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Archive - 2021

Date

March 14th

Kimera Labs Announces New Standard Measurement for Exosome Potency, Characterization

On March 11, 2021, Kimera® Labs (https://kimeralabs.com/), one of the nation's top manufacturers of placental mesenchymal stem cell (pMSC) -derived exosomes, today announced the establishment of a novel and more relevant method to quantify and characterize exosomes - the Ross Unit (Ru), in an effort to standardize the measurement of nanovesicle technology. Kimera® Labs says it has established the Ru in order to rectify a misleading concept perpetuated by the tissue-banking industry that has correlated particle counts obtained by nano tracking analysis (NTA) to exosome concentration. In a novel approach to the subject, the Ru accounts solely for exosomal RNA cargo and protein concentration as opposed to gross quantification of all species (excipients) present in a solution. This scientifically valid process was developed by Kimera® Labs, Inc., and will be implemented in XoGlo® certificates of analysis in the first quarter of 2021. Kimera believes that the Ross Unit (Ru) describes a more accurate measurement of the purity and potency of exosome preparations and provides a reproducible method of therapeutic product characterization that will ultimately translate to improved patient outcomes. "When we debuted the Kimera® exosome product, XoGlo®, in 2014, we expended a significant amount of time and effort simply trying to communicate the concept of pMSC-derived paracrine effectors consisting of an invisible nanoparticle suspended in saline," said Duncan Ross PhD, and CEO of Kimera® Labs. "However, it was difficult to correlate the number of vesicles to the potency of a finished product.

March 13th

Singapore Scientists Develop Novel CRISPR-Cas9-Based Gene Editor to Correct Disease-Causing Mutations; Advance May Open Up Possible Treatment for Up to 40% of Genetic Disorders Caused by Single-Nucleotide Mutations

A team of researchers from the Agency for Science, Technology, and Research's (A*STAR) Genome Institute of Singapore (GIS) has developed a CRISPR-based gene editor, C-to-G Base Editor (CGBE), to correct mutations that cause genetic disorders. Their research was published online on March 2, 2021 in Nature Communications. The open-access article is titled “Programmable C:G to G:C Genome Editing with CRISPR-Cas9-Directed Base Excision Repair Proteins” (https://www.nature.com/articles/s41467-021-21559-9 ). One in seventeen people in the world suffers from some type of genetic disorder. Chances are, you or someone you know--a relative, friend, or colleague--is one of approximately 450 million people affected worldwide. Mutations responsible for these disorders can be caused by multiple mutagens--from sunlight to spontaneous errors in your cells. The most common mutation by far is the single-based substitution, in which a single-base in the DNA (such as G) is replaced by another base (such as C). For example, countless cystic fibrosis patients worldwide have C instead of G, leading to defective proteins that cause the genetic disease. In another case, replacing A with T in hemoglobin causes sickle cell anemia. To fix these substitutions, the team invented a CRISPR-based gene editor that precisely changes the defective C within the genome to the desired G. This C-to-G base editor (CGBE) invention opens up treatment options for approximately 40 per cent of the single-base substitutions that are associated with human diseases such as the aforementioned cystic fibrosis, cardiovascular diseases, musculoskeletal diseases, and neurological disorders.

An Old Antibiotic May Combat Drug-Resistant Tuberculosis

For decades, antibiotics have helped hold tuberculosis back, saving untold millions of lives. But their limits are being seriously tested as the bacterium’s tendency to mutate has led to a steady rise in drug-resistant strains. Without new drugs, scientists fear that tuberculosis, deemed largely a controllable disease, may not remain so. In search of new antibiotics, Rockefeller University scientists have landed on an existing compound, naturally produced by a bacterium. Their research, published online on November 16, 2020 in PNAS, elucidates how sorangicin A, first discovered in the 1980s, can destroy even the antibiotic-resistant bacteria that cause tuberculosis. The findings suggest that the compound may be a good candidate for further development as a first-line antibiotic for tuberculosis. The PNAS article is titled “The Antibiotic Sorangicin A Inhibits Promoter DNA Unwinding in a Mycobacterium tuberculosis Rifampicin-Resistant RNA Polymerase.” “Sorangicin inhibits regular strains in very much the same way as rifampin, one of the primary choices for tuberculosis antibiotics. But now we show that, through a different mechanism, it [sorangicin] also traps those variants that escape rifampin,” says Elizabeth Campbell, PhD, a Research Associate Professor at Rockefeller. The antibiotic rifampin works by blocking RNA polymerase (RNAP), an enzyme crucial to bacteria’s survival. This enzyme walks along a strand of DNA, using the genetic information to build an RNA molecule, one nucleotide at a time. Rifampin snaps into the cavity of one of RNAP’s pockets, and physically clogs the path of the RNA molecule when it’s no more than two or three nucleotides long. Without the proper RNA blueprints, the bacterium can’t make new proteins, and dies.

March 12th

Study Identifies Key Genes in Brain Involved in Encoding Memories

University of Texas Southwestern (UTSW) scientists have identified key genes involved in brain waves that are pivotal for encoding memories. The findings, published online on March 8, 2021 in Nature Neuroscience, could eventually be used to develop novel therapies for people with memory loss disorders such as Alzheimer’s disease and other forms of dementia. The article is titled “Gene-Expression Correlates of the Oscillatory Signatures Supporting Human Episodic Memory Encoding” (https://www.nature.com/articles/s41593-021-00803-x). Making a memory involves groups of brain cells firing cooperatively at various frequencies, a phenomenon known as neural oscillations. However, explain study leaders Bradley C. Lega, MD, Associate Professor of Neurological Surgery, Neurology, and Psychiatry, and Genevieve Konopka, PhD, Associate Professor of Neuroscience, the genetic basis of this process is not clear. “There’s a famous saying for 100 years in neuroscience: ‘Neurons that fire together will wire together,’” says Dr. Lega. “We know that cells involved in learning fire in groups and form new connections because of the influence of these oscillations. But how genes regulate this process in people is completely unknown.” Dr. Lega and Dr. Konopka, both members of UTSW’s Peter O’Donnell Jr. Brain Institute, collaborated on a previous study to explore this question, collecting data on neural oscillations from volunteers and using statistical methods to connect this information to data on gene activity collected from postmortem brains. Although these results identified a promising list of genes, Dr. Konopka says, there was a significant shortcoming in the research: The oscillation and genetic data came from different sets of individuals.

Research Reveals 3D Structure Responsible for Multi-Unit Machine Involved in Regulating Gene Expression

For the first time ever, a Northwestern University-led research team has peered inside a human cell to view a multi-subunit machine responsible for regulating gene expression. Called the Mediator-bound pre-initiation complex (Med-PIC), the structure is a key player in determining which genes are activated and which are suppressed. Mediator helps position the rest of the complex--RNA polymerase II and the general transcription factors--at the beginning of genes that the cell wants to transcribe. The researchers visualized the complex in high resolution using cryogenic electron microscopy (cryo-EM), enabling them to better understand how it works. Because this complex plays a role in many diseases, including cancer, neurodegenerative diseases, HIV, and metabolic disorders, researchers' new understanding of its structure could potentially be leveraged to treat disease. "This machine is so basic to every branch of modern molecular biology in the context of gene expression," said Northwestern's Yuan He (at right in photo with colleague), PhD, senior author of the study. "Visualizing the structure in 3D will help us answer basic biological questions, such as how DNA is copied to RNA." "Seeing this structure allows us to understand how it works," added Ryan Abdella, PhD student and the paper's co-first author. "It's like taking apart a common household appliance to see how everything fits together. Now we can understand how the proteins in the complex come together to perform their function." The study was published online on March 11, 2021 in Science. This marks the first time the human Mediator complex has been visualized in 3D in the human cell. The Science article is titled "Structure of the Human Mediator-Bound Transcription Pre-Initiation Complex" (https://science.sciencemag.org/content/early/2021/03/10/science.abg3074).

RNA Editing Protein ADAR1p110 Protects Telomeres and Supports Proliferation In Cancer Cells; Protein May Be Target for Anti-Cancer Therapy

Scientists at The Wistar Institute in Philadelphia have identified a new function of ADAR1, a protein responsible for RNA editing, discovering that the ADAR1p110 isoform regulates genome stability at chromosome ends and is required for continued proliferation of cancer cells. These findings, reported online on March 12, 2021 in Nature Communications, reveal an additional oncogenic function of ADAR1 and reaffirm its potential as a therapeutic target in cancer. The open-access article is titled “ADAR1 RNA Editing Enzyme Regulates R-Loop Formation and Genome Stability at Telomeres in Cancer Cells” (https://www.nature.com/articles/s41467-021-21921-x). The lab of Kazuko Nishikura, PhD, Professor in the Gene Expression & Regulation Program of The Wistar Institute Cancer Center, was one of the first to discover ADAR1 in mammalian cells and to characterize the process of RNA editing and its multiple functions in the cell. Similar to changing one or more letters in a written word, RNA editing allows cells to make discrete modifications to single nucleotides within an RNA molecule. This process can affect RNA metabolism and how it is translated into proteins and has implications for neurological and developmental disorders and antitumor immunity. There are two forms of the ADAR1 protein, ADAR1p150 and ADAR1p110. While the RNA editing role of the former, located in the cytoplasm, has been extensively characterized, the function of the nuclear ADAR1p110 isoform has remained elusive. "We discovered that, in the nucleus, ADAR1p110 oversees a similar mechanism to ADAR1p150, the better-known cytoplasmic variant, but the editing process in this case targets particular nucleic acid structures called R-loops when formed at the chromosome ends," said Dr. Nishikura. "Through this function, ADAR1p110 seems to be essential for cancer cell proliferation."

March 11th

Monoclonal Antibody Combination from Lilly Reduces Risk of Hospitalization & Death by 87% in Phase 3 Trial for Early COVID-19, According to New Data, Company Announces

On March 10,2021, Eli Lilly and Company (NYSE: LLY) announced new data from the randomized, double-blind, placebo-controlled BLAZE-1 Phase 3 study, demonstrating that the monoclonal antibodies bamlanivimab (LY-CoV555) 700 mg and etesevimab (LY-CoV016) 1400 mg together significantly reduced COVID-19 related hospitalizations and deaths ("events") in high-risk patients recently diagnosed with COVID-19. These results provide additional efficacy and safety data that support the use of the dose recently granted both Emergency Use Authorization by the U.S. Food and Drug Administration (FDA) and a positive scientific opinion by the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP). This new Phase 3 cohort of BLAZE-1 included 769 high-risk patients, aged 12 and older with mild to moderate COVID-19 (therapy: n=511; placebo: n=258). There were 4 events in patients taking bamlanivimab with etesevimab and 15 events in patients taking placebo, representing an 87 percent risk reduction (p<0.0001). Bamlanivimab and etesevimab together also demonstrated statistically significant improvements on key secondary endpoints. These results are consistent with those seen in other data sets from BLAZE-1: in the previous Phase 3 cohort, bamlanivimab 2800 mg with etesevimab 2800 mg reduced the risk of hospitalizations and deaths by 70 percent and in the Phase 2 cohort, bamlanivimab alone reduced the risk of hospitalizations and ER visits by approximately 70 percent. The viral load reductions were also consistent with what was observed in the previous Phase 3 cohort of the study.

March 9th

Targeting Mechanosensitive Protein (MDM4) Could Help Treat Idiopathic Pulmonary Fibrosis (IPF), Animal Study Suggests

Researchers at the University of Alabama at Birmingham (UAB) have identified a new molecular target that could prove useful in the potential treatment of the deadly, aging-related lung disease idiopathic pulmonary fibrosis (IPF). The study, which was published online on March 10. 2021 in the Journal of Experimental Medicine (JEM)( https://rupress.org/jem/article-lookup/doi/10.1084/jem.20202033?PR), suggests that targeting a protein called MDM4 could prevent respiratory failure by initiating a genetic program that removes scar tissue from the lungs. The open-access article is titled “Targeting Mechanosensitive MDM4 Promotes Lung Fibrosis Resolution in Aged Mice.” IPF is characterized by the accumulation of scar tissue that stiffens the lungs and makes it difficult for patients to breathe and get sufficient oxygen into their blood. Though the causes of IPF remain unclear, age is a significant risk factor: the disease is estimated to affect 1 in 200 US adults over the age of 70. The scars are thought to arise from a runaway wound healing process in which lung cells deposit excessive amounts of collagen into their surroundings, stiffening the lung tissue and activating highly contractile cells called myofibroblasts. These myofibroblasts produce still more collagen fibers and stiffen the tissue even further. "Lung fibrosis resolution is thought to involve degradation of excessive collagen, removal of myofibroblasts, and regeneration of normal lung tissue by stem cells," says Yong Zhou, MD, PhD, an Associate Professor in the Department of Medicine, UAB. "However, the mechanisms underlying the reversal of lung fibrosis remain poorly understood."

Capitalizing on Measles Vaccine's Successful History to Protect Against SARS-Cov-2; Researchers Use Live, Attenuated Measles Virus As Vehicle for SARS-CoV-2 Spike Protein Gene to Generate Strong Immune Response and Prevent Infection in Animal Models

A new SARS-CoV-2 vaccine candidate, developed by giving a key protein's gene a ride into the body while encased in a measles vaccine, has been shown to produce a strong immune response and prevent SARS-CoV-2 infection and lung disease in multiple animal studies. Scientists attribute the vaccine candidate's effectiveness to strategic production of the antigen to stimulate immunity: using a specific snippet of the coronavirus spike protein gene, and inserting it into a sweet spot in the measles vaccine genome to boost activation, or expression, of the gene that makes the protein (image). Even with several vaccines already on the market, researchers say this candidate may have advantages worth exploring--especially related to the measles vaccine's established safety, durability, and high-efficacy profile. "The measles vaccine has been used in children since the 1960s, and has a long history of safety for children and adults," said Jianrong Li, DVM, PhD, senior author of the study and a Professor of Virology in The Ohio State University Department of Veterinary Biosciences. "We also know the measles vaccine can produce long-term protection. The hope is that with the antigen inside, it can produce long-term protection against SARS-CoV-2. That would be a big advantage, because right now we don't know how long protection will last with any vaccine platforms." The research was published online on March 9, 2021 in PNAS. The open-access article is titled “A Safe and Highly Efficacious Measles Virus-Based Vaccine Expressing SARS-Cov-2 Stabilized Prefusion Spike” (https://www.pnas.org/content/118/12/e2026153118). The Ohio State Innovation Foundation has exclusively licensed the technology to Biological E. Limited (BE), a Hyderabad, India-based vaccine & pharmaceutical company.

March 9th

Why Odors Trigger Powerful Memories--Sense of Smell More Directly Linked to Brain Memory Center (Hippocampus) Than Other Senses, New Study Shows; Loss of Sense of Smell Highly Correlated with Depression and Poor Quality of Life

Odors can evoke powerful memories, an experience enshrined in literature by Marcel Proust and his beloved madeleine, described in his novel “Remembrance of Things Past.” A new paper authored by investigators at Northwestern University Feinberg School of Medicine, and colleagues, is the first to identify a neural basis for how the brain enables odors to so powerfully elicit those memories. The paper shows unique connectivity between the hippocampus--the seat of memory in the brain--and olfactory areas in humans. This new research suggests a neurobiological basis for privileged access by olfaction to memory areas in the brain. The study compares connections between primary sensory areas--including visual, auditory, touch, and smell--and the hippocampus. It found olfaction has the strongest connectivity. It's like a superhighway from smell to the hippocampus. "During evolution, humans experienced a profound expansion of the neocortex that re-organized access to memory networks," said lead investigator Christina Zelano, PhD, Assistant Professor of Neurology at Northwestern University Feinberg School of Medicine. "Vision, hearing, and touch all re-routed in the brain as the neocortex expanded, connecting with the hippocampus through an intermediary--association cortex--rather than directly. Our data suggests olfaction did not undergo this re-routing, and instead retained direct access to the hippocampus." The new article, "Human Hippocampal Connectivity Is Stronger in Olfaction Than Other Sensory Systems" was published online on February 25, 2021 in Progress in Neurobiology (https://www.sciencedirect.com/science/article/pii/S0301008221000411). In COVID-19, smell loss has become epidemic, and understanding the way odors affect our brains--memories, cognition, and more--is more important than ever, Dr. Zelano noted.