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April 16th, 2021

Neural Plasticity Depends on Transit of a Long Noncoding RNA (ADEPTR) from Nucleus to Synapse

Making memories involves more than seeing friends or taking photos. The brain constantly adapts to new information and stores memories by building connections (called synapses) among neurons. How neurons do this--reaching out arm-like dendrites to communicate with other neurons--requires a ballet of genes, signaling molecules, cellular scaffolding, and protein-building machinery. A new study from scientists at Scripps Research and the Max Planck Florida Institute for Neuroscience finds a central role for one signaling molecule, a long, noncoding RNA (lncRNA) that the scientists named ADEPTR. Using a variety of technologies, including confocal and two-photon microscopy, the scientists track ADEPTR's moves, watching as it forms, travels, amasses at the synapse, and activates other proteins upon a neuron's stimulation. Its journey to the far reaches of a brain cell is made possible by a cellular carrier that tiptoes along a dendrite's microtubule scaffolding. Called a kinesin motor, this carrier deposits ADEPTR near the synapse junction, where it activates other proteins. The team also found that if ADEPTR is silenced, new synapses don't form during stimulation. The study, titled "Activity Regulated Synaptic Targeting of lncRNA ADEPTR Mediates Structural Plasticity by Localizing Sptn1 and AnkB in Dendrites," was published online on April 16, 2021 in an open-access article (https://advances.sciencemag.org/content/7/16/eabf0605 ) in Science Advances. lncRNAs have often been described as "genomic dark matter," because their role in cells has yet to be fully characterized, especially in neurons, says the study's lead author, Scripps Research neuroscientist Sathyanarayanan Puthanveettil, PhD. Dr. Puthanveettil's team is finding that lncRNAs play a signaling role in neural plasticity--how neurons adapt and change with experience.

New CRISPR Technology Offers Unrivaled Control of Epigenetic Inheritance and Has Possibly Tremendous Therapeutic Potential, Particularly for Certain Genetic Diseases

Scientists have figured out how to modify CRISPR's basic architecture to extend its reach beyond the genome and into what's known as the epigenome--proteins and small molecules that latch onto DNA and control when and where genes are switched on or off. In a paper published April 9, 2021 in Cell, researchers at the University of California San Francisco (UCSF) and the Whitehead Institute describe a novel CRISPR-based tool called "CRISPRoff," which allows scientists to switch off almost any gene in human cells without making a single edit to the genetic code. The researchers also show that once a gene is switched off, it remains inert in the cell's descendants for hundreds of generations, unless it is switched back on with a complementary tool called CRISPRon, also described in the paper. Because the epigenome plays a central role in many diseases, from viral infection to cancer, CRISPRoff technology may one day lead to powerful epigenetic therapies. And because this approach doesn't involve any DNA edits, it's likely to be safer than conventional CRISPR therapeutics, which have been known to cause unwanted and potentially harmful changes to the genome. "Though genetic and cellular therapies are the future of medicine, there are potential safety concerns around permanently changing the genome, which is why we're trying to come up with other ways to use CRISPR to treat disease," said Luke Gilbert, PhD, a professor at UCSF's Helen Diller Family Comprehensive Cancer Center and co-senior author of the new paper. The Cell article is titled “Genome-Wide Programmable Transcriptional Memory by CRISPR-Based Epigenome Editing” (https://www.cell.com/cell/fulltext/S0092-8674(21)00353-6). Conventional CRISPR is equipped with two pieces of molecular hardware that make it an effective gene-editing tool.

April 15th

Broadly Neutralizing Antibodies Identified for Tick-Borne Encephalitis (TBE) Virus; These Antibodies Protect from Disease in Mouse Model and May Also Be Effective in Treatment

Tick-borne encephalitis (TBE) is a disease just as nasty as it sounds. Once bitten by an infected tick, some people develop flu-like symptoms that resolve quietly but leave behind rampant neurological disease—brain swelling, memory loss, and cognitive decline. Cases are on the rise in Central Europe and Russia with some 10,000 incidents reported each year. Vaccines can provide protection, but only for a limited time. There is no cure. Now a new study, published online on April 8, 2021 in the Journal of Experimental Medicine, describes antibodies capable of neutralizing the TBE virus transmitted by tick bites. These so-called broadly neutralizing antibodies have shown promise in preventing TBE in mice and could inform the development of better vaccines for humans. Further, preliminary results suggest that the antibodies may not only prevent TBE, but even treat the condition, as well as the disease caused by the related Powassan virus emerging in the United States and perhaps also other tick-borne viral diseases. The open-access article is titled “Broad and Potent Neutralizing Human Antibodies to Tick-Borne Flaviviruses Protect Mice from Disease” (https://rupress.org/jem/article/218/5/e20210236/211958/Broad-and-potent-...). Lead author Marianna Agudelo and colleagues in the laboratory of Rockefeller’s Michel C. Nussenzweig, MD, PhD, examined nearly 800 antibodies obtained from individuals who had recovered from TBE or had been vaccinated to prevent infection. The most potent antibodies, designated VH3-48, turned out to be best suited to fend off future infections.

NanoView Biosciences Launches EPIC Study to Investigate Impact of Exosome-Associated Biomarkers for Immuno-Oncology; Collaboration with Beth Israel Deaconess Medical Center Will Investigate PD-L1 and Status of Disease & Response to Therapy in Cancer

On April 15, 2021, NanoView Biosciences, Inc. ("NanoView"), a leading biomarker characterization company in the emerging field of extracellular vesicle (EV) biology, today announced a collaboration agreement with Beth Israel Deaconess Medical Center ("BIDMC") to study the involvement of biomarkers carried by exosomes in patients undergoing immune checkpoint inhibitor therapy ("ICIT") for cancer. The “ExoPD-L1 to Predict Immunotherapy Response in Cancer (‘EPIC’) Study” will specifically investigate Programmed Death-Ligand 1 ("PD-L1") and status of disease, as well as response to therapy. Exosomes are small EVs, 50-150 nm in size, that facilitate communication between cells by shuttling proteins, lipids, and nucleic acids. NanoView's platform technology, ExoView®, will be used in the EPIC Study to characterize PD-L1 and other biomarkers carried by exosomes in plasma samples from patients undergoing ICIT. "NanoView is excited to collaborate with BIDMC through the EPIC Study," stated Jerry Williamson, CEO of NanoView. "We are pleased that BIDMC will help evaluate data from our ExoView platform to better understand the role that exosome-associated biomarkers play in disease status and therapeutic response for cancer patients." Bruno Bockorny, MD, an oncologist from BIDMC, will serve as the Study Principal Investigator. Co-investigators from the Division of Medical Oncology and Immunotherapy Institute at BIDMC will also participate. "Disease status and response to therapy are difficult to predict for patients involved in ICIT and our aim is to continue to look for better clues that will deliver better outcomes," stated Dr. Bockorny.

April 13th

TGen Identifies Gene That Might Be Targeted to Possibly Help Prevent or Delay Onset of Alzheimer's Disease; Boosting ABCC1 Might Lessen Production of Plaque Linked to Alzheimer's Development

Findings of a study by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, suggest that increasing expression of a gene known as ABCC1 could not only reduce the deposition of a hard plaque in the brain that leads to Alzheimer's disease, but might also prevent or delay this memory-robbing disease from developing. ABCC1, also known as MRP1, has previously been shown in laboratory models to remove a plaque-forming protein known as amyloid beta (Abeta) from specialized endothelial cells that surround and protect the brain and cerebral spinal cord. Building on previous studies, TGen conducted a series of pre-clinical genomic laboratory experiments. Results suggest that ABCC1 not only could export Abeta out of the brain, but that increasing the expression of ABCC1 could reduce Abeta production, thus preventing, or delaying, the onset of Alzheimer's. The findings were published online on January 25, 2021 in Biology Open in an open-access article titled “Adenosine Triphosphate Binding Cassette Subfamily C Member 1 (ABCC1) Overexpression Reduces APP Processing and Increases Alpha- Versus Beta-Secretase Activity, In Vitro” (https://bio.biologists.org/content/10/1/bio054627). "Much work remains toward developing a drug that slows the development of or prevents Alzheimer's disease, but our findings suggest that targeting ABCC1 offers a promising path that could eventually lead to effective therapeutics," said Wayne Jepsen, PhD, a Postdoctoral Fellow in TGen's Neurogenomics Division, and the study's lead author. Alzheimer's disease is the sixth leading cause of death in the U.S., annually killing more than 120,000 people. There is no treatment that can effectively prevent or slow this disease. An estimated 5.8 million Americans age 65 or older have Alzheimer's, and that number is expected to more than double over the next 30 years.

April 13th

Novocure Announces Positive Update on Phase 3 Pivotal LUNAR Trial of Tumor Treating Fields (TTFields) in Non-Small-Cell Lung Cancer (NSCLC)

On April 13, 2021, Novocure (NASDAQ: NVCR) announced an update regarding its phase 3 pivotal LUNAR trial of Tumor Treating Fields (TTFields) in stage 4 non-small-cell lung cancer (NSCLC) following platinum failure. Following a routine review of the study by an independent data monitoring committee (DMC), Novocure was informed that the pre-specified interim analysis for the LUNAR trial would be accelerated given the length of accrual and the number of events observed, to date. The interim analysis included data from 210 patients accrued to the LUNAR trial through February 2021. After review of the interim analysis report, the DMC concluded that the LUNAR trial should continue with no evidence of increased systemic toxicity. The DMC also stated that it is likely unnecessary and possibly unethical for patients randomized to the control arm to continue accrual to 534 patients with 18 months follow-up. The DMC recommended a reduced sample size of approximately 276 patients with 12 months follow-up which it believes will provide sufficient overall power for both primary and secondary endpoints. The DMC recommended no other changes to the design of the trial. Novocure remains blinded to all data. The primary endpoint of the LUNAR trial is superior overall survival when patients are treated with TTFields plus immune checkpoint inhibitors or docetaxel versus immune checkpoint inhibitors or docetaxel alone. The final analysis will also include an analysis of overall survival in the immune checkpoint inhibitor and docetaxel treatment subgroups. Novocure has notified the U.S. Food and Drug Administration (FDA) of the DMC recommendations and of its intent to submit an Investigational Device Exemption (IDE) supplement incorporating the recommended protocol adjustments.

Methylation of RNA May Play Key Role in Autosomal Dominant Polycystic Kidney Disease (ADPKD); New Findings Suggest Dietary Modification & Targeting Methylating Enzyme May Be Two Ways to Control Common, Potentially Fatal Genetic Disorder

A chemical modification of RNA that can be influenced by diet appears to play a key role in autosomal dominant polycystic kidney disease (ADPKD), an inherited disorder that is the fourth leading cause of kidney failure in the U.S., University of Texas Southwestern (UTSW) researchers report in a new study. The findings, published online on April 13, 2021 in Cell Metabolism, suggest possible new ways to treat this incurable condition. The article is titled “A Methionine-Mettl3-N6-Methyladenosine Axis Promotes Polycystic Kidney Disease” (https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00131-5). Approximately 600,000 Americans and 12.5 million people worldwide have ADPKD, a condition caused by mutations in either of two genes, PKD1 or PKD2. These mutations cause kidney tubules (small tubes that filter blood and generate urine) to dilate, forming cysts that grossly enlarge the kidneys. In approximately 50 percent of patients, these cysts eventually cause kidney failure, necessitating dialysis or a kidney transplant. (Image at left shows enormous polycystic kidney versus normal kidney). Although one FDA-approved drug exists to treat ADPKD, it merely slows the decline in kidney function, explain study leaders Vishal Patel, MD, Associate Professor of Internal Medicine at UTSW, and Harini Ramalingam, PhD, a postdoctoral fellow in Dr. Patel's lab. More treatments for this condition are urgently needed, they say, but the molecular mechanisms that cause ADPKD to develop and progress are still not fully known. To better understand this condition, Dr. Patel, Dr. Ramalingam, and their colleagues investigated whether chemical modifications to the genetic molecule RNA, which translates instructions from DNA to produce proteins in the body, could play a part.

How “Imprinting” on Some Smells by Newborn Mice Affects Adult Social Behaviors; Study Sheds Light on Neuro-Developmental Disorders Such As Autism Spectrum Disorders, Suggests More Effective Use of Oxytocin Therapy for Such Disorders at Early Age

The smells that newborn mice are exposed to (or “imprint” on to use the academic term) affect many social behaviors later in life, but how this happens is still a mystery. Scientists from Japan have now discovered three molecules necessary for imprinting. Their new study sheds light on the decision-making process and neurodevelopmental disorders such as autism spectrum disorders (ASDs). It also proposes more effective use of oxytocin therapy for such disorders at an early age. Imprinting is a popularly known phenomenon, wherein certain animals and birds become fixated on sights and smells they experience immediately after being born. In ducklings, this can be the first moving object, usually the mother duck. In migrating fish like salmon and trout, it is the smells they knew as neonates that guides them back to their home river as adults. How does this happen? Exposure to environmental input during a critical period early in life is important for forming sensory maps and neural circuits in the brain. In mammals, early exposure to environmental inputs, as in the case of imprinting, is known to affect perception and social behavior later in life. Visual imprinting has been widely studied, but the neurological workings of smell-based or “olfactory” imprinting remain a mystery. To find out more, scientists from Japan, including Drs. Nobuko Inoue, Hirofumi Nishizumi, and Hitoshi Sakano at the University of Fukui and Drs. Kazutaka Mogi and Takefumi Kikusui at Azabu University, worked on understanding the mechanism of olfactory imprinting during the critical period in mice. Their study, published online on March 5, 2021 in eLife, offers fascinating results. The article is titled “The Olfactory Critical Period is Determined by Activity-Dependent Sema7A/PlxnC1 Signaling within Glomeruli” (https://elifesciences.org/articles/65078).

Study Suggests That Difficulty of Pecking Hole in Parasitic Egg for Gripping Purposes May Explain Why Most Host Birds Fail to Eject Foreign Eggs from Nest

Avian brood parasites lay their eggs in the nests of other bird species, forcing the hosts to do the hard work of raising the unrelated young. A team of scientists wanted to simulate the task of piercing an egg – a tactic that only a minority of host birds use to help grasp and eject the foreign eggs. Their study offers insight into some of the physical challenges the discriminating host birds face. The new findings were published on March 5, 2021 in the Journal of Experimental Biology. The article is titled “Nest Substrate and Tool Shape Significantly Affect The Mechanics and Energy Requirements of Avian Eggshell Puncture” (https://jeb.biologists.org/content/early/2021/03/01/jeb.238832). Take cowbirds, for example. Their eggs look nothing like the host birds’ eggs, “yet most of their hosts do not reject the parasite eggs,” said study co-author Mark Hauber (https://sib.illinois.edu/profile/mhauber), PhD, Professor of Host-Parasite Interaction in the Department of Evolution, Ecology, and Behavior at the University of Indiana and a brood parasitism expert. “One explanation is that the cowbird eggshell is too thick and strong for a small host’s beak to pierce.” To determine whether the difficulty of piercing a brood parasite’s egg played a role in whether the host bird tried to eject it, Daniel Clark, an undergraduate student working in Hauber’s laboratory, teamed up with an Assistant Professor in the same department, Philip Anderson, PhD, an expert in the biomechanics of piercing, slashing, and stabbing. Dr. Anderson has previously studied the characteristics that contribute to the cutting and crushing ability of teeth and the piercing power of viper fangs (https://news.illinois.edu/view/6367/775344) and cactus spines (https://news.illinois.edu/view/6367/719663).

Researchers Develop Promising Blood Test for Depression & Bipolar Disorder; May Open Door to Precise, Personalized Matching with Medications, and Objective Monitoring of Response to Treatment

Worldwide, 1 in 4 people will suffer from a depressive episode in their lifetime. While current diagnosis and treatment approaches are largely trial and error, a breakthrough study by Indiana University (IU) School of Medicine researchers sheds new light on the biological basis of mood disorders, and offers a promising blood test aimed at a precision medicine approach to treatment. Led by Alexander B. Niculescu, MD, PhD, Professor of Psychiatry at IU School of Medicine, the study was published online on April 8, 2021 in Molecular Psychiatry. The work builds on previous research conducted by Dr. Niculescu and his colleagues into blood biomarkers (focused on gene expression from immune cells) that track suicidality, as well as pain, post-traumatic stress disorder, and Alzheimer's disease. The ability to identify peripheral gene expression changes that reflect brain activities is likely due to the fact that the brain and immune system have developmental commonalities, marked by shared reactivity and ensuing gene expression patterns, the authors stated. The open-access Molecular Psychiatry article is titled “Precision Medicine for Mood Disorders: Objective Assessment, Risk Prediction, Pharmacogenomics, and Repurposed Drugs” (https://www.nature.com/articles/s41380-021-01061-w). "We have pioneered the area of precision medicine in psychiatry over the last two decades, particularly over the last 10 years. This study represents a current state-of-the-art outcome of our efforts," said Dr. Niculescu. "This is part of our effort to bring psychiatry from the 19th century into the 21st century; to help it become like other contemporary fields such as oncology.