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Chloride Channel Gene (CLCN6) Identified As Disease Gene for Severe Form of Lysosomal Neurodegenerative Disease

A mutation in the CLCN6 gene (also called CIC-6, for the protein it codes for) is associated with a novel, particularly severe neurodegenerative disorder. Scientists from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and the Max Delbrück Center für Molekulare Medizin (MDC), together with an international team of researchers, have now analyzed the effect of a point mutation that was found in three unrelated affected children. CLCN6 is one of nine members of the CLCN gene family of chloride channels and chloride/proton exchangers and, apart from CLNC-3, was the only one that could not yet be associated with any human disease. The results have just been published online on November 19, 2020 in the American Journal of Human Genetics. The article is titled “A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl−/H+-Exchanger, Causes Early-Onset Neurodegeneration.” The term "lysosomal storage disease" summarizes a number of genetically determined metabolic diseases that are due to incorrect or insufficient function of lysosomes. These cellular organelles are important both for "cellular waste disposal" and for the regulation of cellular metabolism. If lysosomal function is compromised, substances that normally would be degraded may accumulate in the affected cells. This may impair their function and may eventually lead to cell death. In the central nervous system, which is often affected because adult neurons are unable to regenerate, this can lead to neurodegeneration.

Phase 2 Trial of Oxford COVID-19 Vaccine in Healthy Older Adults Finds It Is Safe and Provokes Immune Response; Similar Results Seen in Younger Adults; Phase 3 Trials Ongoing

The UK's vaccine against SARS-CoV-2 shows similar safety and immunogenicity results in healthy older adults (aged 56 years and over) to those seen in adults aged 18-55 years. The promising early-stage results were published online on November 18, 2020 in The Lancet ( The open-access article is titled “Safety and Immunogenicity of ChAdOx1 nCoV-19 Vaccine Administered in a Prime-Boost Regimen in Young and Old Adults (COV002): a Single-Blind, Randomised, Controlled, Phase 2/3 Trial.” The phase 2 trial finds that the vaccine causes few side effects, and induces immune responses in both parts of the immune system in all age groups and at low and standard dose--provoking a T-cell response within 14 days of the first dose of vaccination (i.e., a cellular immune response, it could find and attack cells infected with the virus), and an antibody response within 28 days of the booster dose of vaccination (i.e., humoral immune response, it could find and attack the virus when it was circulating in the blood or lymphatic system). Phase 3 trials are ongoing to confirm these results--as well as how effective the vaccine is in protecting against infection with SARS-CoV-2 - in a broader range of people, including older adults with underlying health conditions. Study lead author Professor Andrew Pollard, University of Oxford, UK, says: "Immune responses from vaccines are often lessened in older adults because the immune system gradually deteriorates with age, which also leaves older adults more susceptible to infections. As a result, it is crucial that COVID-19 vaccines are tested in this group who are also a priority group for immunization." Co-author Dr.

Researchers Discover a Cellular Mechanism for Degradation of miRNAs; Finding May Lead to Insights of How to Control This Mechanism and, Ultimately, to Possible Disease Therapies

University of Texas (UT) Southwestern (UTSW) researchers have discovered a mechanism that cells use to degrade microRNAs (miRNAs), genetic molecules that regulate the amounts of proteins in cells. The findings, reported online on November 12, 2020 in Science (, not only shed light on the inner workings of cells, but could eventually lead to new ways to fight infectious diseases, cancer, and a multitude of other health problems. The article is titled “A Ubiquitin Ligase Mediates Target-Directed Microrna Decay Independently of Tailing and Trimming.” Scientists have long known that genes contain the instructions for making every protein in an organism’s body. However, various processes regulate whether different proteins are produced and in what amounts. One of these mechanisms involves miRNAs, small pieces of genetic material that break down complementary pieces of messenger RNA (mRNA) in cells, preventing the mRNA sequence from being translated into proteins. Since the discovery of miRNAs in 1993, researchers have amassed a wealth of knowledge about the hundreds of different miRNA molecules and their targets as well as mechanisms that control their production, maturation, and roles in development, physiology, and disease. However, explains Joshua Mendell (photo at left; please see mechanism diagram below) (, MD, PhD, Professor and Vice Chair of the Department Of Molecular Biology at UTSW, and postdoctoral fellow Jaeil Han, PhD, very little was known about how cells dispose of miRNAs when they’re finished using them. “As long as miRNA molecules stick around in a cell, they reduce the production of proteins from their target mRNAs,” explains Dr.

Yale Professor Argues That MSC-Derived Exosomes, Rather Than MSCs Themselves, May Be Superior Treatment for Cytokine Storm in COVID-19; Also Says Convalescent Plasma Contains Trillions of Exosomes with Unknown Effects and May Interfere with Antibodies

In an open-access article published online as an editorial in The Journal of Extracellular Vesicles on November 14, 2020, (, Philip Askenase (photo), MD, Professor of Medicine and Pathology, Section of Rheumatology and Clinical Immunology, Department of Internal Medicine, Yale University School of Medicine, (and former 30-Year Chief of Allergy & Clinical Immunology at Yale), argues that, with regard to treatment of severe COVID-19 patients, mesenchymal stromal cell (MSC)-derived-exosomes, rather than MSCs themselves, are likely superior for therapy of the severe pneumonia and cytokine storm. The editorial is titled "COVID-19 Therapy with Mesenchymal Stromal Cells (MSC) and Convalescent Plasma Must Consider Exosome Involvement: Do the Exosomes in Convalescent Plasma Antagonize the Weak Immune Antibodies?" Dr. Askenase notes that MSCs are increasingly being used as possible treatments for COVID-19 and other serious conditions, but that their released exosomes are equivalent, safer, and more convenient. Dr. Askenase states that the exosomes themselves would thus be a better therapeutic choice versus the MSCs. In support of this assertion, he notes that many reports in the literature, and his group’s own data on treatment of spinal cord injury (PLoS One, 2018 Jan 2; 13(1):e0190358; doi: 10.1371/journal.pone.0190358) ( showed that the release of exosomes from the in-vivo-systemically-administered MSCs is actually responsible for the MSC-associated beneficial effects. Furthermore, he emphasizes again that exosomes are simpler, safer, and clinically much more convenient compared to their parental MSCs. Concerning side effects in the context of COVID‐19, Dr.

Moderna’s COVID-19 Vaccine Candidate Meets Primary Efficacy Endpoint in First Interim Analysis of Phase 3 COVE Study; Vaccine Shows 94.5% Efficacy in Early Results

On November 16, 2020, Moderna, Inc. (Nasdaq: MRNA), a biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, today announced that the independent, NIH-appointed Data Safety Monitoring Board (DSMB) for the Phase 3 study of mRNA-1273, its vaccine candidate against COVID-19, has informed Moderna that the trial has met the statistical criteria pre-specified in the study protocol for efficacy, with a vaccine efficacy of 94.5%. This study, known as the COVE study, enrolled more than 30,000 participants in the U.S. and is being conducted in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the Biomedical Advanced Research and Development Authority (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services. The primary endpoint of the Phase 3 COVE study is based on the analysis of COVID-19 cases confirmed and adjudicated starting two weeks following the second dose of vaccine. This first interim analysis was based on 95 cases, of which 90 cases of COVID-19 were observed in the placebo group versus 5 cases observed in the mRNA-1273 group, resulting in a point estimate of vaccine efficacy of 94.5% (p <0.0001). A secondary endpoint analyzed severe cases of COVID-19 and included 11 severe cases (as defined in the study protocol) in this first interim analysis. All 11 cases occurred in the placebo group and none in the mRNA-1273 vaccinated group.

Leronlimab Treatment Inhibits CCR5 in Critically Ill COVID-19 Patients--Decreasing Inflammatory Cytokines, Increasing CD8 T-Cells, and Decreasing SARS-CoV-2 RNA in Plasma by Day 14

Researchers have reported that treatment of ten critically ill COVID-19 patients with the anti-CCR5 monoclonal antibody leronlimab restored depressed CD8 counts which correlated inversely with decreases in plasma viral load of SARS-CoV-2, which moved to undectable by Day 14 of treatment, and that 6 of 10 treated patients showed significant improvement during the 14-day test period. The scientists noted that levels of the normal CCR5-binding immunomodulatory molecule CCL5/RANTES is elevated 3- to 5-fold in mild to moderate COVID patients and over 1000-fold in critical COVID patients, suggesting that blocking the binding of this immunomodulatory molecule might have an influence in COVID-19. The newly reported results include the first report of the highly sensitive measurement of quantitative plasma viral load by droplet digital PCR (ddPCR) in COVID patients. The researchers also described a statistically significant drop in interleukin-6 (IL-6) by Day 14 of leronlimab treatment. In addition, single-cell transcriptome analysis revealed decreased in IL-6 in myeloid cells. The work was reported online on November 9, 2020, in the International Journal of Infectious Diseases. The open-access article is titled “CCR5 Inhibition in Critical COVID-19 Patients Decreases Inflammatory Cytokines, Increases CD8 T-Cells, and Decreases SARS-CoV2 RNA in Plasma by Day 14” ( The authors conclude that, while the current study design precludes clinical efficacy inferences, the results implicate CCR5 as a therapeutic target for COVID-19 and form the basis for ongoing randomized clinical trials. Leronlimab is produced by CytoDyn, Inc., a Vancouver, Washington-based, late-stage biotechnology company (

Why Does COVID-19 Seem to Spare Children? Research Shows Lower Expression of Key TMPRSS2 Enzyme Used to Aid Viral Fusion to Target Cells

Researchers at Vanderbilt University Medical Center (VUMC) and their colleagues have determined a key factor as to why COVID-19 appears to infect and sicken adults and older people preferentially, while seeming to spare younger children. Children have lower levels than adults of an enzyme/co-receptor (TMPRSS2) (image) that SARS-CoV-2, the RNA virus that causes COVID-19, needs to invade airway epithelial cells in the lung. The findings, published online on November 12, 2020 in the Journal of Clinical Investigation, support efforts to block the enzyme to potentially treat or prevent COVID-19 in older people. The article is titled “Age-Determined Expression of Priming Protease TMPRSS2 and Localization of SARS-CoV-2 in Lung Epithelium.” "Our study provides a biologic rationale for why particularly infants and very young children seem to be less likely to either get infected or to have severe disease symptoms," said Jennifer Sucre, MD, Assistant Professor of Pediatrics (Neonatology), who led the research with Jonathan Kropski, MD, Assistant Professor of Medicine. Dr. Sucre and Dr. Kropski are co-corresponding authors of the JCI aticle. Bryce Schuler, MD, PhD, a resident in Pediatrics and Genetics at VUMC and postdoctoral fellow in the Vanderbilt Stimulating Access to Research in Residency program, is the paper's first author. There is still much to learn about SARS-CoV-2. But this much is known: after a viral particle is inhaled into the lungs, protein "spikes" that stick out from the virus body like nail studs in a soccer ball attach to ACE2, a receptor on the surfaces of certain lung cells.A cellular enzyme called TMPRSS2 (transmembrane protease, serine 2) ( slices up the spike protein, enabling the virus to fuse into the cell membrane and "break into" the cell.

Dublin Researcher Wins 2020 AbbVie Innovation Award to Develop Biomarkers for Multiple Sclerosis

On November 12, 2020, it was announced that Paulina Szklanna (photo), PhD, has won the 2020 University College Dublin (UCD) AbbVie Innovation Award for the potential within her research to develop an affordable clinical tool based on blood-borne markers to track the progression of multiple sclerosis over time. AbbVie ( is a publicly traded biopharmaceutical company. Multiple sclerosis (MS) is an inflammatory and neurodegenerative condition that remains the most common cause of non-traumatic disability in young adults. 9,000 Irish people are currently living with MS and their individual disease progression is highly variable. Clinically predicting the course of the disease remains a huge challenge and biomarkers are urgently required to help in this effort. Dr. Szklanna and her colleagues have uncovered biomarkers released in the blood from platelets, the fragments involved in blood clotting. They used an interdisciplinary platform called PALADINTM or platelet-based diagnostics, which draws on cutting-edge biomedical, clinical, and machine learning know-how. The team uses these blood-borne markers with AI_PredictMS (Artificial Intelligence to Predict the future in Multiple Sclerosis); a prototype risk stratification solution for MS. In a recent trial, the researchers have shown that AI_PredictMS can differentiate between people with milder and people with more debilitating forms of multiple sclerosis with 97% accuracy. Dr. Szklanna is an early-career researcher working in the UCD Conway SPHERE group led by Professor Patricia Maguire, PhD, UCD School of Biomolecular & Biomedical Science and Professor Fionnuala Ni Ainle, MD, PhD, UCD School of Medicine. This award will provide Dr Szklanna with a research bursary of €8,000 (~$10,550) to enable her to advance her research.

Two Targeted Therapies Being Developed to Treat Idiopathic Pulmonary FIbrosis (IPF)

New treatment options for lung fibrosis are being developed by Purdue University scientists. People with idiopathic pulmonary fibrosis (IPF) have a life expectancy of less than five years. Fibrotic diseases cause organ failure that lead to about 45% of all deaths in the United States. Lung fibrosis has been a concern for COVID-19 patients. Existing therapies do little to slow progression. Now, Philip S. Low, (, PhD, the Purdue Ralph C. Corley Distinguished Professor of Chemistry and Presidential Scholar for Drug Discovery, has led a team to develop two targeted therapies for people with idiopathic pulmonary fibrosis. The two different therapeutic approaches are published in the October 28, 2020 issue of Science Translational Medicine (“Targeted Inhibition of PI3 Kinase/mTOR Specifically in Fibrotic Lung Fibroblasts Suppresses Pulmonary Fibrosis in Experimental Models”) and online on June 29, 2020 in EMBO Molecular Medicine (“Reprogramming of Profibrotic Macrophages for Treatment of Bleomycin‐Induced Pulmonary Fibrosis”). "This is a horrible disease that claimed the lives of my next-door neighbor and a good friend's wife," Dr. Low said. "We developed two targeted therapies that allow us to use powerful drugs with high toxicities because we specifically deliver them to diseased cells without harming healthy ones." The first of the Purdue team's novel targeted molecules is designed to slow fibrosis and extend life. The second IPF therapy suppresses fibrosis-inducing cytokine production. The two therapies will be moving into human clinical trials within the next several months. The developments come as a number of people with COVID-19 or who have recovered from COVID-19 experience lung fibrosis or other related conditions.

Researchers Find New "Overlapping Gene" in COVID-19 Virus; Same Gene (ORF3d) Has Been Identified in Coronavirus from Pangolin Mammals Used in Traditional Chinese Medicine; ORF3d Gene Product Produces Strong Antibody Response In COVID-19 Patients

A new gene (ORF3d) has been identified in SARS-CoV-2—the virus that causes COVID-19—that may have contributed to its unique biology and pandemic potential. SARS-CoV-2 (image at left) only has about 15 genes, so knowing more about this and other overlapping genes—or “genes within genes”—could have a significant impact on how we combat the virus, scientists say. The description of the new gene, which is also found in a pangolin coronavirus, was published online on October 1, 2020 in the journal eLife ( [Editor’s Note: Pangolins are long-snouted, ant-eating mammals often used in traditional Chinese medicine.] The open-access eLife article is titled “Dynamically Evolving Novel Overlapping Gene As a Factor in the SARS-Cov-2 Pandemic.” “Overlapping genes may be one of an arsenal of ways in which coronaviruses have evolved to replicate efficiently, thwart host immunity, or get themselves transmitted,” said lead author Chase Nelson, PhD, a postdoctoral researcher at Academia Sinica in Taiwan and a visiting scientist at the American Museum of Natural History (AMNH) in New York City. “Knowing that overlapping genes exist and how they function may reveal new avenues for coronavirus control, for example through antiviral drugs.” Rather than discrete blocks that convey a particular set of information, genes can be overlapping and multifunctional, with information cryptically encoded depending on where you start “reading” them. Such “overlapping genes” are hard to spot, but they are common in viruses, where one letter in a genome can contribute to two or even three different genes. “Missing overlapping genes puts us in peril of overlooking important aspects of viral biology,” said Dr. Nelson.

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