.

The team believes they designed a cancer therapy strategy that fits into the emerging precision-medicine treatment model. Duke University has patents granted or applications filed for the technologies developed in this research, with the lead and senior authors listed as inventors. In addition, Chilkoti is the scientific founder and adviser to PhaseBio Pharmaceuticals Inc. in Malvern, Pennsylvania that licenses his work on fusion of elastin-like polypeptides to drug compounds.

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