Category Archives: Molecular Medicine

Scientists at the University of Oxford have developed a new method to 3D-print laboratory-grown cells to form living structures.

The approach could revolutionise regenerative medicine, enabling the production of complex tissues and cartilage that would potentially support, repair or augment diseased and damaged areas of the body.

Printing high-resolution living tissues is hard to do, as the cells often move within printed structures and can collapse on themselves. But, led by Professor Hagan Bayley, Professor of Chemical Biology in Oxfords Department of Chemistry, the team devised a way to produce tissues in self-contained cells that support the structures to keep their shape.

The cells were contained within protective nanolitre droplets wrapped in a lipid coating that could be assembled, layer-by-layer, into living structures. Producing printed tissues in this way improves the survival rate of the individual cells, and allowed the team to improve on current techniques by building each tissue one drop at a time to a more favourable resolution.

To be useful, artificial tissues need to be able to mimic the behaviours and functions of the human body. The method enables the fabrication of patterned cellular constructs, which, once fully grown, mimic or potentially enhance natural tissues.

Dr Alexander Graham, lead author and 3D Bioprinting Scientist at OxSyBio (Oxford Synthetic Biology), said: We were aiming to fabricate three-dimensional living tissues that could display the basic behaviours and physiology found in natural organisms. To date, there are limited examples of printed tissues, which have the complex cellular architecture of native tissues. Hence, we focused on designing a high-resolution cell printing platform, from relatively inexpensive components, that could be used to reproducibly produce artificial tissues with appropriate complexity from a range of cells including stem cells.

The researchers hope that, with further development, the materials could have a wide impact on healthcare worldwide. Potential applications include shaping reproducible human tissue models that could take away the need for clinical animal testing.

Over the coming months they will work to develop new complementary printing techniques, that allow the use of a wider range of living and hybrid materials, to produce tissues at industrial scale. Dr Sam Olof, Chief Technology Officer at OxSyBio, said: There are many potential applications for bioprinting and we believe it will be possible to create personalised treatments by using cells sourced from patients to mimic or enhance natural tissue function. In the future, 3D bio-printed tissues maybe also be used for diagnostic applications for example, for drug or toxin screening.

Dr Adam Perriman from the University of Bristols School of Cellular and Molecular Medicine, added: The bioprinting approach developed with Oxford University is very exciting, as the cellular constructs can be printed efficiently at extremely high resolution with very little waste. The ability to 3D print with adult stem cells and still have them differentiate was remarkable, and really shows the potential of this new methodology to impact regenerative medicine globally.

This article has been republished frommaterialsprovided by the University of Oxford. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:

Graham, A. D., Olof, S. N., Burke, M. J., Armstrong, J. P., Mikhailova, E. A., Nicholson, J. G., . . . Bayley, H. (2017). High-Resolution Patterned Cellular Constructs by Droplet-Based 3D Printing. Scientific Reports, 7(1). doi:10.1038/s41598-017-06358-x

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A New Method of 3D Printing Living Tissues - Technology Networks

CAMBRIDGE, Mass., Aug. 15, 2017 /PRNewswire/ --Cancer Treatment Centers of America (CTCA) and Foundation Medicine today announced a new element to their longstanding partnership to increase awareness of advancements in genomic testing and precision medicine in oncology. The educational initiative directed toward physicians, other caregivers and patients will highlight the importance of integrating comprehensive genomic testing of solid tumors early in an individual's care plan as a model to inform personalized care and improve clinical outcomes for individuals with cancer.

"Precision cancer treatment using advanced genomic testing is changing the science of cancer care," said Maurie Markman, M.D., President of Medicine & Science at CTCA. "As oncologists, we have an obligation to the patients we serve to keep pace with, and, whenever possible, lead the way in the application of the latest diagnostic tools that may help inform treatment decisions. Our partnership with Foundation Medicine empowers our physicians to customize treatment plans according to the individual patient's clinical profile right down to the molecular level, and therefore furnish care in a much more comprehensive and effective manner."

The partnership brings together CTCA, a national network of five cancer treatment hospitals at the forefront of delivering precision cancer treatment to address individual patients' unique treatment needs, and Foundation Medicine, a leader in molecular information that offers a suite of comprehensive genomic profiling (CGP) assays that identifies the molecular alterations in an individual's cancer and matches them with potentially relevant targeted therapies, including immunotherapies.

Through their shared patient-centered philosophy, CTCA and Foundation Medicine will educate the medical community about the successful approach CTCA is using to incorporate FoundationOne for solid tumors into clinical care. Specifically, the educational initiative will feature several patients with cancer, chronicling each person's journey from cancer diagnosis to tumor profiling to treatment. Through this case-based approach, the program aims to provide insights into precision medicine treatment approaches based on an individual's unique cancer, including the selection of targeted therapies, appropriate clinical trials and responses to immunotherapy.

"Precision medicine, and a move to a more personalized, targeted approach to cancer care, is becoming ever more ubiquitous as the published data continues to validate this approach as leading to better clinical outcomes for patients," said Vincent Miller, M.D., Chief Medical Officer for Foundation Medicine. "As such, it's critical that every stakeholder in a patient's care planphysician, patient and care teamis knowledgeable about the benefits of genomic profiling, and importantly, that they have the right tools at the ready to implement such an approach. We applaud CTCA leadership in this area and we're delighted to collaborate with them on this educational initiative."

To learn more about genomics and precision cancer treatment, visit cancercenter.com. To learn more about genomic testing and FoundationOne, visit FoundationMedicine.com.

About Cancer Treatment Centers of AmericaCancer Treatment Centers of America Global, Inc. (CTCA), headquartered in Boca Raton, Fla., is a national network of five hospitals that serves adult patients who are fighting cancer. CTCA offers an integrative approach to care that combines advancements in genomic testing and precision cancer treatment, surgery, radiation, immunotherapy and chemotherapy, with evidence-informed supportive therapies designed to help patients physically and emotionally by enhancing their quality of life while managing side effects both during and after treatment. CTCA serves patients from around the world at its hospitals in Atlanta, Chicago, Philadelphia, Phoenix and Tulsa. Reflecting our patient-centered approach to cancer care, our patient satisfaction scores consistently rank among the highest in the country for cancer care providers, and CTCA is also rated one of the most admired hospital systems in the country in national consumer surveys. For more information, visit cancercenter.com, Facebook.com/cancercenter and Twitter.com/cancercenter.

About Foundation MedicineFoundation Medicine(NASDAQ:FMI) is a molecular information company dedicated to a transformation in cancer care in which treatment is informed by a deep understanding of the genomic changes that contribute to each patient's unique cancer. The company offers a full suite of comprehensive genomic profiling assays to identify the molecular alterations in a patient's cancer and match them with relevant targeted therapies, immunotherapies and clinical trials.Foundation Medicine'smolecular information platform aims to improve day-to-day care for patients by serving the needs of clinicians, academic researchers and drug developers to help advance the science of molecular medicine in cancer. For more information, please visithttp://www.FoundationMedicine.comor followFoundation Medicineon Twitter (@FoundationATCG). Foundation Medicineand FoundationOne are registered trademarks ofFoundation Medicine, Inc.

Cautionary Note Regarding Forward-Looking StatementsThis press release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the objectives of any educational initiatives between CTCA and Foundation Medicine; the importance of integrating comprehensive genomic testing of solid tumors early in an individual's care plan to improve clinical outcomes for individuals with cancer; and the value and performance capabilities of Foundation Medicine's comprehensive genomic profiling assays. All such forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include the risk thateducational initiatives are not developed or launched in the anticipated manner; Foundation Medicine'sCGP andservices will not be able to identify genomic alterations in the same manner as prior clinical data or prior experience; and the risks described under the caption "Risk Factors" inFoundation Medicine'sAnnual Report on Form 10-K for the year endedDecember 31, 2016, which is on file with theSecurities and Exchange Commission, as well as other risks detailed inFoundation Medicine'ssubsequent filings with theSecurities and Exchange Commission.All information in this press release is as of the date of the release, andFoundation Medicineundertakes no duty to update this information unless required by law.

Contact: Michael MyersCancer Treatment Centers of America rel="nofollow">michael.myers@ctca-hope.com 561-923-3179

Lee-Ann MurphyFoundation Medicine 617-245-3077 rel="nofollow">pr@foundationmedicine.com

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Cancer Treatment Centers of America and Foundation Medicine Join Forces to Advance Precision Cancer Treatment - Markets Insider

Once difficult and expensive even for the most technologically advanced labs, genetic testing is fast becoming a cheap and easy consumer product. With a little spit and 200 dollars, you can find out your risk for everything from cystic fibrosis to lactose intolerance.

But its important to remember that not all genetic tests are created equal. And even the best clinical genetic test, carried out in a medical lab under a doctor's supervision, isn't perfectgenes are important, but they don't seal your fate.

Genetic tests are diagnostic, so anyone who is curious about their health can get one done. But they're more informative if you think you might be at risk for a genetic disorder.

Heavy-duty genetic tests have been used as a clinical tool for almost half a centurylong before 23andMe and Ancestry.com began offering direct-to-consumer tests. Lets say that many women in your family have had breast cancer. You can get a genetic test to see if you may have inherited an abnormal version of the BRCA gene, known to increase your risk for breast cancer.

Heidi Rehm, associate professor of pathology at Harvard Medical School, is the director of the Laboratory for Molecular Medicine, where patients get tested for diseases that can be traced to specific genetic roots. She says it is most common for people to get tested when they either suspect or know that they have a genetic disease; it may have affected multiple people in their family or they could show symptoms of something widely known to be genetic, like sickle cell anemia. For these people, genetic tests can provide a much-needed explanation for an illness and help doctors determine the best course of treatment. Babies are often tested for genetic diseases, either while they are still fetuses or shortly after birth.

Others get genetic tests if they and their partner both have family histories of an inherited diseaseeven if they dont have the disease themselves. For example, cystic fibrosis is linked to one particular gene, but you have to inherit the abnormal version of the gene from both your parents to get the disease. If you only inherit one copy, you may never knowyou wont display any of the symptoms. But if you and your partner both carry one copy of the faulty gene, your child could still inherit two copies. Genetic tests can forewarn you of that possibility.

But Rehm says there has been a recent trend of healthy people getting tested to predict whether theyll get certain diseases. I do think there are settings where predictive genetic testing is incredibly important and useful, Rehm says; for example, knowing that youre at risk for breast cancer gives you the opportunity for early intervention (remember when Angelina Jolie got a double mastectomy upon finding out she had a mutated BRCA gene?)

But Rehm also points out that genetic tests may not be as straightforward as they seem. For example, some genes are thought to increase risk of getting a certain disease, but it might only happen if you have specific family history, or you might be able to reduce your risk with lifestyle changes. So remember that a genetic test isnt the final verdictthere are other factors at play too.

Not entirelyits scope is limited. For starters, not all diseases are caused by genes. Plenty of conditions stem from environmental and lifestyle factors; they may interact with your genes, but the external factors are the real trigger.

But even if a disease is caused solely by faulty instructions written in your genes, you wont necessarily be able to test for it. Thats because genetic tests are mainly used for diseases that are penetrant, a term that scientists use to describe a strong connection between having a certain gene (or multiple genes) and getting a disease.

Genetic tests are surprisingly simple on the surface. All thats required of you is a small sample of cells, like a blood sample or saliva (which doesnt have DNA itself, but picks up cheek cells during its journey out of your mouth). It get sent to a lab where sequencing machines match up small pieces of synthetic DNA with your DNA to figure out the overall sequence.

Once they have your sequence, geneticists can compare it with "normal" or disease-causing sequences. In the end, they might give you a yes or no answer, or sometimes youll get a probabilitya measure of how much your genes increase your risk of developing the disease. Then, its up to your doctor to figure out what these genes (in combination with your lifestyle, family history and other risk factors) mean for your health.

With penetrant diseases, theres a very, very high ability to explain the disease, Rehm says. For example, the breast cancer-related gene BRCA1 can give you a 60 percent chance of getting breast cancer (in Jolies case, with her family history, the risk was 87 percent.)

This makes genetic tests better at detecting so-called rare diseases, says Steven Schrodi, associate research scientist at the Marshfield Clinic Research Institutes Center for Human Genetics, but theyre less useful when it comes to more common diseases, like heart disease or diabetes. Genetics can increase your likelihood of getting these disease, but scientists still dont know quite how much. Part of the problem is that there may be dozens or hundreds of genes responsible for these diseases, Schrodi says.

We have an incomplete understanding of why people get diseases, Schrodi says. A large part of it hinges on how we define diseases. Perhaps physicians have inadvertently combined multiple diseases together into a single entity.

Consumer genetic teststhe ones where you send in samples from homesometimes claim to test for these more complex traits, but be careful: Their results might not be very medically relevant, Rehm says. If they tell you that your genes make you twice as likely to develop diabetes, for example, that's a marginal increase that doesn't significantly affect your risk, especially when you take into account lifestyle factors.

Genes do seem to play a role in determining lifespan. After all, some family reunions stretch from great-great-grandparents all the way down to infants. Scientists have studied centenarianspeople who lived to be 100 years oldand found that people with certain versions of genes involved in repairing DNA tend to live longer.

This makes sense because aging leaves its mark on your DNA. Environmental factors can damage DNA, and even the routine chore of replicating cells can introduce errors as the three billion units of your DNA are copied over and over. Long-lived individuals have different sequences that seem to make their cells better at keeping DNA in mint condition.

But figuring out your expiration date is more complex than just testing for a few genes, says Jan Vijg, professor of genetics at Albert Einstein College of Medicine. In theory, you could design a test that looks at specific genes that might measure your risk for developing Alzheimers Disease or other age-related diseases, or your risk for aging quickly. To some extent, yes: Biomarkers will tell you something about your chances of living a long life, Vijg says. Still, that will only work if you live a careful life. And that means no accidents, infections, or cancers.

Aging also affects the exposed ends of your DNA, called "telomeres." DNA is stored as chromosomes, those X-like structures that you may have seen in biology textbooks. The most vulnerable parts of the chromosome are the chromosomes tips, which get shorter as you age because they arent properly replicated. But while telomere length might let you compare your DNA now with your DNA from a decade ago, you cant compare your own telomeres with other peoples telomeres. Theres a lot of variation between individuals, Vijg says. Some of us are just old souls (on the genomic level, that is.)

The methylation test, which looks at how the presence of small chemical groups attached to your DNA changes as you age, might be a better bet. A study at UCLA showed that changes were slower in longer-lived people. But Vijg is hesitant: I would not put my hopes on that as a marker to predict when exactly youre going to die.

For now, just enjoy your life, because you cant predict death. And if you decide to unlock the secrets of your DNA with an at-home test, don't take those results for more than their worth.

More:
What can genetic testing really tell you? - Popular Science

Geoffrey Laff, Ph.D., Spotlight Innovation's Senior Vice President of Business Development, commented, "Dr. Androphy is a prolific researcher and highly-respected thought leader. We are privileged to work with him to develop novel therapies for SMA."

Dr. Androphy is the Chair of the Department of Dermatology of Indiana University School of Medicine and has published widely in high-impact journals including Science, Nature, EMBO Molecular Medicine, Human Molecular Genetics, Journal of Virology, and Molecular Cell. He served as Vice Chair for Research of the Department of Medicine and Director of the M.D./Ph.D. Program at the University of Massachusetts Medical School where his lab characterized the disease-causing mechanism of alternative splicing of the SMN2 gene. At Indiana University School of Medicine, Dr. Androphy has used a novel, cell-based high throughput screen for compounds that increase levels of the SMN protein. This work has led to the identification of pre-clinical drug candidates for SMA.

About Spotlight Innovation Inc.

Spotlight Innovation Inc. (OTCQB: STLT) identifies and acquires rights to innovative, proprietary technologies designed to address unmet medical needs, with an emphasis on rare, emerging and neglected diseases. To find and evaluate unique opportunities, we leverage our extensive relationships with leading scientists, academic institutions and other sources. We provide value-added development capability to accelerate development progress. Whenscientifically significantbenchmarkshave been achieved, we will endeavor to partner with proven market leaders via sale, out-license or strategic alliance. For more information, visit http://www.spotlightinnovation.com or follow us on http://www.twitter.com/spotlightinno.

Forward-Looking Statements

Statements in this press release that are not purely historical are forward-looking statements. Forward-looking statements herein include statements regarding Spotlight Innovation's efforts to develop and commercialize various product candidates, including STL-182, and to achieve its stated benchmarks. Actual outcomes and actual results could differ materially from those in such forward-looking statements. Factors that could cause actual results to differ materially include risks and uncertainties, such as: the inability to finance the planned development of STL-182; the inability to hire appropriate staff to develop STL-182; unforeseen technical difficulties in developing STL-182; the inability to obtain regulatory approval for human use; competitors' therapies proving to be more effective, cheaper or otherwise more preferable; or, the inability to market a product. All of which could, among other things, delay or prevent product release, as well as other factors expressed from time to time in Spotlight Innovation's periodic filings with the Securities and Exchange Commission (SEC). As a result, this press release should be read in conjunction with Spotlight Innovation's periodic filings with the SEC. The forward-looking statements contained herein are made only as of the date of this press release and Spotlight Innovation undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

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Spotlight Innovation Enters into Sponsored Research Agreement with Indiana University to Develop New Therapies for ... - PR Newswire (press release)

Mangaluru, August 16:

The Centre for Systems Biology and Molecular Medicine at Yenepoya University in Mangaluru has been awarded the Biotechnology Skill Enhancement Programme (BiSEP) by the Karnataka Biotechnology and Information Technology Services (KBITS).

Addressing presspersons in Mangaluru on Wednesday, T.S. Keshava Prasad, Deputy Director of the Centre for Systems Biology and Molecular Medicine, said the centre has been awarded the BiSEP to conduct a one-year postgraduate diploma in multiomics technology. (Multiomics is an interdisciplinary subject that includes genomics, proteomics, metabolomics and proteogenomics.)

He said Yenepoya University is the only centre to offer BiSEP in multiomics technology. The centre has facilities and experts in this technology to undertake such a training programme.

Candidates for BiSEP - postgraduate diploma programme - will be selected based on their performance in the Karnataka Biotechnology Aptitude Test to be held in September. Students enrolled in the programme will be provided fellowship of Rs 10,000 a month during the course.

He said 50 per cent of the tuition fee for Karnataka students will be paid by the state government.

Students will undergo a six-month hands-on training programme in different omics platforms at the Centre for Systems Biology and Molecular Medicine. This will be followed by a six-month internship.

He said graduates and postgraduates in the field of life sciences would be equipped with necessary employable skills under BiSEP. This will help make them industry-ready in the field of genomic, proteomic and metabolomic technologies. This programme will enable supply of skilled manpower required by multinational biotechnology and pharmaceutical companies, he added.

(This article was published on August 16, 2017)

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Yenepoya University to offer biotech skill enhancement programme - Hindu Business Line

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How do the multiple different cell types in the blood develop? Scientists have been pursuing this question for a long time. According to the classical model, different developmental lines branch out like in a tree. The tree trunk is composed of stem cells and the branches are made up of various types of progenitor cells that can give rise to a number of distinct cell types. Then it further branches off into the specialized blood cells, i.e., red blood cells, blood platelets and various types of white blood cells that are part of the immune system. In recent years, however, doubts about this model have arisen.

Hans-Reimer Rodewald, a scientist at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, and his co-workers wanted to capture the dynamic events in blood cell formation instead of merely taking snapshots. In close collaboration with a research team led by systems biologist Thomas Hfer, the scientists have developed a new technology that enables them to precisely follow the developmental tracks of cells. To this end, they label stem cells with a kind of genetic barcode in order to be able to clearly identify their offspring later.

"Genetic barcodes have been developed and applied before, but they were based on methods that can also change cellular properties," Rodewald said. "Our barcodes are different: They can be induced tissue-specifically and directly in the genome of mice - without influencing the animals' physiological development." The basis of the new technology is the so-called Cre/loxP system that is used to rearrange or remove specially labeled DNA segments.

Weike Pei und Thorsten Feyerabend in Rodewald's team bred mice whose genomes exhibit the basic elements of the barcode. At a selected site, where no genes are encoded, it contains nine small DNA fragments from a plant called Arabidopsis thaliana. These elements are flanked by ten genetic cutting sites called IoxP sites. By administering a pharmacological agent, the matching molecular scissors called "Cre" can be activated in the animals' hematopoietic stem cells. Then code elements are randomly rearranged or cut out. "This genetic random DNA barcode generator can generate up to 1.8 million genetic barcodes and we can identify the codes that arise only once in an experiment," Hfer said.

"The mice then do the rest of the work," said Rodewald. When these specially labeled hematopoietic stem cells divide and mature, the barcodes are preserved. In collaboration with the Max Delbrck Center for Molecular Medicine, the researchers have performed comprehensive barcode analyses in order to trace an individual blood cell back to the stem cell from which it originates.

These analyses have revealed that two large developmental branches start out from the hematopoietic stem cells of the mice: In one branch, T cells and B cells of the immune system develop; in the other, red blood cells as well as various other types of white blood cells such as granulocytes and monocytes form. All these cell types can arise from a single stem cell. "Our findings show that the classical model of a hierarchical developmental tree that starts from multipotent stem cells holds true for hematopoiesis," Rodewald emphasized.

The system developed by the Heidelberg researchers can also be used for other purposes besides studying blood cell development. This strategy can basically be applied in any tissue. In the future, it might also be used for experimentally tracing the origin of leukemias and other cancers.

Explore further: Live assessment of blood formation

More information: Weike Pei et al, Polylox barcoding reveals haematopoietic stem cell fates realized in vivo, Nature (2017). DOI: 10.1038/nature23653

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Using barcodes to trace cell development - Medical Xpress

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the current issue of Science, Nikolaus Rajewsky and his team at the Berlin Institute of Medical Systems Biology (BIMSB) of the Max Delbrck Center for Molecular Medicine in the Helmholtz Association (MDC), as well as other collaborators within the MDC and Charit, present data that for the first time link a circular RNA to brain function.

RNA is much more than the mundane messenger between DNA and the protein it encodes. Indeed, there are several different kinds of non-coding RNA molecules. They can be long non-coding RNAs (lncRNAs) or short regulatory RNAs (miRs); they can interfere with protein production (siRNAs) or help make it possible (tRNAs). In the past 20 years, scientists have discovered some two dozen RNA varieties that form intricate networks within the molecular microcosm. The most enigmatic among them are circRNAs, an unusual class of RNAs whose heads are connected to their tails to form a covalently closed ring. These structures had for decades been dismissed as a rare, exotic RNA species. In fact, the opposite is true. Current RNA-sequencing analyses have revealed that they are a large class of RNA, which is highly expressed in brain tissues.

Thousands of circular RNAs exist in nematode worms, mice and humans

In 2013, two pioneering studies that characterized circular RNAs appeared in the journal Nature, one of them by Nikolaus Rajewsky and his team. Intriguingly, most circular RNAs are unusually stable, floating in the cytoplasm for hours and even days on end. The systems biologists proposed that at least sometimes circRNAs serve gene regulation. Cdr1as, a large single-stranded RNA loop that is 1,500 nucleotides around, might act as a sponge for microRNAs. For example, it offers more than 70 binding sites for a microRNA called miR-7. MicroRNAs are short RNA molecules that typically bind to complementary sequences in messenger RNAs, thereby controlling the amounts of specific proteins produced by cells.

Additionally, Rajewsky and his collaborators mined databases and discovered thousands of different circRNAs in nematode worms, mice and humans. Most of them were highly conserved throughout evolution. We had found a parallel universe of unexplored RNAs, says Rajewsky. Since publication the field has exploded; hundreds of new studies have been carried out.

Understanding a circle that is mostly present in excitatory neurons

For the current paper in Science, the systems biologists teamed up with Carmen Birchmeiers lab at the MDC to reconsider Cdr1as. This particular circle can be found in excitatory neurons but not in glial cells, says Monika Piwecka, one of the first authors of the paper and coordinator of most of the experiments. In brain tissues of mice and humans, there are two microRNAs called miR-7 and miR-671 that bind to it. In a next step, Rajewsky and his collaborators selectively deleted the circRNA Cdr1as in mice using the genome editing technology CRISPR/Cas9. In these animals, the expression of most microRNAs in four studied brain regions remained unperturbed. However, miR-7 was downregulated and miR-671 upregulated. These changes were post-transcriptional, consistent with the idea that Cdr1as usually interacts with these microRNAs in the cytoplasm.

This indicates that Cdr1as usually stabilizes or transports miR-7 in neurons by sponging them up, while miR-167 might serve to regulate levels of this particular circular RNA, says Rajewsky. If microRNA floated in the cytoplasm without binding anywhere, it would get broken down as waste. The circle would prevent that and also carry it to new places like the synapses. He adds: Maybe we should think about Cdr1as not as a sponge but as a boat. It prevents its passengers from drowning and also moves on to new ports.

The changes in microRNA concentration had dramatic effects on the mRNA and proteins produced by nerve cells, especially for a group called immediate early genes. They are part of the first wave of responses when stimuli are presented to neurons. Also affected were messenger RNAs that encode proteins involved in the maintenance of the animals sleep-wake cycles.

Cdr1as modulates synaptic responses

Using single-cell electrophysiology, Charit-researcher Christian Rosenmund observed that spontaneous vesicle release at the synapse happened twice as often. The synaptic responses to two consecutive stimuli were also altered. Additional behavioral analyses performed at the MDC mirrored these findings. Even though the mice appeared normal in many ways, they were unable to tune down their responses to external signals such as noises. Similar disruptions in pre-pulse inhibition have been noted in patients suffering from schizophrenia or other psychiatric diseases.

It is an everyday experience how much we depend on this filtering function: When a loud noise suddenly disturbs the quiet atmosphere of a library, you cannot avoid being alarmed. The same bang, however, will seem much less threatening next to a construction site. In this instance, the brain has had the chance to process previous noises and filter out unnecessary information. Therefore, the startle reflex is dampened (pre-pulse inhibition). This basic brain function that allows healthy animals and people to temporarily adapt to a strong stimulus and avoid information overload has now been linked to Cdr1as.

Functionally, our data suggest that Cdr1as and its direct interactions with microRNAs are important for sensorimotor gating and synaptic transmission, says Nikolaus Rajewsky. More generally, since the brain is an organ with exceptionally high and diverse expression of circular RNAs, we believe that our data suggest the existence of a previously unknown layer of biological functions carried out by these circles.

Reference

Piwecka, M., Glaar, P., Hernandez-Miranda, L. R., Memczak, S., Wolf, S. A., Rybak-Wolf, A., ... & Trimbuch, T. (2017). Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function. Science, eaam8526.

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Circular RNA Linked to Brain Function - Technology Networks

These are muscle cells from a patient with myotonic dystrophy type I, untreated (left) and treated with the RNA-targeting Cas9 system (right). The MBNL1 protein is in green, repetitive RNA in red and the cells nucleus in blue. MBNL1 is an important RNA-binding protein and its normal function is disrupted when it binds repetitive RNA. In the treated cells on the right, MBNL1 is released from the repetitive RNA. Credit: UCSD

Until recently, the CRISPR-Cas9 gene editing technique could only be used to manipulate DNA. In a 2016 study, University of California San Diego School of Medicine researchers repurposed the technique to track RNA in live cells in a method called RNA-targeting Cas9 (RCas9). In a new study, published August 10 in Cell, the team takes RCas9 a step further: they use the technique to correct molecular mistakes that lead to microsatellite repeat expansion diseases, which include myotonic dystrophy types 1 and 2, the most common form of hereditary ALS, and Huntington's disease.

This is exciting because were not only targeting the root cause of diseases for which there are no current therapies to delay progression, but weve re-engineered the CRISPR-Cas9 system in a way thats feasible to deliver it to specific tissues via a viral vector, said senior author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.

While DNA is like the architects blueprint for a cell, RNA is the engineers interpretation of the blueprint. In the central dogma of life, genes encoded in DNA in the nucleus are transcribed into RNA and RNAs carry the message out into the cytoplasm, where they are translated to make proteins.

Microsatellite repeat expansion diseases arise because there are errant repeats in RNA sequences that are toxic to the cell, in part because they prevent production of crucial proteins. These repetitive RNAs accumulate in the nucleus or cytoplasm of cells, forming dense knots, called foci.

In this proof-of-concept study, Yeos team used RCas9 to eliminate the problem-causing RNAs associated with microsatellite repeat expansion diseases in patient-derived cells and cellular models of the diseases in the laboratory.

Normally, CRISPR-Cas9 works like this: researchers design a guide RNA to match the sequence of a specific target gene. The RNA directs the Cas9 enzyme to the desired spot in the genome, where it cuts DNA. The cell repairs the DNA break imprecisely, thus inactivating the gene, or researchers replace the section adjacent to the cut with a corrected version of the gene. RCas9 works similarly but the guide RNA directs Cas9 to an RNA molecule instead of DNA.

The researchers tested the new RCas9 system on microsatellite repeat expansion disease RNAs in the laboratory. RCas9 eliminated 95 percent or more of the RNA foci linked to myotonic dystrophy type 1 and type 2, one type of ALS and Huntington's disease. The approach also eliminated 95 percent of the aberrant repeat RNAs in myotonic dystrophy patient cells cultured in the laboratory.

Another measure of success centered on MBNL1, a protein that normally binds RNA, but is sequestered away from hundreds of its natural RNA targets by the RNA foci in myotonic dystrophy type 1. When the researchers applied RCas9, they reversed 93 percent of these dysfunctional RNA targets in patient muscle cells, and the cells ultimately resembled healthy control cells.

While this study provides the initial evidence that the approach works in the laboratory, there is a long way to go before RCas9 could be tested in patients, Yeo explained.

One bottleneck is efficient delivery of RCas9 to patient cells. Non-infectious adeno-associated viruses are commonly used in gene therapy, but they are too small to hold Cas9 to target DNA. Yeos team made a smaller version of Cas9 by deleting regions of the protein that were necessary for DNA cleavage, but dispensable for binding RNA.

The main thing we dont know yet is whether or not the viral vectors that deliver RCas9 to cells would elicit an immune response, he said. Before this could be tested in humans, we would need to test it in animal models, determine potential toxicities and evaluate long-term exposure.

To do this, Yeo and colleagues launched a spin-out company called Locana to handle the preclinical steps required for moving RCas9 from the lab to the clinic for RNA-based diseases, such as those that arise from microsatellite repeat expansions.

We are really excited about this work because we not only defined a new potential therapeutic mechanism for CRISPR-Cas9, we demonstrated how it could be used to treat an entire class of conditions for which there are no successful treatment options, said David Nelles, PhD, co-first author of the study with Ranjan Batra, PhD, both postdoctoral researchers in Yeos lab.

There are more than 20 genetic diseases caused by microsatellite expansions in different places in the genome, Batra said. Our ability to program the RCas9 system to target different repeats, combined with low risk of off-target effects, is its major strength.

This article has been republished frommaterialsprovided by University of California, San Diego. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Batra, R., Nelles, D. A., Pirie, E., Blue, S. M., Marina, R. J., Wang, H., ... & Aigner, S. (2017). Elimination of Toxic Microsatellite Repeat Expansion RNA by RNA-Targeting Cas9. Cell.

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New Version of CRISPR Corrects RNA Defects Linked to ... - Technology Networks

Dr. Steven Powell. Credit: Sanford Health

Sanford Health is the first site in the United States to launch a clinical trial using a genetically-engineered virus that aims to destroy therapy-resistant tumors.

The Phase I immunotherapy trial is for those ages 18 and older with metastatic solid tumors that have not responded to standard treatments. The treatment injects an oncolytic (cancer-destroying) virusvesicular stomatitis virus (VSV)into the tumor. The virus is engineered to grow in cancer cells, destroy these tumors, and then spread to other cancer sites. During this process, it recruits the immune system to the area with the goal of triggering an immune response.

The virus, commonly known as VSV, can infect cattle, but it rarely causes serious infections in humans.

The virus is genetically altered by adding two genes. The first gene is a human interferon beta gene, which is a natural anti-viral protein. This protects the normal, healthy cells from being infected, while still allowing the virus to work against cancer cells.

The second gene makes the NIS protein found in the thyroid gland, which allows the researchers to track the virus as it spreads to tumor sites. Vyriad, a biopharmaceutical company in Rochester, Minnesota, developed this technology and is led by Stephen Russell, M.D., Ph.D., a professor of molecular medicine at the Mayo Clinic and an expert in oncolytic virus therapy.

"Oncolytic viruses are the next wave of promising cancer immunotherapy treatments," says Dr. Steven Powell, a medical oncologist with the Sanford Cancer Center in Sioux Falls, S.D., who collaborated with Vyriad on the development of this clinical trial. "We are very excited about using VSV as researchers have seen promising results using other similar viruses, such as the polio virus, in early clinical trials."

Dr. Shannon Peck, an interventional radiologist at Sanford with experience in interventional therapeutics, oversees the viral injection procedures. Enrollees in the trial are given a one-time injection and then are followed for 43 days to evaluate for safety and clinical benefit. To ensure safety during this period, other anti-cancer therapies cannot be used. However, after this 43-day period, chemotherapy, immunotherapy or targeted therapy can be restarted.

Sanford Health is the first in the nation to launch the Vyriad solid tumor oncolytic virus clinical trial. Call 1-877-SURVIVAL to learn more or to see if you qualify.

Explore further: First study of Oncolytic HSV-1 in children and young adults with cancer indicates safety, tolerability

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Clinical trial uses a genetically engineered virus to fight cancer - Medical Xpress

In BriefResearchers from UC San Diego's School of Medicine have tested a modified CRISPR-Cas9 technique designed to target RNA instead of DNA. Rcas9 could potentially improve the lives of patients with ALS, Huntington's disease, or myotonic dystrophy by delaying the progression of their disorders.

The most efficient and effective gene-editing tool in use today is CRISPR-Cas9. Just this year, researchers have successfully used it fora wide variety of experiments, from modifying garden vegetables to encoding a GIF in bacterial DNA. Most recently, the tool was used to remove a genetic disease from a human embryo.

Although undeniably powerful, CRISPR-Cas9 does have its limitations; it can only target DNA. To extend its capabilities to includeRNA editing, researchers from the University of California San Diego (UCSD) School of Medicinedeveloped amodification of CRISPR, and theyre calling their toolRNA-targeting Cas9 (RCas9).

In a study published in Cell, the UCSD team tested their technique by correcting the kinds of molecular mistakes that cause people to develop microsatellite repeat expansion diseases, such ashereditary amyotrophic lateral sclerosis (ALS)and Huntingtons disease.

During standard CRISPR-CAs9 gene editing, a guide RNA is instructed to deliver a Cas9 enzyme to a specific DNA molecule. The researchers from UCSD instead instructed it to target an RNA molecule.

Tests conducted in the laboratory showed that RCas9 removed 95 percent ofproblem-causing RNA for myotonic dystrophy types 1 and 2, Huntingtons disease, and one type of ALS. The technique also reversed 93 percent of the dysfunctional RNA targets in the muscle cells of patients with myotonic dystrophy type 1, resulting in healthier cells.

This is exciting because were not only targeting the root cause of diseases for which there are no current therapies to delay progression, but weve re-engineered the CRISPR-Cas9 system in a way thats feasible to deliver it to specific tissues via a viral vector, senior author Gene Yeo, a cellular and molecular medicine professor at UCSD School of Medicine, explained in a press release.

Across the globe, an estimated 450,000 patients are said to be living with ALS. Roughly 30,000 of those are from the U.S. where 5,600 people are diagnosed with the diseases every year. The exact number of Huntingtons disease cases, however, isnt quite as easy to pin down. One estimate says that around 30,000 Americans display symptoms of it, while more than 200,000 are at risk.

Regardless of the exact numbers, these two neurological diseases clearly affect a significant number of people. This prevalence and the absence of a known curemakes the UCSD teams research all the more relevant. Even more exciting is the fact that the same kinds of RNA mutations targeted by this study are known to cause more than 20 other genetic diseases.

Our ability to program the RCas9 system to target different repeats, combined with low risk of off-target effects, is its major strength, co-first author of the study Ranjan Batra said in the UCSD press release.

However, the researchers do know that what theyve accomplished is just a first step. While RCas9 works in a lab, they still have to figure out how it will fare when tested in actual patients.

The main thing we dont know yet is whether or not the viral vectors that deliver RCas9 to cells would elicit an immune response, explained Yeo. Before this could be tested in humans, we would need to test it in animal models, determine potential toxicities, and evaluate long-term exposure.

Ultimately, while RCas9 couldnt exactly deliver a cure, it could potentially extend patients healthy years. For disease like ALS and Huntingtons, thats a good place to start.

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A New Gene Editing Technique Could Finally Allow Us to Treat ALS - Futurism