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October 29th, 2017

Exosome-Associated MicroRNAs May Be Powerful Biomarkers for Multiple Sclerosis, New Study Shows

A breakthrough study led by the University of Sydney's Brain and Mind Centre and Royal Prince Alfred Hospital has revealed unique molecules in the blood of people with multiple sclerosis (MS) that could become definitive diagnostic biomarkers of the world's most common neurologic disability in young adults. Published online today (October 30, 2017) in Scientific Reports, the discovery identifies tiny “dysregulated” micro-RNA molecules that correctly diagnose MS and discriminate between patients at different disease stages - all in a simple blood test. The open-access article is titled “Exosomal MicroRNA Signatures in Multiple Sclerosis Reflect Disease Status.” Currently, there is no definitive test for MS. Diagnosis and disease monitoring rely on several parameters, including clinical examination, MRI, cerebrospinal fluid assessment, and electrophysiology. MS is a chronic disease, so current diagnostic and monitoring tests are costly and still have limited utility to discriminate between different stages of the disease. In addition to identifying biomarkers that distinguish healthy people from those with MS, the researchers identified nine unique micro-RNA molecules that differentiate between two MS sub-types: relapsing-remitting MS (RRMS) and progressive MS. Relapsing-remitting MS (RRMS) affects 70 percent of MS patients and often evolves into a secondary progressive form of MS. 10-15 percent of people with MS are diagnosed with a progressive form of the disease from the outset known as primary progressive MS. The team also validated eight out of nine micro-RNA molecules in an independent group of progressive MS cases, confirming the reproducibility of the findings.

October 29th

Virus-Based Treatment Delivers Chemotherapy Specifically to Glioma Brain Tumor Cells--Phase 1 Cancer Trial Led by University of Minnesota Medical School's Dr. Clark Chen Shows Promise

New data from a Phase I clinical trial led by Clark Chen, M.D., Ph.D., Lyle French Chair in Neurosurgery and Head of the University of Minnesota Medical School Department of Neurosurgery shows more than a quarter of patients with recurrent high-grade glioma, a form of brain cancer, were alive more than three years after treatment. "Given the deadly nature of this disease, three-year survival is rarely reported in the recurrent setting. It is notable that the survival benefit was seen across a range of patients and not just limited to patients with specific genetic mutations," said Dr. Chen. "This finding indicates that many patients could benefit from this treatment." As Dr. Chen explained in an October 27, 2017 presentation (http://www.abstractsonline.com/pp8/#!/4557/presentation/619) at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Philadelphia, two steps were involved in the treatment of the 56 patients who participated in this clinical trial. First, patients were injected with Toca 511, which is a replicating virus that only infects actively dividing tumor cells. Once inside the cancer cell, the virus delivered a gene for an enzyme, cytosine deaminase (CD). As the virus began to replicate and spread to other cancer cells, it programmed them to make CD. Next, patients received a pill, Toca FC, which is an inert compound. Once inside the cancer cell, CD converted Toca FC into the anticancer drug 5-fluorouracil, which killed the cancer cell. In addition to destroying the cancer cells, 5-fluorouracil killed certain immune suppressive myeloid cells, thus boosting the patient's immune system to recognize and attack the cancer cells. "The treatment we tested in this trial delivers local chemotherapy specifically to the brain tumor.

October 28th

Blocking Fibroblast Activation Protein (FAP) in Normal Cells May Impede Pancreatic Cancer, Penn Vet Team Shows

Cancer of the pancreas is a deadly disease, with a median survival time of less than six months. Only one in 20 people with pancreatic cancer survives five years past the diagnosis. The reason is the cancer's insidiousness; tumor cells hide deep inside the body, betraying no symptoms until late in the disease, when the cancer has almost invariably spread to other organs. New findings from a University of Pennsylvania-led team offer a promising target for future therapies that could potentially root out even well-hidden metastatic cancer lesions. When they deleted the gene encoding this protein in mice with the disease, the animals lived longer, and the cancer's spread to other organs was reduced. "We thought that by targeting this protein we would see a big change in the primary tumor, and, while we do see a delay, the big change was in the metastasis," said Dr. Ellen Puré, the study's senior author and Chair of the Department of Biomedical Science in Penn's School of Veterinary Medicine. "It looks like this protein might be a druggable target, so we're hoping that with some additional follow-up work, it's something that we'll see go into patients." Dr. Puré collaborated on the work with Penn Vet's Drs. Albert Lo, Elizabeth L. Buza, Rachel Blomberg, Priya Govindaraju, Diana Avery, and James Monslow; Dr. Chung-Pin Li of Taipei Veterans General Hospital and National Yang-Ming University School of Medicine; and Dr. Michael Hsiao of the Academia Sinica Genomics Research Center in Taipei. Their paper was published online on October 5, 2017 in the Journal of Clinical Investigation Insight.

ReNeuron Wins New Grant to Advance Its Exosome Therapy Platform

ReNeuron Group plc (the "Company") (AIM: RENE), a UK-based global leader in the development of cell-based therapeutics, was pleased to announce, on October 27, 2017, that it is the lead industry participant in a new grant award from the Welsh Government to advance its emerging exosome therapy platform. The grant has been awarded under the Welsh Government’s SMARTExpertise scheme and will help fund a £1.2 million (~$1.6 million) collaborative program of work to be undertaken by ReNeuron, Ig Innovations, and Swansea University Medical School. The work program will establish methods to refine and optimize the manufacturing process for generating ReNeuron’s CTX cell-derived exosomes with the highest biological efficacy, methods to enhance the characterization of the CTX-derived exosomes against solid tumors to identify new cancer targets, and methods to characterize exosomes with potential therapeutic benefit derived from ReNeuron’s broader proprietary cell line library. ReNeuron is exploiting its exosome therapy platform as a potential new nanomedicine targeting cancer and as a potential delivery system for drugs that would otherwise be unable to reach their site of action. The SMARTExpertise grant follows the award of a grant to ReNeuron last year from Innovate UK to develop manufacturing systems and to conduct pre-clinical testing relating to the Company’s exosome therapy platform. Commenting on the grant award, Dr. Randolph Corteling, Head of Research at ReNeuron, said: “We are delighted to have won this new grant under the Welsh Government’s SMARTExpertise scheme. As a Wales-based business, we are very pleased to be able to work with leading Welsh academic and industry collaborators in order to further progress development of our high-potential exosome therapy platform towards clinical application.”

Survey Results: Genetics Specialists’ Views on Genome Editing; Findings Reported at ASHG 2017 Annual Meeting

Genetics professionals around the globe hold varying views on genome editing in humans, agreeing with the general public on some aspects and differing on others, according to survey results presented on October 19, 2017 at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Floroida. The results were presented by Professor Kelly Ormond, MS, Certified Genetic Counselor, of the Stanford Center for Biomedical Ethics. Led by Alyssa Armsby (photo), MS, of the Stanford University School of Medicine, researchers surveyed members of ten international genetics organizations on their attitudes toward research and potential clinical applications of genome editing, as well as how this relatively new technology fits in with their world view. The CRISPR/Cas9 system, a genome editing tool introduced in 2013, has quickly become widely used in genetics research due to the ease with which it can be customized and its effectiveness across cell types and species. Its quick adoption has sparked social and ethical questions, within both the scientific community and society more broadly, about how it should be studied and used. “There is a need for an ongoing international conversation about genome editing, but very little data on how people trained in genetics view the technology,” said Ms. Armsby. “As the ones who do the research and work with patients and families, they’re an important group of stakeholders,” she said. Among the 500 genetics professionals included in the analysis, the researchers found high support (>85%) for research into somatic uses of gene editing, which mirrors surveys of the American public.

American Society of Human Genetics (ASHG) Honors Kári Stefánsson with William Allan Award

The American Society of Human Genetics (ASHG) has named Kári Stefánsson, MD, founder of deCODE Genetics, the 2017 recipient of the annual William Allan Award. The Allan Award, which recognizes a scientist for substantial and far-reaching scientific contributions to human genetics, was established in 1961 in memory of William Allan, MD (1881-1943), one of the first American physicians to conduct extensive research on human genetics and hereditary diseases. Dr. Stefánsson was to receive his award, which will include an engraved medal and $25,000 prize, on October 18, 2017 during ASHG’s 67th Annual Meeting in Orlando, Florida. He was to present his William Allan Award address immediately thereafter. In 1996, Dr. Stefánsson founded deCODE Genetics with the vision of a large-scale population study in Iceland, a country with a relatively small, isolated, and homogenous population; a high-quality healthcare system; and extensive genealogical records. Through active engagement with the Icelandic population, deCODE has now collected DNA samples from more than 160,000 individuals and contributed greatly to public education about genetics in the country. Their work has inspired similar large-scale studies in other countries, including the UK Biobank and the United States’ All of Us initiative. Central to Dr. Stefánsson’s approach is the use of a single unique identifier for each individual, which allows researchers to measure hundreds of different genotypes and phenotypes in the context of each other and has led to important insights. His group published an influential genetic map in 2002, and has identified variants associated with varied phenotypes, such as type 2 diabetes, prostate cancer, heart attack, and schizophrenia.

October 27th

American Society of Human Genetics (ASHG) Honors Arthur Beaudet with Victor A. McKusick Leadership Award

The American Society of Human Genetics (ASHG) named Arthur L. Beaudet (photo), MD, Henry and Emma Mayer Professor in the Department of Molecular and Human Genetics and the Department of Pediatrics at Baylor College of Medicine, as the 2017 recipient of the annual Victor A. McKusick Leadership Award. This award, named in honor of the late Victor A. McKusick, MD, recognizes individuals whose professional achievements have fostered and enriched the development of human genetics as well as its assimilation into the broader context of science, medicine, and health. The ASHG presented the McKusick Award, which included a plaque and $10,000 prize, to Dr. Beaudet on October 17, 2017 during the organization’s 67th Annual Meeting in Orlando, Florida. In the 1980s, Dr. Beaudet and colleagues were the first to document uniparental disomy, a phenomenon in which a person receives two copies of a chromosome from one parent and zero from the other, in humans. In the following years, the researchers drew an important distinction between genetic and epigenetic diseases that both lead to altered expression of the same genes, and identified ways to study these and better understand the conditions they caused. Currently, Dr. Beaudet’s research focuses on neuronal carnitine deficiency as a risk factor for autism; the role of genomic imprinting in diseases such as Prader-Willi syndrome, Angelman syndrome, and autism; and prenatal genetic diagnosis based on fetal cells isolated from maternal blood. In addition to his scientific leadership, ASHG also recognizes Dr. Beaudet’s contributions to the Society and the broader research community. A longtime member of ASHG, he belonged to its Program Committee from 1984-86, its Board of Directors from 1987-90, and its Awards Committee from 2010-12, and served as President in 1998.

Researchers Quantify Breast Cancer Risk Based on Rare Variants and Background Risk

Rare variants, combined with background genetic risk factors, may account for many unexplained cases of familial breast cancer, and knowing the specific genes involved could inform choice of prevention and treatment strategies, according to findings presented on October 20, 2017 in a plenary session at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Florida. Researchers Na Li, MD, who presented the work; Ian Campbell, PhD, lead investigator; and their colleagues at the Peter MacCallum Cancer Centre in Melbourne, Australia, focused their study on patients at high risk of breast cancer: those with a personal or family history who were seeking an explanation. “When you know which gene is conferring the risk of breast cancer, you can provide a more precise estimate of risk, know what to expect and watch out for, and tailor risk management strategies to the patient,” said Dr. Campbell. Unfortunately, in about half of these high-risk patients, no known genetic cause was found, suggesting a more complicated explanation. In such cases, cancer geneticists had long suspected that polygenic risk (risk conferred by a combination of genetic variants) was involved. Genes do not work on their own, but rather as part of one’s overall genetic context, explained Dr. Li. “That ‘polygenic risk’ background is like a landscape full of hills and valleys, with each risky variant like a house on top of it,” she said. “If you inherit a high-risk variant – a tall house – but live in a valley, your overall risk of breast cancer may end up being average because your genetic landscape pulls it down.” The concept of background genetic risk is not new, but for many years, scientists did not have the tools to collect and analyze the thousands of genomes needed to quantify it.

Duplications of Noncoding DNA May Have Affected Evolution of Human-Specific Traits

Duplications of large segments of noncoding DNA in the human genome may have contributed to the emergence of differences between humans and nonhuman primates, according to results presented on October 18, 2017 at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Florida. Identifying these duplications, which include regulatory sequences, and their effect on traits and behavior may help scientists explain genetic contributions to human disease. Paulina Carmona-Mora, PhD, who presented the work; Megan Dennis, PhD; and their colleagues at the University of California, Davis, study the history of human-specific duplications (HSDs), segments of DNA longer than 1,000 base pairs that are repeated in humans but not in primates or other animals. In this study, they focused on HSD regions that do not code for genes, but instead regulate the expression of other genes. “What’s special about these regulatory elements is that they have the propensity to impact the expression of genes nearby on the same chromosome, as well as elsewhere in the genome,” said Dr. Dennis. “This means that one duplication could affect many genes, amplifying its impact.” Because duplicated segments are more than 98% identical, it is difficult to distinguish between them, Dr. Dennis explained. As a result, they were discarded in many past genomic analyses. For this reason, the researchers began by creating a new human reference genome that included the duplicated segments. This allowed them to identify areas likely to contain enhancers, which are regulatory elements that increase expression of other genes, and to assess their effect on gene expression across organs and tissue types.

Rapid Whole-Genome Sequencing of Neonatal ICU Patients Is Useful and Cost-Effective, Researchers Report at ASHG Annual Meeting

Rapid whole-genome sequencing (WGS) of acutely ill neonatal intensive care unit (NICU) patients in the first few days of life yields clinically useful diagnoses in many cases, and results in lower aggregate costs than the current standard of care, according to findings presented on October 19, 2017 at the American Society of Human Genetics (ASHG) 2017 Annual Meeting in Orlando, Florida. Shimul Chowdhury, PhD, FACMG, Clinical Laboratory Director at the Rady Children’s Institute for Genomic Medicine in San Diego, California, and his colleagues focused their analysis on a broad swath of NICU patients for whom a genetic diagnosis might help inform treatment decisions and disease management. They studied the clinical utility and cost-effectiveness of sequencing infants and their parents. “Newborns often don’t fit traditional methods of diagnosis, as they may present with non-specific symptoms or display different signs from older children,” said Dr. Chowdhury. In many such cases, he explained, sequencing can pinpoint the cause of illness, yielding a diagnosis that allows doctors to modify inpatient treatment and resulting in dramatically improved medical outcomes in both the short and long term. Because of the potential for early intervention and immediate adjustment in care, the researchers used a rapid WGS procedure that took three to seven days from sample collection to delivering results to patients’ families. The process can be further accelerated if medically necessary. In contrast, most clinical diagnostic tests take four to six weeks.