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HUNTINGTON'S DISEASE: Enrollment in Phase 1/2a Study of IONIS-HTT Rx in Patients with HD Completed and Open-Label Extension Study to Open in 2H 2017; Anti-Sense Drug Designed to Reduce Production of All Forms of HTT, Including Mutant HTT

On June 22, 2017, Ionis Pharmaceuticals, Inc. (NASDAQ: IONS) announced completion of enrollment in the Phase 1/2a randomized, placebo-controlled, dose escalation study of IONIS-HTTRx in patients with Huntington's disease (HD). Dosing in the final patient cohort continues, and Ionis plans to report top-line results from this study around year-end 2017. The safety and tolerability profile of IONIS-HTTRx in the completed cohorts of the Phase 1/2a study supports its continued development. Patients who complete the Phase 1/2a study will be eligible to participate in an open-label extension (OLE) study that Ionis plans to initiate in the next several months. Roche, Ionis' partner for this drug, continues to advance and support the program. IONIS-HTTRx is the first therapy in clinical development targeting the cause of HD by reducing the production of the toxic mutant huntingtin protein (mHTT) from the mutated huntingtin gene. "We are encouraged by the safety profile of IONIS-HTTRx we have observed to date in the completed dosing cohorts in the Phase 1/2a study. Upon completion and full analysis of this study, the next step for this program will be to conduct a study to investigate whether decreasing mutant huntingtin protein with IONIS-HTTRx can slow the progression of this terrible disease," said C. Frank Bennett, PhD, Senior Vice President of Research at Ionis Pharmaceuticals. "We believe that IONIS-HTTRx, which is designed to reduce the production of all forms of the huntingtin (HTT) protein – the known cause of HD, represents the most promising opportunity to address this significant unmet medical need.

FDA Grants Pre-Market Approval to Thermo Fisher Scientific for First NGS-Based Companion Diagnostic Test for Biomarkers Associated with Three FDA-Approved Therapies for Non-Small Cell Lung Cancer (NSCLC)

On June 22, 2017, Thermo Fisher Scientific announced that the U.S. Food and Drug Administration (FDA) had granted premarket approval to the company for the first next-generation sequencing (NGS)-based test that simultaneously screens tumor samples for biomarkers associated with three FDA-approved therapies for non-small cell lung cancer (NSCLC). Lung cancer is the leading cause of cancer-related deaths in the U.S., with NSCLC accounting for 85 percent of all lung cancers. The Oncomine Dx Target Test simultaneously evaluates 23 genes clinically associated with NSCLC. Following FDA approval, results from analysis of three of these genes can now be used to identify patients who may be eligible for treatment with one of the following: the combined therapy of Tafinlar® and Mekinist®, XALKORI®, or IRESSA®. With this test, physicians can now match patients to these therapies in days instead of several weeks, which it often takes when screening samples one biomarker at a time. "For people battling non-small cell lung cancer, time is critical and days matter," said Joydeep Goswami, President of Clinical Next-Generation Sequencing and Oncology at Thermo Fisher. "The Oncomine Dx Target Test rapidly guides oncologists toward the right targeted therapy, with the goal of improving patient outcomes and the cost-efficiency of treatments." LabCorp's Diagnostics and Covance Businesses, NeoGenomics Laboratories, and Cancer Genetics, Inc., are among the first laboratories that will offer the Oncomine Dx Target Test as a service to oncologists.

Five-Gene Assay Detects Neuroblastoma with Greater Sensitivity; Improved Disease Assessment Aids Prediction of Relapse in Children

Investigators at The Saban Research Institute of Children's Hospital Los Angeles have developed and tested a new biomarker assay for quantifying disease and detecting the presence of neuroblastoma even when standard evaluations yield negative results for the disease. In a study, led by Araz Marachelian, MD, of the Children's Center for Cancer and Blood Diseases, researchers provide the first systematic comparison of standard imaging evaluations versus the new assay that screens for five different neuroblastoma-associated genes and determine that the new assay improves disease assessment and provides prediction of disease progression. Results of the study were published on May 30, 2017 in Clinical Cancer Research. The article is titled “Expression of Five Neuroblastoma Genes in Bone Marrow or Blood of Patients with Relapsed/Refractory Neuroblastoma Provides a New Biomarker for Disease and Prognosis.” Neuroblastoma is a cancer of the nervous system that exists outside the brain and typically is diagnosed in children 5 years or age or younger. Forty-five percent of patients have high-risk, metastatic tumors (stage 4) when diagnosed. While children with neuroblastoma often respond to therapy and many are declared to be in a "remission" based on standard tests, many will still relapse. "Clearly, there is some remaining tumor in the body that we cannot detect with standard tests and physicians have a hard time predicting if a patient is likely to relapse," said Dr. Marachelian, who is Medical Director of the New Approaches to Neuroblastoma (NANT) consortium, headquartered at CHLA. The new assay, which was developed in the laboratories of Robert Seeger, MD, and Shahab Asgharzadeh, MD, at CHLA, tests for five different genes (CHGA, DCX, DDC, PHOX2B, and TH) that are specific to neuroblastoma.

Study of Parasitic Wasp Venom Reveals Novel & Possibly Widespread Mechanism for Genes to Evolve New Functions; Parasitoid Venoms May Offer “Immense Untapped Cornucopia for Drug Discovery”

Amid the incredible diversity of living things on our planet, there is a common theme. Organisms need to acquire new genes, or change the functions of existing genes, in order to adapt and survive. How does that happen? A common view is that genes are duplicated, with one of the copies picking up a new function while the other copy continues to function as before. However, by studying tiny parasitic Jewel Wasps and their rapidly changing venom repertoires, the Werren Lab at the University of Rochester in New York has uncovered a different process that may be widespread in other species as well. The process involves co-opting single-copy genes to take on new functions. In some cases, these genes appear to continue their previous function as well, in other parts of the wasp's anatomy besides the venom gland. The findings are published in Current Biology. The article is titled “The Evolution of Venom by Co-option of Single-Copy Genes.” "It is almost as if they are now moonlighting," says John (Jack) Werren, Professor of Biology. "They've got a day job, and then take on a night job as well. Over time, if the night job works out, they may give up the day job and evolve as a venom specialist. However, in other cases, we have found that they stop moonlighting as venom genes, but appear to retain their day job." How is a gene co-opted? And what determines which job (or combination of jobs) it performs? In the case of Jewel Wasps, the process called gene regulation is key. As the researchers explain, the rapid turnover in venom genes is accomplished mostly by changes in regulatory regions adjacent to the genes. These regulatory regions control how the genes are expressed--that is, whether the genes are turned "on" or "off" in different tissues. When a gene is turned on, it provides instructions for manufacturing proteins.

Exosomes As “Reconfigurable Therapeutic Systems” Are Focus of New Review; Exosomes Said to Offer “Enormous Potential”

Exosomes - tiny biological nanoparticles that can transfer information between cells - offer significant potential in detecting and treating disease, according to the most comprehensive overview so far of research in the field. Areas that could benefit include cancer treatment and regenerative medicine, say Dr. Steven Conlan from Swansea University (UK), Dr. Mauro Ferrari of Houston Methodist Research Institute in Texas, and Dr. Inês Mendes Pinto from the International Iberian Nanotechnology Laboratory in Portugal. Their commissioned paper, “Exosomes As Reconfigurable Therapeutic Systems,” was published on June 22, 2017 in Trends in Molecular Medicine. Exosomes are sub-cellular particles produced by all cells in the body and are from 30-130 nanometers in size. They act as biological signaling systems, communicating between cells, carrying proteins, lipids, DNA, and RNA. They drive biological processes, from modulating gene expression to transmitting information through breast milk. Though discovered in 1983, the full potential of exosomes is only gradually being revealed. The reviewers show that the possible medical benefits of exosomes fall into three broad categories: detecting disease - by acting as disease-specific biomarkers; activating immune responses to boost immunity; and treating diseases - serving as the vehicle for drugs, for example bearing cancer therapies as their payload, to target tumors. One of the most useful properties of exosomes is that they are able to cross barriers such as the plasma membrane of cells, or the blood/brain barrier. This makes exosomes well-suited to delivering therapeutic molecules in a very targeted way.

Stanford Collaborates with Pacific Biosystems to Carry Out Long-Read Sequencing to Confirm Diagnosis of Very Rare Mendelian Disease; First Use of Long-Read Sequencing in Clinical Setting Is in Synch with Stanford’s Focus on Precision Health

When Ricky Ramon was 7, he went for a routine checkup. The pediatrician, who lingered over his heartbeat, sent him for a chest X-ray, which revealed a benign tumor in the top-left chamber of his heart. For Ramon, it was the beginning of a long series of medical appointments, procedures, and surgeries that would span nearly two decades. During this time, noncancerous tumors kept reappearing in Ramon's heart and throughout his body -- in his pituitary gland, adrenal glands above his kidneys, nodules in his thyroid. When Ramon was 18, doctors thought his symptoms were suggestive of Carney complex, a genetic condition caused by mutations in a gene called PRKAR1A. However, evaluation of Ramon's DNA revealed no disease-causing variations in this gene. Now, eight years later, researchers at the Stanford University School of Medicine have used a next-generation technology -- long-read sequencing -- to secure a diagnosis for Ramon. It is the first time long-read, whole-genome sequencing has been used in a clinical setting, the researchers report in a paper published online on June 22, 2017 in Genetics in Medicine. The article is titled Long-Read Genome Sequencing Identifies Causal Structural Variation in a Mendelian Disease.” Genome sequencing involves snipping DNA into pieces, reading the fragments, and then using a computer to patch the sequence together. DNA carries our genetic blueprint in a double-stranded string of molecular "letters" called nucleotides, or base pairs. The four types of nucleotides are each represented by a letter -- C for cytosine and G for guanine, for example -- and they form links across the two strands to hold DNA together.

Study Answers Why Ketamine Helps Depression, Suggests Target For Safer Therapy

University of Texas (UT) Southwestern Medical Center scientists have identified a key protein that helps trigger ketamine’s rapid antidepressant effects in the brain, a crucial step to developing alternative treatments to the controversial drug being dispensed in a growing number of clinics across the country. Ketamine is drawing intense interest in the psychiatric field after multiple studies have demonstrated it can quickly stabilize severely depressed patients. But ketamine – sometimes illicitly used for its psychedelic properties – could also impede memory and other brain functions, spurring scientists to identify new drugs that would safely replicate ketamine’s antidepressant response without the unwanted side effects. A new study from the Peter O’Donnell Jr. Brain Institute at UT Southwestern has jump-started this effort in earnest by answering a question vital to guiding future research: what proteins in the brain does ketamine target to achieve its effects? “Now that we have a target in place, we can study the pathway and develop drugs that safely induce the antidepressant effect,” said Dr. Lisa Monteggia (photo), Professor of Neuroscience at UT Southwestern’s O’Donnell Brain Institute. The study, published online on June 21, 2017 in Nature, shows that ketamine blocks a protein responsible for a range of normal brain functions. The blocking of the N-methyl-D-aspartate (NMDA) receptor creates the initial antidepressant reaction, and a metabolite of ketamine is responsible for extending the duration of the effect. The Nature article is titled “Effects of a Ketamine Metabolite on Synaptic NMDAR Function.” The blocking of the NMDA receptor also induces many of ketamine’s hallucinogenic responses. The drug – used for decades as an anesthetic – can distort the senses and impair coordination.

Thousands of Genes Influence Most Complex Diseases, Stanford Researchers Report in Cell; “Compelling Paper” Presents “Plausible and Fascinating Model”

A core assumption in the study of complex-disease-causing genes has been that they are clustered in molecular pathways directly connected to the disease. But work by a group of researchers at the Stanford University School of Medicine suggests otherwise. The gene activity of cells is so broadly networked that virtually any gene can influence disease, the researchers found. As a result, most of the heritability of complex diseases is due not to a handful of core genes, but to tiny contributions from vast numbers of peripheral genes that function outside disease pathways. Any given trait, it seems, is not controlled by a small set of genes. Instead, nearly every gene in the genome influences everything about us. The effects may be tiny, but they add up. The work is described in a Perspective piece published in the June 15, 2017 issue of Cell. Jonathan Pritchard (photo), PhD, Professor of Genetics and of Biology, is the senior author. Graduate student Evan Boyle and postdoctoral scholar Yang Li, PhD, share lead authorship. The article is titled “An Expanded View of Complex Traits: From Polygenic to Omnigenic.” The researchers call their provocative new understanding of complex disease genes an "omnigenic model" to indicate that almost any gene can influence complex diseases and other complex traits. In any cell, there might be 50 to 100 core genes with direct effects on a given complex trait, as well as easily another 10,000 peripheral genes that are expressed in the same cell with indirect effects on that complex trait, said Dr. Pritchard, who is also a Howard Hughes Medical Institute investigator. Each of the peripheral genes has a small effect on the complex trait.

Penn Study Details Impact of Antibiotics, Antiseptics on Skin Microbiomes; Results Show Antibiotic Effects Can Linger, Antiseptic Impact Not As Strong As Expected

The use of topical antibiotics can dramatically alter communities of bacteria that live on the skin, while the use of antiseptics has a much smaller, less durable impact, according to results of a new study. The study, conducted in mice in the laboratory of Elizabeth Grice, PhD, an Assistant Professor of Dermatology in the Perelman School of Medicine at the University of Pennsylvania, is the first to show the long-term effects of antimicrobial drugs on the skin microbiome. Researchers published their findings online on June 20, 2017 in Antimicrobial Agents and Chemotherapy. The article is titled “Topical Antimicrobial Treatments Can Elicit Shifts to Resident Skin Bacterial Communities and Reduce Colonization by Staphylococcus aureus Competitors.” The skin, much like the gut, is colonized by a diverse multitude of microorganisms which generally coexist as a stable ecosystem -- many of which are harmless or even beneficial to the host. However, when that ecosystem is disturbed or destabilized, colonization and/or infection by more dangerous microbes can occur. Antiseptics, such as ethanol or iodine, are commonly used to disinfect the skin prior to surgical procedures or following exposure to contaminated surfaces or objects. Topical antibiotics may be used to decolonize skin of specific types of bacteria or for rashes, wounds, or other common conditions. In the gut, research shows medication that alters microbial communities can lead to complications like Clostridium difficile, or C. diff -- which causes diarrhea and is the most common hospital-acquired infection. But when it comes to the skin, the impact of these medications on bacteria strains like Staphylococcus aureus, or S. aureus -- the most common cause of skin infections -- is still largely unstudied.

Research into Octopus Sight Leads to Screening Device for Age-Related Macular Degeneration in Humans; Work Recognized with BBSRC Innovator of the Year 2017 Award

In a June 20, 2017 press release, it was announced that Dr. Shelby Temple, from the University of Bristol’s School of Biological Sciences, has been named Innovator of the Year 2017 for his ground-breaking work into polarization and macular degeneration. The Biotechnology and Biological Sciences Research Council (BBSRC) award recognizes Dr Temple’s work in developing a device that can rapidly screen people at increased risk of age-related macular degeneration (AMD), the worldwide leading cause of incurable blindness in people over 55. The innovation arose from BBSRC-funded research carried out at the University of Bristol, which looked at the ability of octopuses, cuttlefish, and coral reef fish to see polarized light - an aspect of light that humans aren’t typically aware they can see. Dr. Temple invented a series of unique devices to display polarized light to animals, and in doing so, realized he could see a pattern as well. “What I was seeing was an effect known as Haidinger’s brushes, which happens within the eye when people perceive polarized light. The ability to see this phenomenon is linked to an aspect of eye health and can be an early indicator of disease. “It became clear that the tools I had developed for octopuses and cuttlefish could be the foundation for a novel ophthalmic device that could rapidly screen people for susceptibility to AMD,” said Dr. Temple. This award acknowledges the important impact this device could have in preventing sight loss worldwide. In the UK alone, AMD affects more than 600,000 people and is estimated to cost the healthcare system £1.6 billion (~$2 billion) annually.

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