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Stem Cells Treat Vision Disorders in Animal Tests

Stem cell colony

Human embryonic stem cell colony (National Institute of General Medical Sciences, NIH)

4 May 2015. Tests with lab rats of a therapy for degenerating retinas in the eyes, show the treatments derived from human embryonic stem cells can restore visual functions. Results of the treatments, developed by Cell Cure Neurosciences Ltd., are scheduled to be reported today by a research team from Oregon Health and Science University at a meeting of Association for Research in Vision and Ophthalmology in Denver.

The study, led by OHSU’s Trevor McGill, tested Cell Cure’s lead product OpRegen, which is derived from human embryonic stem cells that are cultured in the company’s lab to transform into retinal pigmented epithelial cells that support and nourish human retinas, the layer of tissue inside the eye that changes light waves to nerve impulses. Cell Cure, a subsidiary of the biotechnology company BioTime Inc., is developing OpRegen as a potential treatment for age-related macular degeneration and retinitis pigmentosa.

Age-related macular degeneration is a common eye disorder, where damage to the macula, a small spot in the center of the retina, becomes damaged, resulting in progressive loss of vision. Retinitis pigmentosa is a family of inherited eye disorders that result in damage to the retina, specifically breakdown and failure of photoreceptor cells in the retina also leading to progressive vision loss.

Cell Cure Neurosciences is a spin-off company from Hadassah Medical Center in Jerusalem, Israel located on the its campus. The company says its technology cultures stem cells into highly purified retinal pigmented epithelial cells that are transplanted into the degenerating retinas of patients. Cure Cell adds that its process, called xeno-free, transforms the stem cells without exposure to animal products, thus bypassing many safety issues.

The study by McGill and colleagues induced lab rats of various ages with retinal degeneration, and tested 3 dosage levels of clinical-grade OpRegen, with a 4th group left untreated for comparison. The researchers used electroretinography that measures the electrical response of light-sensitive areas of the retina and optomotor responses — movements of the eye to stabilize the image on the retina — as indicators of visual acuity after the treatments.

The results show the rats receiving treatments with OpRegen outperformed the rats left untreated on the visual function tests, although there were no statistically reliable differences among the 3 dosage levels. In addition, the researchers found in the treated rats a regrown layer of retinal and photoreceptor cells that transform light waves in images to signals sent for the brain.

Cure Cell received clearance from Food and Drug Administration and Israel’s health ministry to conduct a clinical trial of OpRegen with individuals having geographic atrophy, a severe form of dry age-related macular degeneration, for which there’s no current therapy. In the dry form of macular degeneration, protein deposits accumulate on the retina distorting one’s vision. In geographic atrophy, the protein deposits accumulate into more of a mass, leading to damage and loss of photoreceptor cells. The trial is recruiting 15 patients in Israel to test OpRegen’s safety and efficacy.

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Heart Drug Developer Raises $46M in Venture Funds

Heart angiogram

(NASA.gov)

1 May 2015. MyoKardia Inc., a developer of therapies for inherited heart diseases, raised $46 million in its second venture funding round. Taking part in the financing for the South San Francisco, California company are the drug company Sanofi that already holds an equity stake in MyoKardia, as well as venture capital firms Casdin Capital, Cormorant Asset Management, Perceptive Life Sciences, BridgeBio LLC, and an undisclosed public investment fund.

MyoKardia designs small-molecule therapies for two types of genetic heart disorders: hypertrophic cardiomyopathy and dilated cardiomyopathy that result from mutations in protein genes of muscles used in heart contractions. With hypertrophic cardiomyopathy, heart muscles become abnormally thick, making it more difficult for the heart to pump blood. In dilated cardiomyopathy, the heart’s left ventricle — the main pumping chamber — becomes enlarged, resulting in less pumping force than a healthy heart.

The company was started in 2012 by four academic researchers in heart muscle biology and cardiovascular genetics from Harvard Medical School, Brigham and Women’s Hospital, and University of Colorado, and received its initial financing of $38 million from Third Rock Ventures, a life sciences venture capital firm.

MyoKardia’s lead product, code-named MYK-461, is a therapy that regulates proteins resulting from molecular changes caused by mutations in the genes associated with heart muscles, thus addressing the underlying causes of hypertrophic cardiomyopathy. The company is recruiting patients for early-stage clinical trials of MYK-461, testing its safety and potential efficacy among healthy volunteers and individuals with the disorder.

The new financing further extends Sanofi’s involvement in MyoKardia. In September 2014, Sanofi and MyoKardia began a collaboration to develop and commercialize three MyoKardia therapies, two for hypertrophic cardiomyopathy and one addressing dilated cardiomyopathy. The partnership could provide as much as $200 million to MyoKardia in upfront and milestone payments. In addition, Sanofi acquired an equity stake in MyoKardia.

Under the deal, MyoKardia retains product product rights for the two hypertrophic cardiomyopathy therapies, while Sanofi has worldwide rights to develop and commercialize the dilated cardiomyopathy drug. The companies divide up geographic commercialization activities, with MyoKardia responsible for commercialization of the hypertrophic cardiomyopathy drugs in the U.S., and Sanofi responsible for areas outside the U.S. where it now operates.

If further uses of the therapies emerge, Sanofi will have the option to co-promote either of the hypertrophic cardiomyopathy therapies in the U.S., while MyoKardia will have the option to co-promote the dilated cardiomyopathy drug in the U.S.

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Robotic Exoskeleton Developed for Upper-Body Rehab

Ashish Deshpande

Ashish Deshpande (University of Texas, Austin)

1 May 2015. A robotic device that helps recover upper-body functions for people with neurological or spinal injuries is being developed by engineers at University of Texas in Austin. Developers of the exoskeleton, called Harmony, plan clinical trials of the device later in 2015.

Harmony is a project of UT-Austin’s Rehabilitation and Neuromuscular Robotics Laboratory led by mechanical engineering professor Ashish Deshpande. He and a group of graduate students designed Harmony to provide individualized rehabilitation for the upper body that fits the individual’s physical size, and also collects data to adjust patients’ rehab programs as they make progress. The system aims to develop strength and coordination, to restore motor skills needed for day-to-day living after injuries that require rehab.

Harmony connects to three areas on each side of the upper body with 14 actuators to allow for a wide range of motion. The device pays particular attention to the shoulder, where complex and coordinated movements are necessary to restore normal scapulohumeral rhythm, the rotational action of the shoulder joint.

In addition, Harmony has built-in sensors that collect data 2,000 times each second. The data are then fed back to the device to provide individualized interactions with the patient, as well as offering guidance for clinicians and therapists. As a result, force administered by Harmony can be adjusted to feel almost weightless to the patient. But the system’s software can also be programmed to have the device exert increasing pressure or difficulty, requiring more force by the patient to build strength and coordination.

Deshpande and colleagues built the first exoskeleton prototypes in 2011, then collaborated with the company Meka Robotics in 2013 to create the first working model. The developers foresee enhancing the system to allow for an screen or gaming-type environment to allow for instructional routines.

In the meantime, the UT-Austin team plans human clinical trials of Harmony with 20 to 30 healthy volunteers, beginning recruitment in June 2015. Following this initial trial, the team plans to test Harmony with patients in rehabilitation from stroke or spinal cord injuries, compared to conventional rehab.

In the following brief (49 second) video, team members demonstrate and tell more about the Harmony system.

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Cancer Biotech Raising $147 Million in IPO

Wall Street signs

(A. Kotok)

30 April 2015. Blueprint Medicines, a developer of cancer therapies that block enzymes supporting tumor growth, is raising some $146.7 million in its initial public stock offering. The Cambridge, Massachusetts enterprise, listed on the NASDAQ exchange under the symbol BPMC, issued 8.15 million shares at $18.00.

The company began trading today with its share price going as high as $23.89, but settling back to $18.80 by the closing bell, up 4.4 percent over the IPO price. By comparison, NASDAQ’s biotechnology stock index fell today by more than 3 percent.

Blueprint develops cancer therapies that limit the actions of kinases, enzymes supporting cancer growth resulting from genomic mutations. The company’s technology is designed to generate treatments for patients that address their precise genomic alterations, with a library of kinase inhibitors referencing some 200 kinases. The company says these kinase inhibitors can be the building blocks for powerful cancer-fighting medications.

Blueprint’s lead drug candidates are still in preclinical testing. Earlier this month, the company reported on tests of its BLU-285 therapy that aims to block kinases released by mutations in a gene (KIT exon 17) associated with gastrointestinal stromal tumors or GISTs, at a meeting of American Association for Cancer Research.

The tests show the highest doses of BLU-285 resulted in significant tumor regression in mice induced with gastrointestinal stromal tumors and prevented regrowth of the tumors for 28 days. Blueprint says it plans early-stage clinical trials of BLU-285 later this year.

The company reported last week on another therapy, code-named BLU-554, that limits activity of mutations generating the enzyme fibroblast growth factor receptor 4, associated with hepatocellular carcinoma, a common type of liver cancer. Tests of BLU-554 reported at the International Liver Congress, show that mice induced with hepatocellular carcinoma from amplified fibroblast growth factor receptor 4 had complete tumor remission when treated with the highest doses of BLU-554. Blueprint also plans early-stage trials of BLU-554 later this year.

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Hat tip: Fortune/Term Sheet

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Phone Add-On Designed to Image DNA Molecules

Aydogan Ozcan (UCLA)

Aydogan Ozcan (UCLA)

30 April 2015. A bioengineering lab at University of California in Los Angeles is developing a smartphone attachment that can image and measure the length of DNA molecules. The team led by engineering professor Aydogan Ozcan is scheduled to describe the system on 14 May at the Conference on Lasers and Electro-Optics sponsored by the Optical Society and other organizations in San Jose, California.

Ozcan and colleagues are building a device to provide point-of-care diagnostics for complex disorders such as Alzheimer’s disease, antibiotic-resistant bacteria, and some types of cancer that require an analysis of individual DNA molecules. The researchers designed the system to offer the same capabilities that now use large and expensive analytical microscopes installed in laboratories, but for small clinics, often in remote locations.

The UCLA system includes a lens, thin-film optical filter that allows certain wavelengths to pass through, and laser-producing diode chip installed in a 3-D printed case that attaches to a smartphone. The system first requires DNA molecules be isolated and labeled with fluorescent tags, which makes it possible to record images of ultra-thin DNA strands, each about 2 nanometers wide.

The DNA images are first analyzed by software on the phone that combine Windows applications with custom computational algorithms, then sent to a server in the Ozcan lab for measurement. Once a reliable connection is established, say the researchers, a full analysis takes about 10 seconds. Ozcan notes similar devices built by his lab and others can record images of individual cells, but this is the first of its kind to drill down to individual DNA molecules.

Tests of the device show the system can accurately image stretched and fluorescent-tagged DNA molecules of 10,000 base pairs or larger. The researchers say DNA molecules of this size include those found in many key genes, including the gene that make staph bacteria resistant to antibiotics, which has some 14,000 base pairs. Base pairs are basic chemical building blocks of DNA whose order determines an individual’s genetic code. Human DNA contains about 3 billion bases.

Tests also show that the microscope is less accurate in measuring DNA molecules with 5,000 base pairs or less. Ozcan says the problem can be fixed using a lens with a higher numerical aperture, making it better able to gather light and resolve more detail in the image. The lab plans to test the system next in the field to detect the presence of malaria-related drug resistance.

Ozcan is credited as an inventor in 50 patents on biomedical imaging filed or granted since 2005.

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Taking a break

Airport schedule board

(rhythmuswege/Pixabay)

16 April 2015. We will be traveling for the next two weeks, to recharge our batteries and see some of the world beyond beyond science and business. Regular posting will resume on 30 April.

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Plant Science Biotech Gets Genome Editing Technology

Dan Voytas

Dan Voytas (Cellectis Plant Sciences)

16 April 2015. Cellectis Plant Sciences, a biotechnology company in Minnesota developing higher quality crops through genetic engineering, licensed CRISPR genome editing technology from University of Minnesota. Financial details of the agreement between Cellectis and the university were not disclosed.

The technology licensed by Cellectis covers techniques known as CRISPR, short for clustered, regularly interspaced short palindromic repeats, applied to genomic engineering of plants. CRISPR is adapted from a natural process used by bacteria to protect against attack by viruses, where a protein that deactivates or replaces genes binds to targeted RNA molecules generated by the genome. The RNA molecules then guide the editing protein to specific genes needing changes.

University of Minnesota applied for a patent on the technology, which lists among its inventors Dan Voytas, a plant biology professor as well as chief scientist at Cellectis, a 5 year-old enterprise based in nearby New Brighton. The company is developing new crop varieties that increase their health benefits to consumers, using genetic engineering techniques.

The company is already working with existing genome editing techniques, including zinc finger nucleases, proteins of short-chain amino acids that make it possible to modify DNA sequences through corrections or insertions into those sequences. Another genomic-editing tool used by Cellectis is transcription activator-like effector nucleases or TALENs, programmable proteins that bind to DNA sequences and like CRISPR can address specific targets in the genome.

Cellectis operates mainly by licensing its technologies and collaborating with partners to develop commercial products. The company last year entered into two agreements with Bayer CropScience for gene-editing technologies. Cellectis and Bayer were already collaborating on development of genetically engineered potatoes, soybean, and canola plants.

A collaboration with SESVanderHave, a Belgian company producing sugar beet seeds, is applying genomic engineering to speed development of new sugar beet varieties. Another collaboration, with the European oil company Total, is developing genomic engineering techniques to produce new types of algae for renewable biofuel sources.

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Aduro Biotech Raises $108 million in IPO

Listeria bacteria

Listeria bacteria (CDC.gov)

15 April 2015. Aduro Biotech Inc., a developer of immunotherapies to treat cancer, issued its initial public stock offering today that expects to net the company some $108 million, after issuing 7 million shares priced at $17.00. The Berkeley, California enterprise trades on the Nasdaq exchange under symbol ADRO. As of the Nasdaq closing bell at 4:00 pm ET today, Aduro shares were priced at $41.06.

Aduro’s immunotherapy technology creates therapeutic vaccines from an engineered form of listeria bacteria targeting specific tumor cells. Listeria, in its natural form, is a bacterium associated with food poisoning, but in the lab can be weakened and engineered to safely deliver antigens stimulating an immune response. Aduro calls its listeria-based cancer antigens live, attenuated, double-deleted or LADD agents, which the company says can work alone or with other cancer treatments, including chemotherapy.

An emerging technology at Aduro harnesses cyclic dinucleotides, naturally occurring molecules, found in both bacteria and mammals, but in mammals activate a signaling mechanism in immune-system cells. When stimulated, this pathway, known as Stimulator of interferon genes or Sting, induces production of cells and proteins that support and amplify the immune system.

The company says its engineered cyclic dinucleotides are more potent in stimulating the Sting pathway than the naturally-produced variety, to encourage a response in T cells, key immune system cells. In tests with lab animals, the company reports injections of its cyclic dinucleotides directly into tumors, sharply inhibited growth of melanoma, colon, and breast tumors, and protected against regrowth of those tumors as well as spreading of cancer cells.

In March, the pharmaceutical company Novartis licensed Aduro’s cyclic dinucleotide technology for commercialization outside the U.S. in a deal with a potential total value to Aduro of $750 million. Part of the deal includes Novartis taking a 2.7 percent equity stake in Aduro, with the option for expanding that stake later on.

Aduro has immunotherapies in early or intermediate-stage clinical trials being tested as treatments for pancreatic cancer, mesothelioma, and glioblastoma multiforme, an aggressive brain cancer.

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Trial Shows Multiple Sclerosis Drug Improves Optic Nerves

Nerve cell networks

(NIH.gov)

15 April 2015. A clinical trial testing a new therapy for multiple sclerosis shows the drug improves the performance of optic nerves in patients with acute optic neuritis, a condition highly associated with multiple sclerosis. Researchers from the biotechnology company Biogen present their findings next week at the annual meeting of American Academy of Neurology in Washington, D.C.

Multiple sclerosis is an autoimmune condition where the immune system attacks the central nervous system and damages myelin, the fatty, protective substance around nerve fibers, as well as nerve cells themselves. Scar tissue from the damaged myelin, known as sclerosis, distorts the nerve signals sent to and from the brain and spinal cord, causing symptoms ranging from mild numbness to loss of vision or paralysis. Optic neuritis is inflammation of the optic nerve that transmits visual information from the eye to the brain, leading to pain and temporary vision loss, and is considered an indicator of multiple sclerosis.

Biogen, in Cambridge, Massachusetts, is developing an antibody treatment for multiple sclerosis and optic neuritis that aims to block a neurologic protein called Lingo-1 that normally supports myelin growth on nerve cells. In people with multiple sclerosis, however, Lingo-1 proteins appear to limit rather than encourage myelin growth when it binds to its receptors. Biogen’s antibody, code-named BIIB033, is designed to block the actions of Lingo-1, allowing for myelin to regrow.

The intermediate-stage clinical trial enrolled 82 adults with acute optic neuritis who were randomly assigned to receive 6 infusions of BIIB033 or a placebo every 4 weeks over a 20-week period. Participants were then assessed every four weeks up to 6 months, with a final evaluation 8 months after the last infusion. The study looked primarily at responsiveness of the optic nerves between participants’ damaged and normal eyes, as indicators of myelin restoration around nerve fibers, measured by ability to conduct electrical signals between the retina and the brain.

Results show participants receiving BIIB033 showed faster average optic nerve response of 7.6 milliseconds or 34 percent after 6 months compared to their counterparts receiving a placebo. After 8 months, average optic nerve response improved to 9.1 milliseconds, or 41 percent, compared to the placebo group. In addition, more than half (53%) of participants receiving BIIB033 showed optic nerve responses in their damaged eyes within 10 percent of their normal eyes, compared to about a quarter (26%) of those receiving the placebo.

The trial also measured changes in thickness of optic nerve cells and fibers using optical coherence tomography, similar to MRI and ultrasound imaging, but found little change in nerve cell or fiber thickness as a result of the treatments. The researchers point to the extensive damage to patients’ optic nerves as a probable cause. The study reported as well that treatments of BIIB033 were well tolerated with comparable rates and severity of adverse effects — generally fatigue, nausea, and sensations of burning or tingling — between patients receiving the test drug or the placebo.

Biogen has another intermediate-stage clinical trial underway testing BIIB033 among people with multiple sclerosis, and expects to report its first results next year.

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Smart Treadmill Adjusts to Running Speed Changes

Steven Devor and treadmill

Steven Devor, right, with automated treadmill during tests of the system (Ohio State University)

14 April 2015. Researchers at Ohio State University designed an automated treadmill that adjusts to changes in running speed by users, thus making the experience more like running outdoors. Steven Devor, professor of kinesiology, with former graduate student Cory Scheadler (now on the faculty at Northern Kentucky University), describe tests of a prototype model of the treadmill in an article published last week in the journal Medicine & Science in Sports & Exercise (paid subscription required).

Ohio State reports filing a patent application for the system, with the objective of its licensing and commercialization for eventual use in health clubs.

Devor says the objective of the system is to make the experience of using a treadmill more realistic and pleasant. “So many people call it the ‘dreadmill,’ notes Devor in a university statement. “It is boring and monotonous. An automated treadmill makes the experience much more natural and you can just run without thinking of what pace you want to set.”

The key to device is an inexpensive, off-the-shelf sonar range finder, positioned behind the runner and aimed between the shoulder blades. Sonar beams measure the distance from the range finder to the runner. A built-in microcontroller and processor read the measurements and adjust the speed of the treadmill’s belt.

When the runner is in the middle of the belt’s length, measured from front to back, the treadmill keeps the speed constant. But if the distance of the runner from the sonar device increases — moves closer to the front of the belt — the treadmill increases the speed of the belt accordingly. Likewise, if the device detects the runner moving toward the back of the belt, the belt speed slows until the runner reaches the mid-point.

The journal article reports on a test with 13 experienced endurance runners who ran three sets on the automated treadmill, and later on the same treadmill, but without the sonar and computerized controller. Devor and Sheadler measured peak work rates and maximum oxygen volume, and report that the automated treadmill allowed for more accurate measurements of maximum oxygen volume than the non-automated device.

More accuracy in measuring maximum oxygen volume, say the researchers, helps determine heart rate target zones that guide training regimens.

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