Syndicate content

Mn+2 Activates NLRP3 Inflammasome Signaling, Propagates Exosomal Release of Inflammasome Adaptor Protein ASC in Microglial Cells; Welders Exposed to Manganese-Containing Fumes Had Plasma Exosomes with More ASC Than Controls; Association with Parkinson’s

Researchers from Iowa State University (ISU) and Penn State Health Milton S. Hershey Medical Center have reported work showing that manganese activates NLRP3 inflammasome signaling and propagates exosomal release of inflammasome adaptor protein ASC [apoptosis-associated speck-like protein containing CARD)]in microglial cells. Their article was published online on January 8, 2019, in Science Signaling. At the outset, the scientists, led by senior author Anumantha G. Kanthasamy, PhD, ISU Chair of Biomedical Sciences & Eminent Scholar in Veterinary Medicine, state that chronic occupational exposure to manganese is associated with the development of Parkinson’s disease. They note that others had earlier found that exposure of primed microglial cells or mice to manganese increased NLRP3 inflammasome expression and activation. Manganese caused mitochondrial dysfunction in treated microglial cells and stimulated their release of exosomes containing the inflammasome adaptor protein ASC. The effects of manganese on inflammasome activation were sensitive to reduced endocytosis and transferable by exposure of cells to purified exosomes from ASC-sufficient cells. Similarly, serum exosomes from welders contained more ASC protein and were more inflammatory than those from normal donors, suggesting that occupational manganese exposure may increase systemic inflammasome activation due to exosome-mediated transfer of ASC. The authors note that chronic, sustained inflammation underlies many pathological conditions, including neurodegenerative diseases, and that divalent manganese (Mn2+) exposure can stimulate neurotoxicity by increasing inflammation. In the current study, the researchers examined whether Mn2+ activates the multiprotein NLRP3* inflammasome complex to promote neuroinflammation.

Scientists ID Transcription Factor (Tcf7) Required for Success of Immune Checkpoint Blockades in Cancer Therapy; Finding May Advance Understanding of How These Therapies Elicit Their Response

There have been many success stories for immune checkpoint blockade therapies, both in preclinical models and in patients with cancer. But many questions remain about exactly how such immunotherapies elicit their response and what determines when and where checkpoint blockade therapy succeeds or fails at reinvigorating the immune system to eradicate cancer. A new study led by investigators from Brigham and Women's Hospital in Boston, in collaboration with colleagues at the Broad Institute, also in Boston, examines the effects of immune checkpoint blockade therapies on different populations of T-cells, a key class of immune cells in tumors. The team's surprising results point to a population of T-cells that has been overlooked in the past and have led to the identification of a molecular factor that may be predictive of response to treatment. The investigators' findings were published online on January 8, 2019 in Immunity. The article is titled “Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells.” "Our study takes advantage of the observation that there is great diversity in the T-cells within tumors. When we looked at the effect of therapies on different cell populations, we were surprised and puzzled to find that even T-cells that don't express checkpoint inhibitors showed significant changes at the genetic level," said co-corresponding author Ana Anderson (photo), PhD, Associate Scientist at the Brigham, and Associate Professor of Neurology at Harvard Medical School. "These are cells that have largely been ignored before. Our study broadens the focus of what checkpoint blockade therapy may be doing and how it mediates its effects." Dr.

Bristol-Myers Squibb to Acquire Celgene for $74 Billion to Create a Premier Innovative Biopharma Company; Combined Company Will Have More Than $1 Billion in Annual Sales

On January 3, 2018, Bristol-Myers Squibb Company (NYSE:BMY) and Celgene Corporation (NASDAQ:CELG) announced that they have entered into a definitive merger agreement under which Bristol-Myers Squibb will acquire Celgene in a cash and stock transaction with an equity value of approximately $74 billion. Under terms of the agreement, Celgene shareholders will receive 1.0 Bristol-Myers Squibb share and $50.00 in cash for each share of Celgene. Celgene shareholders will also receive one tradeable Contingent Value Right (CVR) for each share of Celgene, which will entitle the holder to receive a payment for the achievement of future regulatory milestones. The Boards of Directors of both companies have approved the combination. The transaction will create a leading focused specialty biopharma company well-positioned to address the needs of patients with cancer, inflammatory and immunologic disease, and cardiovascular disease through high-value innovative medicines and leading scientific capabilities. With complementary areas of focus, the combined company will operate with global reach and scale, maintaining the speed and agility that is core to each company’s strategic approach. Based on the closing price of Bristol-Myers Squibb stock of $52.43 on January 2, 2019, the cash and stock consideration to be received by Celgene shareholders at closing is valued at $102.43 per Celgene share and one CVR (as described below). When completed, Bristol-Myers Squibb shareholders are expected to own approximately 69 percent of the company, and Celgene shareholders are expected to own approximately 31 percent.

PMWC 2019 Silicon Valley Has Grown to World's Largest Precision Medicine Conference – Jan 20-23 in Santa Clara Convention Center

PMWC (Precision Medicine World Conference), the preeminent precision medicine global gathering that attracts recognized leaders, top international researchers and medical professionals, and innovators across the healthcare and biotechnology sectors, announced, on January 3, 2019, that PMWC 2019 Silicon Valley has grown to be the largest precision medicine conference, which, for the first time, will be held at the Santa Clara Convention Center in California January 20-23. Thousands of healthcare leaders, representing a variety of companies, technologies, research teams, and medical centers, with leadership roles in precision medicine are expected to attend. Over 400 speakers will be featured in more than 60 sessions. The conference will touch upon relevant topics such as how big data sciences and artificial intelligence (AI) applications advance precision medicine; how new emerging technologies drive genomics and medical practices; how patient data has become so valuable and how it impacts regulatory policy; how continuous advancements in immunotherapy are changing the way cancer is treated; and how thriving genome initiatives such as Genomic England are improving health care. The conference will recognize individuals who play a significant role in transforming today’s health care by advancing precision medicine into the clinic. This year's distinguished group of awardees includes Dr. Feng Zhang, Professor of Neuroscience at the Broad Institute (Harvard/MIT), who made vital contributions to the development of optogenetics and CRISPR technologies, and Dr. Carl June, Professor of Immunotherapy at the University of Pennsylvania, who was a crucial contributor to the development of the revolutionary CAR-T immunotherapy for cancer.

Bill & Melinda Gates Foundation Funds Evox Therapeutics to Support Development of Cell-Targeted, Exosome-Based Approaches to More Effectively Deliver Nucleic Acid-Based Anti-Infective Drug

On December 10, 2018, Evox Therapeutics Ltd ('Evox' or the 'Company'), a leading exosome therapeutics company, announced that it has secured an undisclosed amount of funding from the Bill & Melinda Gates Foundationn. The funds will be used to support the Company's development of cell-targeted exosome-based approaches to more effectively deliver a nucleic acid-based anti-infective drug. Evox is engineering exosomes, the body's natural vesicular delivery system, to enable a wide variety of drugs to reach previously inaccessible tissues and compartments, such as crossing the blood-brain barrier to deliver drugs to the central nervous system, intracellular delivery of biologics, and extra-hepatic delivery of RNA therapeutics. Dr Antonin de Fougerolles, CEO of Evox, commented: "We are pleased to be working with the Bill & Melinda Gates Foundation to maximize the effectiveness of their therapeutic drug through cell- and tissue-targeted exosome-mediated delivery. The foundation has a reputation for working with partners that can drive meaningful change - this funding is a testament to the quality of our platform and its potential application in areas of high medical need." Evox Therapeutics is a privately held, Oxford-based biotechnology company focused on harnessing and engineering the natural delivery capabilities of extracellular vesicles, known as exosomes, to develop an entirely new class of therapeutics. Backed by leading life sciences venture capital groups and supported by a comprehensive intellectual property portfolio, Evox's mission is to positively impact human health by creating novel exosome-based therapeutics for the treatment of various severe diseases with limited options for patients and their families.

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.

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.

Syndicate content