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Pen-Dispensed Bio-Inks Developed for On-Demand Sensors

Biosensors drawn directly on the skin

Biosensors drawn directly on the skin (Jacobs School of Engineering/UC San Diego)

3 March 2015. Researchers at University of California in San Diego developed a way to create bioactive inks to use in hand-drawn sensors when needed at the point of care and other applications in the field. The team from the lab of nanoengineering professor Joseph Wang reported on their proof-of-concept findings last week in the journal Advanced Healthcare Materials (paid subscription required).

The San Diego team was seeking simple techniques to create sensors for tests involving biological processes, such as detection of pathogens or biological agents, health screening, and environmental monitoring. The solution needed to be safe for animals (including humans) and plants, adhere to surfaces, conduct an electric current, and easy to store and apply when needed.

Wang and colleagues tested a number of compounds and materials with the capability to meet these conditions. One of the key ingredients in their solution is polyethylene glycol, a biocompatible polymer found in cosmetics and skin creams as a binder and emulsifier, as well as over-the-counter medications, such as laxatives. For electrical conductivity, the researchers added graphite powder.

For the ink to stick to surfaces after being applied, researchers added chitosan, a natural sugar found in the hard outer skeleton of shellfish and used in wound dressings to stop bleeding. They also included xylitol, a naturally occurring alcohol used as a sugar substitute, but in this case to stabilize the active enzymes for testing added to the inks.

The team then loaded the inks into standard off-the-shelf ballpoint pens to be dispensed and applied. The first demonstration was to test for blood sugar or glucose levels, with a test enzyme added to the ink. Participants in the test drew a specified test pattern on a flexible plastic strip fitted with an electrode. The subjects next drew a drop of blood from a fingertip and spread the blood on the strip, which recorded their glucose levels, and transmitted the readings to a measuring device. The subjects then cleaned the strip and repeated the test after a meal, showing changes in glucose levels.

In a similar test, the researchers showed test patterns could be drawn directly on the skin rather than using a plastic strip. The readers were then transmitted over a Bluetooth link to a potentiostat, a device for measuring biochemical reactions.

A different test showed the inks could be applied to test for the presence of pollutants or hazardous materials. The researchers added enzymes to test for the compound phenol, also known as carbolic acid, an industrial chemical found in cosmetics and sunscreen, but also considered toxic by regulatory authorities in the U.S. and overseas. The team drew test patterns with the phenol test ink on leaves, then dipped the leaves in a water mixed with phenol, with readings on a connected pollution detector showing the presence of phenol in the water.

Wang and colleagues next plan to develop more wireless links to the hand-drawn sensors, and test the process further in more demanding conditions, such as extreme temperatures and longer exposure to sunlight.

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Trial to Test Video Game Therapy for Autism

Adam Gazzaley

Adam Gazzaley (University of California, San Francisco)

2 March 2015. A clinical trial plans to begin recruiting participants to test a video game designed to engage areas of the brain for building cognitive skills affected by autism. The trial, conducted by Akili Interactive Labs that developed the game, is funded by Delivering Scientific Innovation for Autism or Delsia LLC, a subsidiary of the foundation Autism Speaks for supporting technologies to treat the disorder. Financial details were not disclosed.

Autism spectrum disorder is a collection of neurodevelopmental conditions, marked by communication difficulties and impaired social interaction, as well as repetitive and stereotyped patterns of behavior. At age 8, some 1 in 88 children have autism spectrum disorder, according to Centers for Disease Control and Prevention. Classic autism is considered the most severe form of the syndrome.

Akili Interactive Labs is a spin-off enterprise from University of California in San Francisco, based on research from the lab of neuroscientist Adam Gazzaley, a co-founder and scientific advisor to the company. Gazzaley and colleagues at UCSF designed a video game to detect signs of cognitive decline among elderly individuals, and discovered that the game not only detected cognitive decline, it also had therapeutic effects. The researchers found participants who played the game over 4 weeks improved the subjects’ memory and cognitive skills.

Gazzaley went on the start Akili in 2011, under the tutelage of life sciences start-up accelerator PureTech Ventures in Boston. The company is applying Gazzaley’s concepts to detection and treatment of cognitive deficits, but to a broader population, including children.

Akili’s first program is a platform called EVO that uses a tablet- or smartphone-based electronic game to test multi-tasking skills. EVO requires players to guide a friendly alien down a river, while tapping the screen when a designated animal appears. The company says the game gets progressively more difficult, automatically adapting to the player’s ability level, and capturing progress by the participant.

The clinical trial aims to recruit 125 individuals, age 8 to 16, diagnosed with autism spectrum disorder and attention deficits. Sites for the trial are expected to be selected later this year. Autism Speaks says the EVO project, supported by Delsia, could serve as a model for other technology-based therapies for autism.

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Genome Editing Shown to Repair Sickle Cell Gene

Blood cells with sickle cell disease

Red blood cells with sickle cell disease (NIH.gov)

2 March 2015. Geneticists at the biotechnology company Editas Medicine show how genome editing techniques could repair mutations in the gene that causes sickle cell disease. Cecilia Cotta-Ramusino, a researcher with Editas, presented her findings today at the Keystone Symposium for Genomic Instability and DNA Repair in Whistler, British Columbia, Canada.

Sickle cell disease is a genetic blood disorder affecting hemoglobin that delivers oxygen to cells in the body. People with sickle cell disease have hemoglobin molecules that cause blood cells to form into an atypical crescent or sickle shape. That abnormal shape causes the blood cells to break down, lose flexibility, and accumulate in tiny capillaries, leading to anemia and periodic painful episodes. The disease is prevalent worldwide, and affects 70,000 to 80,000 people in the U.S., including about 1 in 500 people of African descent.

Editas Medicine develops therapies with the ability to turn off and on and repair genes causing disease. The company’s technology harnesses discoveries including clustered, regularly interspaced short palindromic repeats (CRISPR) and related CRISPR-associated protein 9, known as CRISPR/Cas9. With CRISPR/Cas9, the Cas9 protein binds to targeted RNA molecules generated by the human genome. The RNA molecules then guide Cas9 proteins to specific genes needing repair, making it possible to address root causes of many diseases.

The gene targeted in this case is the hemoglobin beta or HBB gene, where a mutation changes a protein building block that causes the components of hemoglobin to stick together in long rigid molecules. These abnormal molecules in turn bend red blood cells into the sickle or crescent shape characteristic of sickle cell disease.

Cotta-Ramusino and colleagues at Editas, applied their technology in a technique called gene conversion, where the mutated gene is repaired with a different, but closely related gene. The repair — performed in lab cultures, not with humans or lab animals — used material from the hemoglobin delta or HBD gene, a cousin of hemoglobin beta.

The team tested several Cas9 enzymes to repair the HBB gene, and found one known as D10A that in about 30 percent of the cases could repair HBB genes with HBD material. The tests show as well D10A enzymes could repair HBB genes without material from an external donor. The tests suggest that a potential gene conversion therapy could be designed with HBD genetic material from a person afflicted with sickle cell disease, eliminating the need to find a compatible donor.

“While the results are early and further work is needed to see if this approach could be used therapeutically, says Katrine Bosley, Editas Medicine’s CEO in a company statement, “these data suggest gene conversion as a possible new approach to genomic repair for certain kinds of genetic mutations.”

Editas Medicine, in Cambridge, Massachusetts, began in 2013 and licensed technologies developed by the company’s scientific founders and others from Harvard University, MIT, Massachusetts General Hospital, and Duke University.

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Adult Stem Cell Quality Control Methods Devised

Stem cells (NSF)

Stem cells (National Science Foundation)

27 February 2015. A European research team developed a process for testing the safety and quality of adult stem cells before being used in gene therapy treatments on patients. The team led by stem cell scientist Yann Barrandon at the Swiss Federal Institute of Technology in Lausanne published its findings today in the journal EMBO Molecular Medicine.

Barrandon and colleagues sought a way to prevent serious problems with gene therapies using regenerated skin cells from adult stem cells, even stem cells taken from the patient needing the therapy. The problems occur when mutations develop in the cloned or regenerated cells that lead to irreversible transformations in the cells, and more complications for patients rather than cures.

The authors designed and tested the concept of assessing potential effectiveness and safety of cultured adult stem cells before transplanting into patients, in this case with recessive dystrophic epidermolysis bullosa, an inherited skin condition. The condition occurs when individuals do not produce a specific type of collagen protein that anchors the epidermal or outer layers of skin to underlying tissue, resulting in blistering of the skin, and can range from mild to serious, causing disfigurement and vision loss.

The researchers cultured adult skin stem cells with recessive dystrophic epidermolysis bullosa with the gene that encodes the protein missing from people with the condition. The team then produced modified cells for replacement, but first submitted the replacement cells to a series of quality tests.

The tests included the ability to regenerate new outer-layer skin cells, produce the missing protein, anchor the outer skin layer to underlying tissue, and renew themselves over the long term. The researchers also submitted the cells to a series of safety tests, including genomic sequencing. The results indicate only a few of the replacement cells could pass both the quality and safety tests.

Barrandon and colleagues tested the cells passing both quality and safety steps by transplanting these cells into lab mice with weakened immune systems and bred to express the recessive dystrophic epidermolysis bullosa condition. The mice receiving the transplanted cells were able to produce the missing protein and regenerate new skin that did not blister.

The authors believe the findings point to measures that can improve outcomes for patients needing stem cell transplants, as well as newer types of gene therapies. “Until now there has not been a systematic way to ensure that adult epidermal stem cells meet all the necessary requirements for safety before use as treatments for disease,” says Barrandon in an EMBO statement, adding their techniques “should make it possible to integrate some of the more recent technologies for targeted genome editing that offer more precise ways to change genes in ways that may further benefit the treatment of disease.”

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Registry to Track Psoriasis Drug Safety

Psoriasis on arm

(National Library of Medicine, NIH)

26 February 2015. A new registry of patients with psoriasis will track the safety of a recently approved biologic drug designed to treat that disorder. The Corrona Psoriasis Registry is a joint undertaking of National Psoriasis Foundation and Corrona LLC, a company in Southborough, Massachusetts hosting registries of patients with chronic diseases.

Psoriasis is an autoimmune disorder, where the body’s immune system is tricked into attacking healthy cells, in this case resulting in inflammation and red, scaly patches of dead skin cells typically in the scalp, or near knees and elbows. According to the foundation, some 125 million people worldwide have psoriasis, including 7.5 million Americans.

Corrona and National Psoriasis Foundation say the registry will begin with collecting and analyzing safety data of the biologic drug secukinumab, marketed by the pharmaceutical company Novartis under the brand name Cosentyx, and approved by Food and Drug Administration in January 2015. The drug works by binding to the interleukin-17A cytokine, a protein that activates inflammation. By binding to this protein, Cosentyx blocks interleukin-17A from binding to its receptor that triggers the inflammation, thus preventing the red, itchy scales on the skin.

FDA approved Cosentyx for plaque psoriasis patients who qualify for systemic therapy — treatments that go through the blood stream — or treatments with ultraviolet light, or both. The drug is given as an injection under the skin. Under terms of the approval, Novartis is preparing a medications guide with warnings about potential effects of Cosentyx on the immune system, including reports of serious allergic reactions. The most common side-effects of Cosentyx are diarrhea and upper respiratory infections.

The Corrona Psoriasis Registry is expected to enroll some 3,000 people with psoriasis taking Cosentyx and follow their treatment for at least 8 years. Patients with psoriasis and their physicians will complete up to 2 registry questionnaires per year during office visits.

Corrona provides patient registries for rheumatoid arthritis and spondyloarthritis, a collection of related inflammatory rheumatic diseases that cause arthritis, as well as psoriasis. Its registries are designed to capture data about the long-term safety and effectiveness of drugs that are rarely, if ever, collected in clinical trials. The company says data for registries are screened by biostatisticians, and made available to researchers to assess drug safety and effectiveness over time, as well as better understand the nature of the disorders.

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Illumina Adds $40M for Genomic Accelerator Start-Ups

Base sequence illustration (Genome.gov)

(Genome.gov)

26 February 2015. Illumina Inc., a developer of genomic analysis systems, is adding $40 million for investments in new enterprises based on genomic science that graduate from its accelerator program. The additional financing is provided by Viking Global Investors, an equity and hedge fund investment company in Greenwich, Connecticut.

The Illumina Accelerator program provides promising start-up companies designing products or services based on genomics with seed financing, lab space at Illumina facilities in San Francisco, access to Illumina sequencing systems, mentoring and business guidance, and non-exclusive rights to Illumina intellectual property. Seed funding consists of $100,000 in convertible notes — debt financing that converts to equity — and an unsecured credit line of $20,000. Teams in early-stage business formation are encouraged to apply, with the next application deadline set for 9 March 2015.

The new $40 million investment fund will support Illumina Accelerator participants after they emerge from the program, and will be provided as matching funds for companies raising between $1 and $5 million on their own. “This capital commitment will be instrumental in driving value for our start-ups as they advance breakthrough applications in genomics,” says Amanda Cashin, who leads Illumina Accelerator in a company statement.

The first group of three start-ups in the Illumina Accelerator was selected in October 2014:

– Biopharmaceutical company Encoded Genomics

– Agricultural therapies company EpiBiome, developing treatments for infections in dairy cattle

Xcell Biosciences, commercializing cell culture solutions for growing primary cells from a patient’s blood

The Illumina Accelerator was first formed in February 2014. Technology investor Yuri Milner provided initial seed financing, with additional funding and banking services from Silicon Valley Bank.

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Patent Issued for Mobile Pulse Oximetry Technology

Kenek O2 pulse oximeter

Kenek O2 pulse oximeter, connected to iPhone 6 (LionsGate Technologies Inc.)

25 February 2015. LionsGate Technologies Inc., a medical device company in Vancouver, Canada, received a patent for techniques and processes that connect sensors measuring blood oxygen levels to smartphones and tablets. Patent number 8,958,859 was issued by U.S. Patent and Trademark Office on 17 February 2015 to inventors Mark Ansermino, LionsGate’s chief medical officer, and research executives Guy Dumont and Christian Petersen.

The patent describes LionsGate’s technology that makes it possible to connect mobile devices to standard sensors measuring blood oxygen saturation in pulse oximeters. The technology adapts the standard pulse oximeters, worn on a hospital patient’s fingertip to detect hypoxemia, a condition where blood in the arteries is not sufficiently oxygenated. Blood oxygen saturation can also serve as an early warning for pregnant women at risk of developing preeclampsia, a rapidly progressive and dangerous condition usually diagnosed with a pregnant woman’s blood pressure readings that can occur in the second or third trimester.

Pulse oximeters shine red and infrared light on the skin and measure the waves that pass through. The proportions of different light waves passing through are then calculated into a percentage of oxygen saturation. The patent covers hardware adaptions required to connect sensors, such as LEDs, capturing the different light waves to the audio parts of mobile devices.

Unlike standard hospital pulse oximeters, the LionsGate technology takes advantage of processing power in mobile devices to to analyze the readings and return blood oxygen measurements, as well as communicate results from the point of care in remote locations. The patent describes functions of software controlling signals passing through the audio port, as well as conversion of analog to digital signals.

In addition, the patent covers the application program interface for apps on mobile devices that interpret the pulse oximetry data into vital signs for patients and clinicians. LionsGate offers as well apps that turn mobile devices running Apple’s iOS operating system into pulse oximeters.

LionsGate also says its Kenek O2 pulse oximeter received licensing from Health Canada, the country’s regulatory authority for medical devices. The device — that includes a free smartphone app — records and tracks heart rate as well as blood oxygen saturation. The company plans to market the device in Canada, which will be available without a prescription, and sell for about $80.00.

LionsGate is a spin-off company from University of British Columbia, Child & Family Research Institute, and BC Children’s Hospital, all in Vancouver. Electrical and Computer Engineering in Medicine, a University of British Columbia research institute, conducted the studies leading to pulse oximeters powered by mobile devices.

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Paper Strip Test Developed for Ebola, Other Diseases

Paper strip test to detect Ebola

Paper strip test to detect Ebola and other viruses. On the left is the unused device, opened to reveal the contents inside. On the right, the device has been used for diagnosis; the colored bands show positive tests. (Massachusetts Institute of Technology)

25 February 2015. Biological and engineering researchers at Massachusetts Institute of Technology designed a simple device that can test in the field for several viral diseases at once, including Ebola. The team from the labs of microbiologist Lee Gehrke and engineering professor Kimberly Hamad-Schifferli described the device earlier this month in the journal Lab on a Chip (registration required).

The MIT researchers sought a quicker and easier method for clinical teams in remote locations to diagnose infectious diseases, which as seen in the current Ebola epidemic, can be devastating to entire communities. Testing for Ebola now requires taking blood samples and sending them to labs for analysis, which identify the presence of Ebola genetic material, but takes time, expensive equipment, and skilled staff. In limited resource regions, these lab facilities are often few and far between.

In addition, clinicians in the field are often confronted with symptoms associated with multiple diseases. “As we saw with the recent Ebola outbreak, sometimes people present with symptoms and it’s not clear what they have,” says Hamad-Schifferli in a university statement. “We wanted to come up with a rapid diagnostic that could differentiate between different diseases.”

For their device, the researchers adapted lateral flow technology, a process trapping the specimen sample in an absorbent paper or polymer plastic strip, which then flows with capillary action to active particles that change color when exposed to the targeted protein or pathogen. Probably the most well-known example of lateral flow technology is the home pregnancy test that indicates the presence of a hormone closely associated with pregnancy.

In this device, the MIT team devised a simple process to test for three infectious diseases at one time. The device uses a paper strip with silver nanoparticles colored red, orange, and green linked to antibodies associated with Ebola, yellow fever, and dengue fever respectively. A blood sample flowing through the paper strip comes in contact with the nanoparticles that react and change color if the targeted viral protein is present. The test takes about 10 minutes.

“When we run a patient sample through the strip, if you see an orange band you know they have yellow fever, if it shows up as a red band you know they have Ebola, and if it shows up green then we know that they have dengue,” notes Hamad-Schifferli.

The team is testing the device in the lab with synthetic viral proteins, as well as blood serum samples from infected animals. Their hope is to gain approval from the U.S. Food and Drug Administration to use the device in areas where the Ebola outbreak, while diminished overall, continues.

The researchers also believe the technology can be adapted to other infectious diseases. “There will undoubtedly be other viral outbreaks,” notes Gehrke. “It might be Sudan virus, it might be another hemorrhagic fever. What we’re trying to do is develop the antibodies needed to be ready for the next outbreak that’s going to happen.”

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System Personalizes Cancer Nanomedicine Treatments

Chemotherapy (National Institutes of Health)

(National Institutes of Health)

24 February 2015. Medical and engineering researchers at University of California in Los Angeles designed a system that generates a personalized combination of drugs, including medicines with nanodiamonds, to treat metastatic cancer. The team led by Dean Ho from UCLA’s dentistry school and Chih-Ming Ho, a professor of mechanical engineering, published its findings last week in the journal ACS Nano (paid subscription required).

The UCLA researchers sought a solution for treating people with advanced cancer that metastasizes, or spreads to other parts of the body, and who often receive simultaneous combinations of drugs to overcome resistance to single drugs. Even with genetic information to guide the choice and dosages of drugs, mutations in tumors can limit or negate the drugs’ effectiveness.

“Drug combinations are conventionally designed using dose escalation,” says Dean Ho in a university statement. “Until now, there hasn’t been a systematic way to even know where the optimal drug combination could be found, and the possible drug-dose combinations are nearly infinite.”

The team aimed to provide a more systematic way process for assembling a personalized cancer drug combination that accounts for the properties and complexity of tumors, as well as drug efficacy and toxicity. In addition, the process was designed to accommodate advances in nanomedicine, where adding nanodiamonds to compounds increases the ability of drugs to bind to tumor cell surfaces, a specialty of study co-leader Dean Ho. The added binding power increases the exposure of drugs to the cancer targets, boosting their efficacy and making possible lower dosages.

The UCLA researchers adapted a system known as Feedback System Control developed in Chih-Ming Ho’s engineering lab that studies control mechanisms in complex biological systems. The team modified Feedback System Control to analyze phenotypes or physical traits of cells along with drug efficacy and toxicity to determine optimal drug combinations.

The team tested combinations of current cancer drugs doxorubicin, mitoxantrone, bleomycin, and paclitaxel on breast cancer cell lines in the lab. The tests included various combinations with three of the drugs boosted with nanodiamonds and the fourth drug in its original state. The researchers also treated non-cancer cell lines with the drugs as indicators of safety. The tests covered single drugs against drug combinations, nanodiamond-boosted drugs compared to unmodified drugs, and random combinations of drugs versus combinations recommended by Feedback System Control.

The results show optimized drug combinations with nanodiamonds recommended by Feedback System Control were safer and more effective against cell lines than optimized combinations of original drugs. In addition, system-recommended drug combinations with nanodiamonds outperformed drugs combined randomly.

The authors say this system can be extended to disorders other than cancer. “This optimized nanodrug combination approach can be used for virtually every type of disease model and is certainly not limited to cancer,” says Chih-Ming Ho, adding, “this study shows that we can design optimized combinations for virtually every type of drug and any type of nanotherapy.”

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Bristol-Myers Squibb Acquires Biotech Cancer Therapies

New York Stock Exchange entrance (A. Kotok)

(A. Kotok)

24 February 2015. Bristol-Myers Squibb is purchasing biotechnology company Flexus Biosciences Inc., gaining many of that company’s cancer therapies in a deal valued as much as $1.25 billion to Flexus’s shareholders. The deal allows Flexus Biosciences shareholders to spin-off a new enterprise to develop the remaining drug programs, including treatments for cancer.

The acquisition gives Bristol-Myers Squibb Flexus’s assets developing cancer therapies that harness the immune system. Among those assets is a low molecular weight drug limiting expression of the indoleamine 2,3-dioxygenase or IDO1 gene generating enzymes that repress immune system cells attacking tumors. Flexus planned to file a new drug application with FDA in the second half of 2015 to begin clinical trials for the compound, code-named F001287.

In addition, Bristol-Myers Squibb acquires Flexus’s assets aimed at discovering other drugs targeting IDO enzymes, as well as tryptophan-2,3-dioxygenase or TDO pathway, also generating enzymes suppressing anti-tumor immune responses.

The agreement calls for Bristol-Myers Squibb to purchase all outstanding Flexus Biosciences stock, with an initial payment of $800 million. Flexus, in San Carlos, California, is also eligible for future developmental milestone payments of up to $450 million.

The deal enables Flexus shareholders to spin-off a new company to develop the company’s remaining drug programs that aim to limit the action of enzymes expressed by FLT3, CDK4, and CDK6 genes, as well as preclinical and discovery work on regulatory T-cells. Among the remaining assets is Flexus’s cancer immunotherapy drug code-named FLX925 now recruiting participants in an early-stage clinical trial of the drug’s safety and anti-tumor response in patients with acute myeloid leukemia.

Adding the Flexus programs will bolster Bristol-Myers Squibb’s current line-up of several immunotherapy drugs for cancer, says chief scientist Francis Cuss in a company statement. “With the addition of a potentially best-in-class IDO1 inhibitor and the broad IDO/TDO programs,” says Cuss, “Bristol-Myers Squibb will accelerate its ability to explore numerous immunotherapeutic approaches across tumor types, including combinations with our biologic checkpoint and co-stimulatory agents that target different and complementary pathways.”

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