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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.

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.

Exosome-Mediated mRNA Delivery for SARS-CoV-2 Vaccination—Preclinical Advances Published in PrePrint by Capricor Therapeutics; Data Demonstrates Enhanced Expression & Lower Toxicity Compared to Lipid Nanoparticles; Webcast Thursday

On March 9, 2021, Capricor Therapeutics, Inc. (NASDAQ: CAPR) (https://capricor.com/), a biotechnology company focused on the development of transformative cell- and exosome-based therapeutics for the treatment and prevention of a broad spectrum of diseases, in collaboration with researchers, announced that new advances from its positive preclinical study for a multi-valent exosome-based mRNA vaccine for COVID-19 have been posted on the bioRxiv preprint server (https://www.biorxiv.org/content/10.1101/2020.11.06.371419v2) and the article been submitted for publication. The title of the preprint is “Exosome-Mediated mRNA Delivery for SARS-CoV-2 Vaccination.” “Capricor previously demonstrated that our exosome-based multivalent RNA delivery platform can induce long-lasting immune responses to multiple SARS-CoV-2 proteins, and potentially elicit a broad-based, cellular and humoral immunity. We decided to explore further the expression of RNAs with our exosome-based delivery system and compare exosomes with lipid nanoparticles specifically focused on short-term toxicity,” said Linda Marbán, PhD, CEO of Capricor. “The data demonstrated functional RNA expression in vivo, further showing the power of our exosome platform to potentially expand into areas beyond SARS-CoV-2. This strengthens my belief that our exosome platform can deliver RNA effectively into cells and drive the expression of functional proteins. The opportunities for pipeline expansion are very exciting, both in vaccines and in the delivery of therapeutic RNAs.”

New CAR T-Cell Therapy Extends Remission in Heavily Relapsed Multiple Myeloma Patients

A new type of CAR T-cell therapy more than triples the expected length of remission for multiple myeloma patients who have relapsed several times, according to an international clinical trial with the University of Texas Southwestern (UTSW) as the lead enrolling site. Results of the trial, published in the February 25, 2021 issue of the New England Journal of Medicine, were significantly better than those seen with other therapies available to heavily relapsed and refractory myeloma patients who had already received the three main classes of treatment. Nearly three-quarters of the patients had at least a partial response to the therapy. About a third achieved a complete remission, with the disappearance of all traces of cancer. Median time without the disease worsening was 8.8 months with this new treatment, but Larry D. Anderson (photo), MD, PhD, Associate Professor of Internal Medicine and co-first author of the journal article, points out that patients who received the trial's maximum dose of engineered T-cells experienced longer remissions, bringing the average to more than 12 months. Previously, similar patients treated with currently available therapies following multiple relapses have only had an average of three to four months of remission before their disease returned. The NEJM article is titled “Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma” (https://www.nejm.org/doi/10.1056/NEJMoa2024850). "We have patients that are over two years out from their single infusion of CAR T-cells and still in remission despite having no other treatment options when they were enrolled in this trial," says Dr. Anderson, a member of the UTSW’s Harold C. Simmons Comprehensive Cancer Center who cares exclusively for patients with plasma cell disorders, mostly myeloma patients.

MIT Study Reveals How Egg Cells (Oocytes) Get So Big—“Balloon Effect” Is Key

Egg cells are by far the largest cells produced by most organisms. In humans, they are several times larger than a typical body cell and about 10,000 times larger than sperm cells. There’s a reason why egg cells, or oocytes, are so big: They need to accumulate enough nutrients to support a growing embryo after fertilization, plus mitochondria to power all of that growth. However, biologists don’t yet understand the full picture of how egg cells become so large. A new study in fruit flies, by a team of MIT biologists and mathematicians, reveals that the process through which the oocyte grows significantly and rapidly before fertilization relies on physical phenomena analogous to the exchange of gases between balloons of different sizes. Specifically, the researchers showed that “nurse cells” surrounding the much larger oocyte dump their contents into the larger cell, just as air flows from a smaller balloon into a larger one when they are connected by small tubes in an experimental setup. “The study shows how physics and biology come together, and how nature can use physical processes to create this robust mechanism,” says Jörn Dunkel, PhD, an MIT Associate Professor of Physical Applied Mathematics. “If you want to develop as an embryo, one of the goals is to make things very reproducible, and physics provides a very robust way of achieving certain transport processes.”

Putting a Protein into Overdrive to Heal Spinal Cord Injuries--Scar-Forming Cells (NG2 Glia) Engineered to Overproduce SOX2 Protein Make New Neurons, Improving Recovery in Mouse Model

Using genetic engineering, researchers at the University of Texas Southwestern (UTSW) and Indiana University have reprogrammed scar-forming cells in mouse spinal cords to create new nerve cells, spurring recovery after spinal cord injury. The findings, published online on March 5, 2021 in Cell Stem Cell, could offer hope for the hundreds of thousands of people worldwide who suffer a spinal cord injury each year. The article is titled “In vivo Reprogramming of NG2 Glia Enables Adult Neurogenesis and Functional Recovery Following Spinal Cord Injury” (https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00059-X). Cells in some body tissues proliferate after injury, replacing dead or damaged cells as part of healing. However, explains study leader Chun-Li Zhang, (https://profiles.utsouthwestern.edu/profile/29691/chun-li-zhang.html ), PhD, Professor of Molecular Biology and a W.W. Caruth, Jr. Scholar in Biomedical Research at UTSW, the spinal cord typically does not generate new neurons after injury--a key roadblock to recovery. Because the spinal cord acts as a signal relay between the brain and the rest of the body, he adds, its inability to self-repair permanently halts communication between these two areas, leading to paralysis, loss of sensation, and sometimes life-threatening consequences such as an inability to control breathing or heart rate. Dr. Zhang notes that the brain has some limited capacity to produce new nerve cells, relying on progenitor cells to turn on distinct regenerative pathways. Using this knowledge as inspiration, he and his colleagues looked for cells that might have similar potential for regeneration in the spinal cord.

Targeting Viral Protein (Nsp1) That Blocks Export of Host mRNA from Nucleus Could Be Therapeutic Approach to Treating COVID-19

A study that identifies how a coronavirus protein called Nsp1 blocks the activity of genes that promote viral replication provides hope for new COVID-19 treatments. Since the start of the pandemic, scientists have worked endlessly to understand SARS-CoV-2, the coronavirus that causes COVID-19. Even with the arrival of vaccines, the virus is still spreading and there is a need to develop alternative therapies. Scientists hope to achieve this by studying how SARS-CoV-2 infects cells and propagates itself while avoiding the body’s natural immune system. Now, researchers at the University of Texas Southwestern (UTSW) have contributed to unravelling this puzzle with their results published in the February 5, 2021 issue of Science Advances. The open-access article is titled “Nsp1 Protein of SARS-CoV-2 Disrupts the mRNA Export Machinery to Inhibit Host Gene Expression” (https://advances.sciencemag.org/content/7/6/eabe7386). “When a virus infects a cell, the way the host cell reacts is to alter cellular pathways (or networks) in certain ways to counteract the viral infection. Viruses can target many of these pathways to favor their own replication,” says Beatriz Fontoura (photo), PhD, Professor of Cell Biology at UTSW and corresponding author of the paper. Viruses replicate by suppressing the host cell’s genes in favor of their own. One way they do this is by blocking the export of messenger RNA (mRNA) from the nucleus of the cell to another compartment called the cytoplasm. Some of these mRNAs code for proteins that can only be made by the cell in the cytoplasm. So, by blocking their export from the nucleus, viruses prevent some proteins from being made (e.g., antiviral proteins) and simultaneously free up the cell’s machinery for their own replication.

Researchers Use Machine Learning to Identify Nine Biomarkers for Autism Spectrum Disorder (ASD) in Blood; Findings May Permit Earlier Diagnosis and Treatment

Using machine-learning tools to analyze hundreds of proteins, University of Texas Southwestern (UTSW) researchers have identified a group of nine biomarkers in blood that could lead to an earlier diagnosis of children with autism spectrum disorder (ASD) and, in turn, more effective therapies sooner. The identification of nine serum proteins whose levels strongly predict ASD was reported in a study published online on February 24, 2021 by PLOS ONE. The open-access article is titled “Blood Biomarker Discovery for Autism Spectrum Disorder: A Proteomic Analysis” (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246581). Earlier diagnosis, followed by prompt therapeutic support and intervention, could have a significant impact on the 1 in 59 children diagnosed with autism in the United States. Being able to identify children on the autism spectrum when they are toddlers could make a big difference, says Dwight German, PhD, Professor of Psychiatry at UTSW and senior author of the study. Currently, the average age of a child diagnosed with ASD in the U.S. is 4 years old. Diagnosis before the age of 4 means that a child is more likely to get effective, evidence-based treatment, such as therapies directed at core ASD symptoms, including inflexible behaviors and the lack of communication or social skills. Many blood-based biomarker candidates have been investigated, including neurotransmitters, cytokines, and markers of mitochondrial dysfunction, oxidative stress, and impaired methylation. However, given the prevalence of ASD, the use of machine learning to incorporate demographic and clinical data into the analysis could more powerfully examine disease status and symptom severity.

Exosome-Based Urinary Test May Provide Non-Invasive Early Diagnosis of Human Kidney Transplant Rejection; Analysis Reveals Rejection Signature of 15 mRNAs in Urinary Exosomes; Approach May Enable Earlier, More Effective Treatment

Patients can spend up to six years waiting for a kidney transplant. Even when they do receive a transplant, up to 20 percent of patients will experience rejection. Transplant rejection occurs when a recipient's immune cells recognize the newly received kidney as a foreign organ and refuse to accept the donor's antigens. Current methods for testing for kidney rejection include invasive biopsy procedures, causing patients to stay in the hospital for multiple days. A study by investigators from Exosome Diagnostics (https://www.exosomedx.com/) and Brigham and Women's Hospital proposes a new, noninvasive way to test for transplant rejection using exosomes--tiny vesicles that can contain mRNA--from urine samples. Their findings were published online on March 2, 2021 in the Journal of the American Society of Nephrology. The open-access article Is titled “Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection” (https://jasn.asnjournals.org/content/early/2021/03/03/ASN.2020060850). "Our goal is to develop better tools to monitor patients without performing unnecessary biopsies. We try to detect rejection early, so we can treat it before scarring develops," said Jamil Azzi (photo), MD, Associate Physician in the Division of Renal Transplant at the Brigham and an Associate Professor of Medicine at Harvard Medical School. "If rejection is not treated, it can lead to scarring and complete kidney failure. Because of these problems, recipients can face life-long challenges." Before this study, physicians ordered biopsies or blood tests when they suspected that a transplant recipient was rejecting the donor organ. Biopsy procedures pose risks of complications, and 70-80 percent of biopsies end up being normal.

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