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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, (https://www.chem.purdue.edu/people/profile/plow), 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 (https://elifesciences.org/articles/59633). [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.

Discovery in Rare Neonatal Diabetes May Offer Clues to Common Diabetes Affecting Millions; Mutations in YIPF1 Gene Found to Cause Rare Neonatal Diabetes; Gene Essential for Insulin-Producing Beta Cells; Malfunction Causes Fatal Cell Stress

Solving the genetic puzzle of why babies developed a rare type of diabetes has uncovered a new biological pathway that is fundamental to insulin production, and could boost research into new treatments for more common forms of diabetes. Published on November 9, 2020 in the Journal of Clinical Investigation, the study used genome sequencing to reveal that a group of babies with shared clinical features, who developed diabetes soon after birth, all had genetic changes in the YIPF5 gene. The research combined stem cell research and CRISPR gene editing tools to show that this gene is essential for function of the cells producing insulin. The article is titled “YIPF5 Mutations Cause Neonatal Diabetes and Microcephaly Through Endoplasmic Reticulum Stress” (https://www.jci.org/articles/view/141455). The research article is accompanied by a commentary titled “YIPF5 Mutations Cause Neonatal Diabetes and Microcephaly: Progress for Precision Medicine and Mechanistic Understanding” (https://www.jci.org/articles/view/142364). The research team, led by scientists at the University of Exeter (UK), the Université Libre de Bruxelles (Belgium), and University of Helsinki (Finland), working with other international collaborators, went on to show how these genetic changes result in high levels of stress within the cells, causing cell death. The study shows for the first time that YIPF5 gene function is essential for neurons and insulin-producing beta cells, but appears to be dispensable for the function of other cells.

Lilly's Neutralizing Anti-Spike-Protein Antibody Bamlanivimab (LY-Cov555) Receives FDA Emergency Use Authorization for Treatment of Recently Diagnosed COVID-19 in High-Risk Patients

On November 9, 2020, the U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for Eli Lilly and Company's (NYSE: LLY) investigational neutralizing antibody bamlanivimab (LY-CoV555) 700 mg. Bamlanivimab is a recombinant, human IgG1 monoclonal antibody (mAb) directed against the spike protein of SARS-CoV-2. It is designed to block viral attachment and entry into human cells, thus neutralizing the virus, potentially treating COVID-19. Bamlanivimab is authorized for the treatment of mild to moderate COVID-19 in adults and pediatric patients 12 years and older with a positive COVID-19 test, who are at high risk for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab should be administered as soon as possible after a positive COVID-19 test and within 10 days of symptom onset. The authorization allows for the distribution and emergency use of bamlanivimab, which is administered via a single intravenous infusion. "This emergency authorization allows us to make bamlanivimab available as a COVID-19 treatment for recently diagnosed, high-risk patients--adding a valuable tool for doctors fighting the now-increasing burden of this global pandemic," said David A. Ricks, MBA, Lilly's Chairman and CEO. "The rapid development and availability of bamlanivimab could not have been achieved without the relentless work of our Lilly team, collaboration across the industry, and the urgent work being done by the government to ensure appropriate allocation to patients who need it the most." The EUA is based on data from BLAZE-1, a randomized, double-blind, placebo-controlled Phase 2 study in patients with recently diagnosed mild to moderate COVID-19 in the outpatient setting. Patients treated with bamlanivimab showed reduced viral load and rates of symptoms and hospitalization.

Vaccine Candidate Against COVID-19 Achieves Greater Than 90% Effectiveness in First Interim Analysis from Ongoing Phase 3 Study, Pfizer and BioNTech Announce; "Great Day for Science & Humanity," Pfizer CEO States

On November 9, 2020, Pfizer Inc. (NYSE: PFE) and BioNTech SE (Nasdaq: BNTX) announced that their mRNA-based vaccine candidate, BNT162b2, against SARS-CoV-2 has demonstrated evidence of efficacy against COVID-19 in participants without prior evidence of SARS-CoV-2 infection, based on the first interim efficacy analysis conducted on November 8, 2020 by an external, independent Data Monitoring Committee (DMC) from the Phase 3 clinical study. After discussion with the FDA, the companies recently elected to drop the 32-case interim analysis and conduct the first interim analysis at a minimum of 62 cases. Upon the conclusion of those discussions, the evaluable case count reached 94 and the DMC performed its first analysis on all cases. The case split between vaccinated individuals and those who received the placebo indicates a vaccine efficacy rate above 90%, at 7 days after the second dose. This means that protection is achieved 28 days after the initiation of the vaccination, which consists of a 2-dose schedule. As the study continues, the final vaccine efficacy percentage may vary. The DMC has not reported any serious safety concerns and recommends that the study continue to collect additional safety and efficacy data as planned. The data will be discussed with regulatory authorities worldwide. “Today is a great day for science and humanity. The first set of results from our Phase 3 COVID-19 vaccine trial provides the initial evidence of our vaccine’s ability to prevent COVID-19,” said Albert Bourla, PhD, Chairman and CEO of Pfizer. “We are reaching this critical milestone in our vaccine development program at a time when the world needs it most with infection rates setting new records, hospitals nearing over-capacity, and economies struggling to reopen.

Bacterial Origins of Trench Fever in Humans Traced Back Centuries by Real-Time PCR-Based DNA Analysis of Ancient Remains; Remnants of Infections Demonstrated in Civilians As Well As Soldiers

First observed among British Expeditionary Forces in 1915, trench fever sickened an estimated 500,000 soldiers during World War I. Since then, the disease has become synonymous with the battlefield. But now, new research from an international team of scientists has uncovered evidence challenging this long-held belief. The research, published online on November 4, 2020 in PLOS ONE, outlines the discovery of DNA evidence of the disease in civilian remains predating WWI by thousands of years. In total, the team analyzed bone fragments and teeth of 145 individuals alive between the 1st and 19th centuries. Approximately 20% of those remains contained traces of Bartonella quintana, the bacteria responsible for trench fever. Davide Tanasi, PhD, an Associate Professor with the University of South Florida (USF) History Department and member of the Institute for the Advanced Study of Culture and the Environment, excavated remains for this project from a Roman cemetery in Syracuse, Sicily. Dr. Tanasi, who is also the Director of USF's Institute for Digital Exploration, first began work at the site to better understand the dietary habits and health of the Christian population living there during the 3rd and 4th centuries. Through a collaboration with French epidemiologists, researchers used real-time polymerase chain reaction (PCR) testing to detect B. quintana DNA within the remains.
"Once contracted, there are diseases, like trench fever, that can leave traces within your DNA and can integrate your DNA with further information," Dr. Tanasi said. "This means that once a person dies, even as far back as 2,000 years ago, it is still possible to find traces of the bacterium that infected them."

Hyperacylation of Key Enzymes in Pathways Known to Be Dysregulated In MMA (Methylmalonic Acidemia) Likely Contributes to Altered Metabolism and Identifies New Set of Targets for Therapeutic Intervention

On Day 3 (Thursday, October 29) of the American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (https://www.ashg.org/meetings/2020meeting/), one of the multiple stimulating morning sessions was “From Genes to Therapeutic Targets and Clinical Trials” (#031). Among the six presentations given during this session was a particularly interesting one titled “Aberrant Post-Translational Modifications Contribute to MMA Pathophysiology and Identify New Targets for Therapy,” delivered by PamelaSara Head (photo), PhD, Prat Fellow, National Institute of General Medical Sciences, NIH. In the abstract for her talk, Dr. Head noted that organic acidemias (OAs), such as methylmalonic acidemia (MMA), are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino- and fatty acids. She said that OAs are difficult to treat and have multisystemic manifestations such as hyperammonemia and ketotic hyperglycinemia (KH), leading to increased morbidity and mortality. Build-up of acyl-CoA species is postulated to cause intracellular toxicity. In the work reported here, Dr. Head and colleagues explored an alternative pathophysiological consequence of impaired acyl-CoA metabolism: i.e., the accumulation of aberrant post-translational modifications (PTMs) that modify enzymes in critical intracellular pathways. Using a mouse model that recapitulates the hepatic mitochondriopathy of MMA, the group surveyed PTMs in hepatic extracts with propionyl- and malonyl-lysine antibodies. The team discovered widespread hyper-acylation in the MMA mice compared to controls, but not in animals with Acsf3 deficiency, a disorder of acyl-CoA synthesis.

Dramatic Clinical Improvement Described in Rare Skin Disease (ILVEN) That Has Previously Proved Highly Treatment-Resistant; Treatment Choice Guided by Molecular Genetic Dissection of Disease in Two Patients That Revealed Mosaic Mutations in CARD14 Gene

On Day 3 (Thursday, October 29) of the American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (https://www.ashg.org/meetings/2020meeting/), one of the multiple stimulating morning sessions was “From Genes to Therapeutic Targets and Clinical Trials” (#031). Among the six presentations given during this session was a particularly interesting one titled “Molecular Genetic Dissection of Inflammatory Linear Verrucous Epidermal Naevus Leads to Successful Targeted Therapy,” delivered by Melissa Riachi (photo), PhD, Post-Doctoral Research Associate, Francis Crick Institute (UK). In the abstract to her talk, Dr. Riachi noted that inflammatory linear verrucous epidermal naevus (ILVEN) is a rare childhood disease characterized by Blaschko-linear erythematous scaly skin. The disease is highly pruritic, causes distressing disfigurement, and is so notoriously treatment-resistant that this characteristic forms part of the diagnostic criteria. The cause has been unknown, other than a recent single case of GJA1 mosaicism [Editor’s Note: GJA1 is the abbreviation for gap junction protein alpha 1.] Using deep next-generation whole exome sequencing of affected skin and blood, Dr. Riachi’s group discovered mosaic mutations in the gene CARD14 as the cause of ILVEN in two patients with treatment-resistant disease. [Editor’s Note: CARD14 is the acronym for caspase recruitment domain family member 14.] Functional characterization of patient cultured keratinocytes demonstrated two increased interleukins (IL-12A and IL-23A) at expression and protein levels in a non-NF-kB-dependent manner. Dramatic clinical improvement was seen with IL12/IL23-inhibitor ustekinumab, chosen as a direct result of the genetic finding.

Inhibition of HDL-Related Protein Improves Survival in Sepsis—Results Presented at American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (October 27-30)

On Day 3 (Thursday, October 29) of the American Society of Human Genetics (ASHG) 2020 Virtual Annual Meeting (https://www.ashg.org/meetings/2020meeting/), one of the multiple stimulating morning sessions was “From Genes to Therapeutic Targets and Clinical Trials” (#031) (https://www.abstractsonline.com/pp8/#!/9070/presentation/1474). Among the six presentations given during this session was a particularly interesting one titled “Genetic and Pharmacological Inhibition of Cholesteryl Ester Transfer Protein Improves Survival in Sepsis,” delivered by Mark Trinder (photo), MD/PhD Candidate and Vanier Scholar at the University of British Columbia, University of British Columbia. In the abstract to his talk, Trinder noted that sepsis is a dysregulated host response to infection that is responsible for up to 1 of 5 deaths globally. He said that numerous clinical trials have failed to identify drugs that improve outcomes from sepsis, suggesting the need for therapies that target pathways causal to the pathogenesis of the condition. Along these lines, he noted that high-density lipoprotein (HDL) particles, although best-known for their inverse association with coronary artery disease, possess many properties that are relevant to sepsis. The quantity of HDL, as reflected by the concentration of HDL cholesterol (HDL-C), declines drastically during severe infections such as sepsis and greater decline of HDL-C is associated with worse clinical outcomes. In the work described at the ASHG meeting, Trinder and colleagues tested the hypothesis that genetic or pharmacologic inhibition of cholesteryl ester transfer protein (CETP), which facilitates the metabolism of HDL-C, would decrease mortality from sepsis in humans and mice.

MSC-Derived Exosomes and Exosome-Educated Macrophages Can Differentially Improve Ligament Healing

Each year, ligament injuries sideline thousands of athletes and regular citizens. Recovery is long and painful, and sometimes a return to full function is never realized due to scar formation--a factor that makes ligament injuries prone to further damage. A new, exosome-based study published on Tuesday (November 3, 2020) in Stem Cells may lead to a welcome solution in the future. The open-access article is titled “Exosome‐Educated Macrophages and Exosomes Differentially Improve Ligament Healing.” (See image at left and, in larger view, at bottom). This study demonstrates how certain exosomes and exosome-educated macrophages can each promote ligament healing and reduce scarring. Exosomes are tiny sub-cellular membrane-bounded sacs that are released by all cells studied thus far and that can shuttle proteins and genetic information between cells. Macrophages are a type of white blood cell that typically kills microorganisms and removes dead cells, but can also stimulate the action of other immune system cells. “Educated macrophages” (EEMs) are macrophages that have been “educated” by interaction with information-conveying exosomes—in this case, mesenchymal stromal cell (MSC)-derived exosomes. Last year, the team behind the current study, researchers at the University of Wisconsin-Madison (UW-Madison), released another study (also published as an open-access article in Stem Cells) (https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/stem....) that showed how treating an Achilles tendon with EEMs reduces inflammation and improves tendon strength. The EEMs were generated by exposing CD14+ macrophages to MSC-derived exosomes. "Our previous study was done on a mouse model," said Ray Vanderby, PhD, Professor of Orthopedics and Rehabilitation at UW-Madison.

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