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Researchers discover that the COVID-19 virus can trigger the production of 'abzymes' -- antibodies that act like enzymes -- which may explain why long COVID symptoms persist even after the infection is cleared. UVA Health researchers have discovered a potential explanation for some of the most perplexing mysteries of COVID-19 and long COVID. The surprising findings could lead to new treatments for the difficult acute effects of COVID-19, long COVID and possibly other viruses. Researchers led by UVA's Steven L. Zeichner, MD, PhD, found that COVID-19 may prompt some people's bodies to make antibodies that act like enzymes that the body naturally uses to regulate important functions -- blood pressure, for example. Related enzymes also regulate other important body functions, such as blood clotting and inflammation. Doctors may be able to target these "abzymes" to stop their unwanted effects. If abzymes with rogue activities are also responsible for some of the features of long COVID, doctors could target the abzymes to treat the difficult and sometimes mysterious symptoms of COVID-19 and long COVID at the source, instead of merely treating the downstream symptoms. "Some patients with COVID-19 have serious symptoms and we have trouble understanding their cause. We also have a poor understanding of the causes of long COVID," said Zeichner, a pediatric infectious disease expert at UVA Children's. "Antibodies that act like enzymes are called 'abzymes.' Abzymes are not exact copies of enzymes and so they work differently, sometimes in ways that the original enzyme does not. If COVID-19 patients are making abzymes, it is possible that these rogue abzymes could harm many different aspects of physiology. If this turns out to be true, then developing treatments to deplete or block the rogue abzymes could be the most effective way to treat the complications of COVID-19." Understanding COVID-19 Abzymes SARS-CoV-2, the virus that causes COVID, has protein on its surface called the Spike protein. When the virus begins to infect a cell, the Spike protein binds a protein called Angiotensin Converting Enzyme 2, or ACE2, on the cell's surface. ACE2's normal function in the body is to help regulate blood pressure; it cuts a protein called angiotensin II to make a derivative protein called angiotensin 1-7. Angiotensin II constricts blood vessels, raising blood pressure, while angiotensin 1-7 relaxes blood vessels, lowering blood pressure. Zeichner and his team thought that some patients might make antibodies against the Spike protein that looked enough like ACE2 so that the antibodies also had enzymatic activity like ACE2, and that is exactly what they found. Recently, other groups have found that some patients with long COVID have problems with their coagulation systems and with another system called "complement." Both the coagulation system and the complement system are controlled by enzymes in the body that cut other proteins to activate them. If patients with long COVID make abzymes that activate proteins that control processes such as coagulation and inflammation, that could explain the source of some of the long COVID symptoms and why long COVID symptoms persist even after the body has cleared the initial infection. It also may explain rare side effects of COVID-19 vaccination. To determine if antibodies could be having unexpected effects in COVID patients, Zeichner and his collaborators examined plasma samples collected from 67 volunteers with moderate or severe COVID on or around day 7 of their hospitalization. The researchers compared what they found with plasma collected in 2018, prior to the beginning of the pandemic. The results showed that a small subset of the COVID patients had antibodies that acted like enzymes. While our understanding of the potential role of abzymes in COVID-19 is still in its early stages, enzymatic antibodies have already been detected in certain cases of HIV, Zeichner notes. That means there is precedent for a virus to trigger abzyme formation. It also suggests that other viruses may cause similar effects. Zeichner, who is developing a universal coronavirus vaccine, expects UVA's new findings will renew interest in abzymes in medical research. He also hopes his discovery will lead to better treatments for patients with both acute COVID-19 and long COVID. "We now need to study pure versions of antibodies with enzymatic activity to see how abzymes may work in more detail, and we need to study patients who have had COVID-19 who did and did not develop long COVID," he said. "There is much more work to do, but I think we have made a good start in developing a new understanding of this challenging disease that has caused so much distress and death around the world. The first step to developing effective new therapies for a disease is developing a good understanding of the disease's underlying causes, and we have taken that first step." Findings Published The researchers have published their findings in the scientific journal mBio, a publication of the American Society for Microbiology. The research team consisted of Yufeng Song, Regan Myers, Frances Mehl, Lila Murphy, Bailey Brooks, and faculty members from the Department of Medicine, Jeffrey M. Wilson, Alexandra Kadl, Judith Woodfolk. "It's great to have such talented and dedicated colleagues here at UVA who are excited about working on new and unconventional research projects," said Zeichner. Zeichner is the McClemore Birdsong Professor in the University of Virginia School of Medicine's Departments of Pediatrics and Microbiology, Immunology and Cancer Biology; the director of the Pendleton Pediatric Infectious Disease Laboratory; and part of UVA Children's Child Health Research Center. The abzyme research was supported by UVA, including the Manning Fund for COVID-19 Research at UVA; the Ivy Foundation; the Pendleton Laboratory Fund for Pediatric Infectious Disease Research; a College Council Minerva Research Grant; the Coulter Foundation; and the National Institutes of Health's National Institute of Allergy and Infection Diseases, grant R01 AI176515. Additional support came from the HHV-6 Foundation.

近日（3月25日），丹麦的制药巨头诺和诺德宣布将收购一家专注于心脏病的德国Biotech公司Cardior Pharmaceuticals。诺和诺德表示交易总价值约为11亿美元（10.25亿欧元）。该金额包括预付款以及取决于某些开发和商业里程碑的额外付款。近年来，大药厂对于心血管领域的布局越来越频繁，而诺和诺德也是如此，例如自家的司美格鲁肽跨界应用和IL-6抑制剂ziltivekimab等等。而此次诺和诺德看重的是Cardior的核心管线CDR132L，这是全球首个进入心脏病临床试验的基于非编码RNA的疗法。CDR132L与心衰心衰是世界上导致死亡的主要病症之一。目前使用的心力衰竭的治疗药物选项包括血管紧张素调节剂、β受体阻滞剂、利尿剂、醛固酮拮抗剂、血管紧张素I-受体阻滞剂与脑啡肽酶抑制剂、血管扩张剂、正性肌力剂或SGLT-2抑制剂的组合。尽管几项临床研究已显示，所有这些药剂均可显著降低心力衰竭诱发的死亡率，但5年死亡率仍令人难以接受地高达近50％。因此，非常需要开发新型且更高效的心力衰竭治疗方法。心肌肥大是心衰的重要原因，最初心脏肥大是一种生理上的代偿机制，旨在减小壁应力和增加心输出量。然而，长时间的心脏肥大就会发展为收缩功能障碍、心脏代偿失调和最终导致心力衰竭。这其中就涉及许多关键心肌肥大信号。miRNA正好能在这种不利的心脏重构中起着关键作用，Cardior的研究团队2013年就发现miR-132通过靶标转录因子FOXO3起作用，可以诱导心脏肥大，反之抑制miR-132就有可能治疗心脏肥大引起的心衰。CDR132L就是这一发现临床转化的产物。CDR132L是心肌细胞中miR-132表达的有效抑制剂，是由DNA和LNA构件(building block)组成的混合物，具有核苷间硫代磷酸酯键联。根据专利可知可能结构如下所示：目前CDR132L已在多国布局专利：CDR132L的临床意义目前现有技术的心力衰竭药物疗法主要局限于不太晚期的疾病阶段(纽约心脏协会NYHA设定了I期和II期；NYHA I/II)。然而，现有的治疗药物不能阻止至晚期(NYHA的III期和IV期)的进展，而这些晚期患者往往频繁住院，1年死亡率甚至超过70％。作为最后的手段，植入泵(左心室辅助装置，LVAD)和最终的心脏移植可能是极少数末期心力衰竭患者唯一的救命选择。然而，这两种最后手段价格需求极高：①LVAD的安装和维护费用极高，包括设备本身的成本、手术费、住院费、后期定期维护和更换电池等费用。②心脏移植其费用同样非常高昂，而且还有心脏供体的稀缺问题，价格方面涵盖了手术费、供体心脏获取费用、手术前后长期的免疫抑制药物费用、康复治疗费用以及可能发生的并发症治疗费用。他人的心脏还存在排异问题，还需要长期观察，一旦出现问题后果可能严重。因此，迫切需要降低死亡率和住院率的新型、高效的疾病中止疗法来为患者提供治愈希望。而CDR132L作为下一代心衰药物可以通过钙信号传导和收缩性以及心脏功能的正常化，改变心脏自噬和稳态，适应不良的心脏重构的减弱。而在I期临床中，CDR132L展现出了对多个生物标志物和关键指标的改善：比如，对心脏的射血分数(EF)有积极影响，NT-proBNP作为心脏安全标志物未受到CDR132L治疗的不利影响。，这表明心室舒张功能障碍的患者可以从中受益。又比如，心脏纤维化生物标志物I型前胶原蛋白C端前肽(PICP)和半乳糖凝集素-3(Gal-3)在CDR132L治疗的心衰患者中显示水平降低，表明具有抗纤维化作用。而CDR132L在心脏组织内的半衰期约为3周，安全性良好，未发现严重不良事件。目前CDR132L正处于II期临床，尝试在心肌梗死患者中进行恢复治疗。未来这一疗法可能向与标准治疗联用等方法开发。对于诺和诺德的意义有趣的是，对于诺和诺德来说，司美格鲁肽在心血管方面的益处已经通过监管机构的审批而可能在跨界市场占据巨大的优势。但是……如果不是肥胖的患者，那可能就无法享受这一益处。而恰巧CDR132L的治疗范围，反而选定在并不是那么肥胖的患者中，收购CDR132L意味着覆盖面不会重叠，或者是肥胖的患者瘦身下来后，可以继续服用CDR132L来确保对心脏功能重建的益处。不仅不会和司美格鲁肽冲突，还能恰巧适配。另外考虑到CDR132L的临床大多集中在欧洲，在获得诺和诺德的青睐后，该药品可以迅速在全球开展临床，同时也有已申请专利保护未来市场。总结总的来说，CDR132L具有一定潜力，此次被诺和诺德收购也是对潜力的认可，有可能加入现有联合疗法增强疗效，当然潜在的挑战也有，如CDR132L的持久性，停药后是否会反弹，是否对心脏以外的miR-132也有靶向作用等等，可以期待未来的发展情况。

THE WOODLANDS, Texas, March 25, 2024 (GLOBE NEWSWIRE) -- Lexicon Pharmaceuticals, Inc. (Nasdaq: LXRX) today announced that four data presentations related to sotagliflozin, an inhibitor of two sodium glucose transport proteins (SGLT2 and SGLT1), will be delivered during the American College of Cardiology 73rd Annual Scientific Session & Expo being held April 6 - 8, 2024 in Atlanta, Georgia, including results from a post-hoc evaluation of the efficacy of sotagliflozin in reducing stroke events in patients with type 2 diabetes, chronic kidney disease (CKD), and high cardiovascular (CV) risk in the SCORED Phase 3 clinical trial. “Following FDA’s 2023 approval of INPEFA® (sotagliflozin) for heart failure (HF), researchers are adding to the overall scientific understanding of sotagliflozin, including clinical evidence of its ability to reduce the risk of stroke and myocardial infarction (MI), or heart attack,” said Craig Granowitz, M.D., Ph.D., Lexicon’s senior vice president and chief medical officer. Details of the presentations are as follows: Sotagliflozin Reduces Stroke Outcomes in Patients with Diabetes and Chronic Kidney Disease – a moderated poster presentation, Monday, April 8, 12:15 - 12:25 p.m. ET, Theater 8‚ presented by Rahul Aggarwal, M.D., Icahn School of Medicine at Mount Sinai, New York, New YorkStudy researchers evaluated the efficacy of sotagliflozin in reducing all-cause and cause-specific stroke outcomes among patients with type 2 diabetes, CKD, and high CV risk. In a post-hoc analysis of data from the 10,584 patients in the SCORED Phase 3 clinical trial, 213 all-cause stroke events occurred, including 29 (13.6%) fatal events. Sotagliflozin reduced the risk of all-cause stroke by 34%, with 1.2 events per 100 patient-years in the sotagliflozin group and 1.8 events per 100 patient-years in the placebo group. Similarly, sotagliflozin reduced the risk of ischemic stroke by 32%, with 0.8 events per 100 patient-years in the sotagliflozin group and 1.2 events per 100 patient-years in the placebo group.Click here to access additional study details in the online abstract. Sotagliflozin, a Dual SGLT 1 and 2 Inhibitor, Modulated Expression of Glucose Transport and Inflammatory Proteins in Endothelial Cells following Angiotensin II Stimulation – a poster presentation, Sunday, April 7, 1:15 – 2:00 p.m. ET, 1425-157, Hall B4-5, presented by Preston Mason, Ph.D. MBA, Elucida Research, Beverly, MassachusettsStudy researchers found that sotagliflozin modulated expression of proteins linked to the Akt signaling pathway, glucose transport and vasodilation in human endothelial cells exposed to an inflammatory stimulus in vitro. The favorable endothelial cell actions of sotagliflozin during inflammation add to the body of knowledge of sotagliflozin’s mechanism of action and are consistent with the reduced atherothrombotic risk demonstrated in outcome trials.Click here to access additional study details in the online abstract. Sotagliflozin, a First-in-Class SGLT1/2 Inhibitor, Inhibits Clotting Potential in the Vessel via Inhibition of Platelet Activation, Integrin Activation, and Aggregation in Human Platelets – a moderated poster presentation, Sunday, April 7, 11:30 - 2:40 a.m. ET, Theater 5‚ presented by Livia Stanger, Ph.D. Candidate, University of Michigan, Ann Arbor, MichiganStudy researchers found that sotagliflozin inhibits platelet activation through simultaneously targeting SGLT1 and SGLT2. These findings provide insight into the potential mechanism by which sotagliflozin impacts stroke and MI risk in patients with type 2 diabetes and CKD and provides a basis for further studies to explore the role of sotagliflozin for CV protection in patients at increased risk for ischemic events.Click here to access study details in the online abstract. Temporal Shift in Heart Failure Medications Prescribed to Hospitalized Patients According to Sex and Age. Results from Two Large US Integrated Health Systems – a poster presentation, Sunday, April 7, 9:15 – 10:00 a.m. ET, 1343-121, Hall B4-5, presented by Mario Enrico Canonico, M.D., Ph.D., CPC Clinical Research, University of Colorado, Aurora, ColoradoStudy researchers found that substantial opportunity exists to further improve the prescription of guideline-directed medical therapy (GDMT) for patients with HF. Differences in timing of initiation of these therapies by sex and age highlight the need to evaluate care gaps by these and other determinants of health.Click here to access additional study details in the online abstract. On May 26, 2023, the U.S. Food and Drug Administration approved INPEFA® (sotagliflozin), a once-daily oral tablet, to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with: heart failure ortype 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. About Lexicon Pharmaceuticals Lexicon is a biopharmaceutical company with a mission of pioneering medicines that transform patients’ lives. Through its Genome5000™ program, Lexicon scientists studied the role and function of nearly 5,000 genes and identified more than 100 protein targets with significant therapeutic potential in a range of diseases. Through the precise targeting of these proteins, Lexicon is pioneering the discovery and development of innovative medicines to treat diseases safely and effectively. Lexicon has advanced multiple medicines to market and has a pipeline of promising drug candidates in heart failure, neuropathic pain, diabetes and metabolism and other indications. For additional information, please visit www.lexpharma.com. About INPEFA® (sotagliflozin) Discovered using Lexicon’s unique approach to gene science, INPEFA® (sotagliflozin) is an oral inhibitor of two proteins responsible for glucose regulation known as sodium-glucose cotransporter types 2 and 1 (SGLT2 and SGLT1). SGLT2 is responsible for glucose reabsorption by the kidney and SGLT1 is responsible for glucose absorption in the gastrointestinal tract. INPEFA has been studied in multiple patient populations encompassing heart failure, diabetes, and chronic kidney disease in clinical studies involving approximately 20,000 patients. INDICATION INPEFA is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with: heart failure ortype 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors IMPORTANT SAFETY INFORMATION Dosing: Assess renal function and volume status and, if necessary, correct volume depletion prior to initiation of INPEFA. INPEFA dosing for patients with decompensated heart failure may begin when patients are hemodynamically stable, including when hospitalized or immediately upon discharge. Contraindications: INPEFA is contraindicated in patients with hypersensitivity to any component. Warnings and Precautions: Ketoacidosis: INPEFA increases the risk of ketoacidosis in patients with type 1 diabetes mellitus (T1DM). Type 2 diabetes mellitus (T2DM) and pancreatic disorders are also risk factors. The risk of ketoacidosis may be greater with higher doses. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes using sodium glucose transporter 2 (SGLT2) inhibitors. Before initiating INPEFA, assess risk factors for ketoacidosis. Consider ketone monitoring in patients with T1DM and consider ketone monitoring in others at risk for ketoacidosis, and educate patients on the signs/symptoms of ketoacidosis. Patients receiving INPEFA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis. Assess patients who present with signs and symptoms of metabolic acidosis or ketoacidosis, regardless of blood glucose level. If suspected, discontinue INPEFA, evaluate, and treat promptly. Monitor patients for resolution of ketoacidosis before restarting INPEFA. Volume Depletion: INPEFA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR < 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INPEFA in patients with one or more of these characteristics, assess volume status and renal function, and monitor for signs and symptoms of hypotension during therapy. Urosepsis and Pyelonephritis: Treatment with SGLT2 inhibitors, including INPEFA, increases the risk for urinary tract infections. Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly. Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INPEFA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used with INPEFA. Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Reports of Fournier’s Gangrene, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors. Assess patients who present with pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INPEFA, closely monitor patient signs and symptoms, and provide appropriate alternative therapy for heart failure. Genital Mycotic Infections: INPEFA increases the risk of genital mycotic infections. Monitor and treat as appropriate. Urinary Glucose Test and 1,5-anhydroglucitol (1,5-AG) Assay: these are not reliable for patients taking SGLT2 inhibitors. Use alternative testing methods to monitor glucose levels. Common Adverse Reactions: the most commonly reported adverse reactions (incidence ≥ 5%) were urinary tract infection, volume depletion, diarrhea, and hypoglycemia. Drug Interactions: Digoxin: Monitor patients appropriately as there is an increase in the exposure of digoxin when coadministered with INPEFA 400 mg.Uridine 5'-diphospho-glucuronosyltransferase (UGT) Inducer: The coadministration of rifampicin, an inducer of UGTs, with sotagliflozin resulted in a decrease in the exposure of sotagliflozin.Lithium: Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INPEFA initiation and with dosage changes. Use in Specific Populations: Pregnancy and Lactation: INPEFA is not recommended during the second and third trimesters of pregnancy, nor while breastfeeding.Geriatric Use: No INPEFA dosage change is recommended based on age. No overall differences in efficacy were detected between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be at increased risk for volume depletion adverse reactions, including hypotension.Renal Impairment: INPEFA was evaluated in patients with chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m2) and in patients with heart failure with eGFR <60 mL/min/1.73 m2. The safety profile of INPEFA across eGFR subgroups in these studies was consistent with the known safety profile. There was an increase in volume-related adverse events (e.g., hypotension, dizziness) in patients with eGFR <30 mL/min/1.73m2 relative to the overall safety population. Efficacy and safety studies with INPEFA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. After starting therapy in the studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m2 or were initiated on chronic dialysis.Hepatic Impairment: INPEFA is not recommended in patients with moderate or severe hepatic impairment. Click here for full Prescribing Information. Safe Harbor Statement This press release contains “forward-looking statements,” including statements relating to the therapeutic and commercial potential, research and clinical development and regulatory status of INPEFA® (sotagliflozin). In addition, this press release also contains forward looking statements relating to Lexicon’s financial position and long-term outlook on its business, growth and future operating results, discovery and development of products, strategic alliances and intellectual property, as well as other matters that are not historical facts or information. All forward-looking statements are based on management’s current assumptions and expectations and involve risks, uncertainties and other important factors, specifically including Lexicon’s ability to meet its capital requirements, successfully commercialize INPEFA in heart failure on the timeline and/or at the prices currently contemplated or at all, conduct preclinical and clinical development and obtain necessary regulatory approvals of INPEFA (in other indications), LX9211 and its other drug candidates on its anticipated timelines, achieve its operational objectives, obtain patent protection for its discoveries and establish strategic alliances, as well as additional factors relating to manufacturing, intellectual property rights, and the therapeutic or commercial value of its drug candidates. Any of these risks, uncertainties and other factors may cause Lexicon’s actual results to be materially different from any future results expressed or implied by such forward-looking statements. Information identifying such important factors is contained under “Risk Factors” in Lexicon’s annual report on Form 10-K for the year ended December 31, 2023 and other subsequent disclosure documents filed with the Securities and Exchange Commission. Lexicon undertakes no obligation to update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise. For Investor Inquiries:Lisa DeFrancescoLexicon Pharmaceuticals, Inc.lexinvest@lexpharma.com For Media Inquiries:Alina CocuzzaLexicon Pharmaceuticals, Inc.acocuzza@lexpharma.com