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Archive - Jan 2019

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January 3rd

Jazz Pharmaceuticals & Codiak BioSciences Announce Strategic Collaboration to Research, Develop, and Commercialize Engineered Exosomes to Create Therapies for Hard-to-Treat Cancers; Codiak to Receive $56 Million Upfront & Up to $1 Billion in Milestones

On January 3, 2018, Jazz Pharmaceuticals plc (Nasdaq: JAZZ) and Codiak BioSciences, Inc., announced that the companies have entered into a strategic collaboration agreement focused on the research, development, and commercialization of exosome therapeutics to treat cancer. Codiak granted Jazz an exclusive, worldwide, royalty-bearing license to develop, manufacture, and commercialize therapeutic candidates directed at five targets to be developed using Codiak’s engEx™ precision engineering platform for exosome therapeutics. The targets focus on oncogenes that have been well validated in hematological malignancies and solid tumors, but have been undruggable with current modalities, including NRAS and STAT3. Under the terms of the agreement, Codiak is responsible for the execution of pre-clinical and early clinical development of therapeutic candidates directed at all five targets through Phase 1/2 proof-of-concept studies. Following the conclusion of the applicable Phase 1/2 study, Jazz will be responsible for future development, potential regulatory submissions, and commercialization for each product. Codiak has the option to participate in co-commercialization and cost/profit-sharing in the U.S. and Canada on up to two products. As part of the agreement, Jazz will pay Codiak an upfront payment of $56 million. Codiak is eligible to receive up to $20 million in preclinical development milestone payments across all five programs. Codiak is also eligible to receive milestone payments totaling up to $200 million per target based on Investigational New Drug application acceptance, clinical and regulatory milestones, including approvals in the U.S., European Union and Japan, and sales milestones.

WGS of Bulldogs, French Bulldogs, & French Terriers IDs 1 Mutation in 12 Million Variations That Causes “Screwtail”-- Mutation Is in DISHEVELlED 2 (DVL2), Gene Similar to DVL1 & DVL3 That Are Mutated in Rare Human Disease Robinow Syndrome

With their small size, stubby faces, and wide-set eyes, bulldogs, French bulldogs, and Boston terriers are among the most popular of domestic dog breeds. Now, researchers at the University of California (UC), Davis, School of Veterinary Medicine have found the genetic basis for these dogs' appearance, and linked it to a rare inherited syndrome in humans. Bulldogs, French bulldogs and Boston terriers aren't the only dogs with short, wide heads, but they do share another feature not found in other breeds: a short, kinked tail or "screwtail," said Professor Danika Bannasch, Department of Population Health and Reproduction in the UC Davis School of Veterinary Medicine. These three breeds all lack the vertebrae that make up the tail bone, she said. The researchers sequenced the whole genome -- the entire DNA sequence -- of 100 dogs, including 10 from screwtail breeds. All the participating dogs were privately owned pets seen at the UC Davis Veterinary Medical Teaching Hospital, whose owners agreed to participate. Graduate students Tamer Mansour and Katherine Lucot, with Dr. C. Titus Brown, Associate Professor at the School of Veterinary Medicine and Genome Center, searched through the DNA sequences to find changes associated with screwtail breeds. From more than 12 million individual differences they were able to identify one mutation, in a gene called DISHEVELLED 2 (DVL2). This variant was found in 100 percent of the bulldogs and French bulldogs sampled, and was very common in Boston terriers. This kind of whole genome comparison is relatively new, Dr. Bannasch said. "Normally, we would have first had to identify a region of DNA and work from there," she said. "We could look at breed-specific traits, but not as well as we can now." Professor Henry Ho at the UC Davis School of Medicine studies similar genes in humans.

Altering Activity of Brain Development Gene Cdk5 Causes Breakdown in Autophagy, Prompting Hyperactive Innate Immunity Attack That Destroys Dopamine-Releasing Neurons in Fly Brains; Similar Process May Occur in Several Neurodegenerative Diseases

In a study of fruit flies, NIH scientists sugges that the body's immune system may play a critical role in the damage caused by aging brain disorders. The results are based on experiments in which the researchers altered the activity of Cdk5, a gene that preclinical studies have suggested is important for early brain development and may be involved in neurodegenerative diseases, such as Lou Gehrig’s disease (ALS), Alzheimer's, and Parkinson's disease. Previously, they found that altering Cdk5 sped up the genetic aging process, causing the flies to die earlier than normal and have problems with walking or flying late in life and greater signs of neurodegenerative brain damage. In the current study, published in the January 2, 2019 issue of Cell Reports, the researchers suggested that altering Cdk5 resulted in the death of dopamine-releasing neurons, especially in the brains of older flies. Typically, Parkinson's disease damages the same types of cells in humans. Further experiments in flies suggested the neuron loss happened because altering Cdk5 slowed autophagy, a cell's waste disposal system that rids the body of damaged cells in a contained, controlled fashion, which, in turn, triggered the immune system to attack the animal's own neurons. This immune system attack is a much "messier" and more diffuse process than autophagy. Genetically, restoring the waste system or blocking the immune system's responses prevented the reduction in dopamine neurons caused by altering Cdk5.

January 2nd

Stem Cell Medicine Ltd Licenses Exosome Technology (Exosomes Derived from Adult Stem Cells) for Intranasal Treatment of Autism Spectrum Disorder (ASD) from Tel Aviv University; Pre-Clinical Testing Shows Improvement in Several Behavioral Phenotypes

On January 2, 2019, Stem Cell Medicine Ltd. (SCM), a biotechnology company developing new therapies for neurological indications, including mesenchymal stem cells (MSCs) and anti-BMP (bone morphogenic protein) molecules for the treatment of multiple sclerosis, and gene therapy for the treatment of neuropathic pain, announced that it has licensed an innovative exosomes-based technology for the treatment of neurodegenerative and neuropsychiatric indications, specifically, autism spectrum disorder (ASD). The treatment is based on exosomes, derived from adult stem cells (MSC-exo), that are administered intranasally. The technology was developed by Professor Dani Offen, Sackler School of Medicine, Sagol School of Neurosciences, Tel Aviv University, and was licensed from Ramot, the Business Engagement Center at Tel Aviv University. The first indication to be developed with the exosome technology is ASD, which is a group of neurodevelopmental disorders characterized by three core symptoms: severe impairment of social interactions and communication skills, increased repetitive behaviors, and cognitive inflexibility. The prevalence of ASD has been steadily increasing in children over the past several years, with no effective treatment, hence, it represents a growing unmet medical need. More than 3.5 million Americans live with ASD. According to the US Department of Health and Human Services (CDC), the prevalence of autism in US children in 2018 is estimated to be 1 in 59 children and has increased from 1 in 110 children in 2010, making it the fastest-growing developmental disability with currently no FDA-approved drug. Given the size of the patient population and lack of treatments, the market opportunity is compelling.

Sex Differences in Glioblastoma Brain Tumors Revealed by Analysis of Patient Imaging, Transcriptome, and Survival Data—“We Should Definitely Develop and Evaluate Sex-Specific Treatment Regimens for Glioblastoma,” Research Leader Says

For decades, scientists have recognized that more males get cancer and die of the disease than females. This is true for many types of cancer, including the deadly brain tumor glioblastoma (GBM). Now, a team of researchers led by scientists at the Washington University School of Medicine in St. Louis has identified distinct molecular signatures of glioblastoma in men and women that help explain such underlying disparities in patients’ response to treatment and survival. The research suggests that tailoring treatments to men and women with glioblastoma based on the molecular subtypes of their tumors may improve survival for all patients. The findings were published January 2, 2019 in Science Translational Medicine. The open-access article is titled “Sex Differences in GBM Revealed by Analysis of Patient Imaging, Transcriptome, and Survival Data.” “It is our expectation that this study could have an immediate impact on the care of patients with glioblastoma and further research, as the findings indicate we should be stratifying male and female glioblastoma into risk groups and evaluating the effectiveness of treatment in a sex-specific manner,” said Joshua B. Rubin, MD, PhD, a Washington University Professor of Pediatrics and of Neuroscience and the study’s co-senior author. “The biology of sex differences and its applications in medicine are highly relevant, but almost always ignored aspects of personalized treatments.” Glioblastoma is the most common malignant brain tumor and kills about half of patients within 14 months of diagnosis. It is diagnosed nearly twice as often in males, compared with females. The tumor is most often diagnosed in people over age 50, and standard treatment is aggressive -- surgery, followed by chemotherapy and radiation.

New Findings on Genes Driving Male-Female Brain Differences & Puberty Timing; Scientists ID Genetic Pathway to Sexual Maturation in C. elegans That May Serve Same Function in Humans; Sex Differences in Men’s & Women’s Brains May Be Hard-Wired

Researchers have identified a group of genes that induces differences in the developing brains of male and female roundworms and triggers the initiation of puberty, a genetic pathway that may have the same function in controlling the timing of sexual maturation in humans. The study, led by Columbia University scientists, offers new evidence for direct genetic effects in sex-based differences in neural development and provides a foundation to attempt to understand how men's and women's brains are wired and how they work. The research was published January 1, 2019 in eLife, an open-access journal founded by the Howard Hughes Medical Institute (HHMI), the Max Planck Society, and the Wellcome Trust. The article is titled “Timing Mechanism of Sexually Dimorphic Nervous System Differentiation.” Scientists have long known that puberty is accompanied by substantial changes in the brain characterized by the activation of neurons that produce hormonal signals. But what causes the brain to start releasing the hormones that switch on puberty has remained elusive. "In this paper we show that a pathway of regulatory genes acts within specific neurons to induce anatomical and functional differences in the male versus female brain," said lead study author Oliver Hobert, PhD, Professor in Columbia's Department of Biological Sciences and a HHMI investigator. "Remarkably, we found that each member of this pathway is conserved between worms and humans, indicating that we have perhaps uncovered a general principle for how sexual brain differences in the brain are genetically encoded." For their study, the researchers worked with the transparent roundworm C. elegans, the first multicellular organism to have its genome sequenced.

January 1st

Why Olfactory Cilia Use Outward-Flowing Cl−, Not Inward-Flowing Na+, to Generate Current; Need for Consistent Response in Variable Environments & Tiny Volume of Cilia Are Key; Findings Relevant to Nerve-Ending Pathology in Neurodegenerative Disease

Imagine trying to figure out how something works when that something takes place in a space smaller than a femtoliter: one quadrillionith of a liter. Now, two scientists with a nose for solving mysteries have used a combination of mathematical modeling, electrophysiology, and computer simulations to explain how cells communicate effectively in highly constricted spaces such as the olfactory cilia, where odor detection takes place. The findings will inform future studies of cellular signaling and communication in the olfactory system and also in other confined spaces of the nervous system. Study co-author Johannes Reisert, PhD, a Monell Chemical Senses Center cell physiologist, comments, "Ion channels and how their currents change ion concentrations inside cells are notoriously difficult to study. Our modeling-based approach enables us to better understand, not only how olfaction works, but also the function of small nerve endings such as dendrites, where pathology is associated with many neurodegenerative diseases." In the study, published online on December 31, 2018 in PNAS, the scientists asked why olfactory receptor cells communicate with the brain using a fundamentally different series of electrical events than used by sensory cells in the visual or auditory systems. The article is titled “Ca2+-Activated Cl− Current Ensures Robust and Reliable Signal Amplification in Vertebrate Olfactory Receptor Neurons.” Olfaction begins when, in a process similar to a key fitting into a lock, an airborne chemical molecule travels through the nasal mucus to bind with an olfactory receptor embedded on the wall of a nerve cell within the nose. The olfactory receptors are located on cilia, elongated super-thin threadlike structures less than 0.000004 inches in diameter, which extend from the nerve cell into the mucus.

Chemotherapy Can Stimulate Release of Metastasis-Promoting Exosomes from Breast Cancer Cells; The Exosomes Release Their Contents in the Lungs; Monocyte Inhibitors May Block This Chemotherapy/Exosome-Associated Metastasis

Some patients with breast cancer receive chemotherapy before the tumor is removed with surgery. This approach, called “neoadjuvant” therapy, helps to reduce the size of the tumor to facilitate breast-conserving surgery, and can even eradicate the tumor, leaving few or no cancerous cells for the surgeon to remove. In those cases, the patients are very likely to remain cancer-free for life after surgery. But not all tumors shrink under chemotherapy. If the tumor resists neoadjuvant therapy, there can be a higher risk of developing metastatic disease, meaning that the tumor will recur in other organs, such as bones or lungs. This could be due to cancerous cells that resist chemotherapy and spread to other organs while the primary tumor is being treated. Now, an international team of scientists led by Dr. Michele De Palma, PhD, at EPFL (Ecole Polytechnique Fédérale De Lausann) in Switzerland, has shed new light into this process. Working with experimental tumor models, the researchers found that two chemotherapy drugs frequently used for patients, paclitaxel and doxorubicin, induce mammary tumors to release small vesicles called exosomes. Under chemotherapy, the exosomes contain the protein annexin-A6, which is not present in the exosomes released from untreated tumors. "It seems that loading of annexin-A6 into exosomes is significantly enhanced in response to chemotherapy," explains Ioanna Keklikoglou, PhD, first author of the study. After being released from a chemotherapy-treated tumor, the exosomes circulate in the blood. Upon reaching the lung, the exosomes release their content, including annexin-A6. This stimulates the lung cells to release another protein, CCL2, which attracts immune cells called monocytes.