DDR2

Craniosynostosis, the premature fusion of the top of the skull in infants, is caused by an abnormal excess of a previously unknown type of bone-forming stem cell, according to a preclinical study. Craniosynostosis, the premature fusion of the top of the skull in infants, is caused by an abnormal excess of a previously unknown type of bone-forming stem cell, according to a preclinical study led by researchers at Weill Cornell Medicine. Craniosynostosis arises from one of several possible gene mutations, and occurs in about one in 2,500 babies. By constricting brain growth, it can lead to abnormal brain development if not corrected surgically. In complex cases, multiple surgeries are needed. In the study, which appears Sept. 20 in Nature, the researchers examined in detail what happens in the skull of mice with one of the most common mutations found in human craniosynostosis. They found that the mutation drives premature skull fusion by inducing the abnormal proliferation of a type of bone-making stem cell -- the DDR2+ stem cell -- that had never been described before. "We can now start to think about treating craniosynostosis not just with surgery but also by blocking this abnormal stem cell activity," said study co-senior author Dr. Matt Greenblatt, an associate professor of pathology and laboratory medicine at Weill Cornell Medicine and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center. The other co-senior author of the study was Dr. Shawon Debnath, a research associate in the Greenblatt laboratory. In a study published in Nature in 2018, Drs. Debnath and Greenblatt and their colleagues, described the discovery of a type of bone-forming stem cell they called the CTSK+ stem cell. Because this type of cell is present in the top of the skull, or "calvarium," in mice, they suspected that it has a role in causing craniosynostosis. In the new study, they investigated that possibility by engineering mice in which CTSK+ stem cells lack one of the genes whose loss of function causes craniosynostosis. They expected that the gene deletion somehow would induce these calvarial stem cells to go into bone-making overdrive. This new bone would fuse the flexible, fibrous material called sutures in the skull that normally allow it to expand in infants. "We were surprised to find that, instead of the mutation in CTSK+ stem cells leading to these stem cells being activated to fuse the bony plates in the skull as we expected, mutations in the CTSK+ stem cells instead led to the depletion of these stem cells at the sutures -- and the greater the depletion, the more complete the fusion of the sutures," Dr. Debnath said. The unexpected finding led the team to hypothesize that another type of bone-forming stem cell was driving the abnormal suture fusion. After further experiments, and a detailed analysis of the cells present at fusing sutures, they identified the culprit: the DDR2+ stem cell, whose daughter cells make bone using a different process than that utilized by CTSK+ cells. The team found that CTSK+ stem cells normally suppress the production of the DDR2+ stem cells. But the craniosynostosis gene mutation causes the CTSK+ stem cells to die off, allowing the DDR2+ cells to proliferate abnormally. To investigate these stem cells in human tissue, the team formed a collaboration with craniosynostosis surgeon Dr. Caitlin Hoffman, neurogeneticist Dr. Elizabeth Ross, and neuropathologist Dr. David Pisapia, all at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center; and craniosynostosis surgeon Dr. Thomas Imahiyerobo of Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian/Columbia University Irving Medical Center. The researchers found the human versions of DDR2+ stem cells and CTSK+ stem cells in calvarial samples from craniosynostosis surgeries -- underscoring the likely clinical relevance of their findings in mice. The findings suggest that inappropriate DDR2+ stem cell proliferation in the calvarium, in infants with craniosynostosis-linked gene mutations, could be treated by suppressing this stem cell population, through mimicking the methods that CTSK+ stem cells normally use to prevent expansion of DDR2+stem cells. The researchers found that the CTSK+ stem cells achieve this suppression by secreting a growth factor protein called IGF-1, and possibly other regulatory proteins. "We observed that we could partly prevent calvarial fusion by injecting IGF-1 over the calvarium," said study first author Dr. Seoyeon Bok, a postdoctoral researcher in the Greenblatt laboratory. "I can imagine DDR2+ stem cell-suppressing drug treatments being used along with surgical management, essentially to limit the number of surgeries needed or enhance outcomes," Dr. Greenblatt said. In addition to treatment-oriented research, he and his colleagues now are looking for other bone-forming stem cell populations in the skull. "This work has uncovered much more complexity in the skull than we ever imagined, and we suspect the complexity doesn't end with these two stem cell types," Dr. Greenblatt said.

AUSTIN, Texas, April 14, 2023 /PRNewswire/ -- The main results of the Magnetic Resonance Imaging Evaluation of Mineralocorticoid Receptor Antagonism in Diabetic Atherosclerosis (MAGMA) trial, a National Heart, Lung, and Blood Institute (NHLBI) sponsored trial were presented. Although the results of the trial are not final, they offer valuable information for patients using the generic drug Spironolactone. This drug therapy activates white cells and reduces tissue damage as well as reduces proteins that would normally be considered inflammatory. The results from this study will be presented at the National Kidney Foundation's (NKF) NKF Spring Clinical Meetings during the "late-breaking presentations" at the largest multidisciplinary gathering of kidney care professionals in North America from April 11-15 in Austin, Texas. My message to patients is to consider using Spironolactone as their generic drug choice if they can. QUOTE FROM RESEARCHER "My message to patients is to consider using Spironolactone as their generic drug choice if they can for appropriate indications. We want to consider using this drug in high-risk patients with diabetes and atherosclerosis, because the benefit of the drug might extend not only to preventing heart failure and kidney disease progression but potentially other benefits," explained Sanjay Rajagopalan, MD, FACC, FAHA, Chief of the Division of Cardiovascular Medicine and Chief Academic and Scientific Officer of UH Harrington Heart & Vascular Institute; Herman K. Hellerstein, MD, Chair in Cardiovascular Research and a professor at the Case Western Reserve University School of Medicine. "Having a drug that works on these systems in a connective manner is a big benefit to a patient, and this drug happens to be one of those." Highlights of the interim results include: Results: Seventy-nine patients were randomized at 4 sites in US and Canada to Spironolactone (n=37) vs placebo (n=42) for 12 months, after a 2-week single-blind placebo lead-in period and 4-week dose escalation phase. Mean age was 64±8 years; HbA1c 7.3±1.3%; eGFR 44 ml/min/1.73m2; baseline systolic BP 132 ±19 mmHg. The results demonstrated a marked reduction in thoracic plaque volume (Percent change in wall volume) response to Spironolactone at the end of 12 months compared to placebo. These changes were accompanied by changes in left ventricular mass and fibrosis. Spironolactone treatment did not change clinic systolic blood pressure but did cause a statistically significant change in 24-hour mean systolic and diastolic blood pressures compared to baseline and versus placebo respectively. Spironolactone also reduced LV wall mass and a measure of LV fibrosis (native T1 values). Plasma proteomic analysis revealed significant downregulation of a number of pathways involved in immune activation/inflammation, leukocyte activation, proliferation and pathways involved in cytokine stimulation. The top 2 molecules downregulated were DDR2, and oxidized LDL receptor-1 (LOX-1) involved in collagen synthesis and inflammation respectively. Additional top downregulated proteins included known Aldosterone targets such as Sodium/potassium-transporting ATPase subunit beta-3 and Adenylyl cyclase-associated protein 1. Data are mean ± SD. Change was defined as the value at 12 months minus the value at baseline. †p < 0.05; †††p < 0.001 Thousands of kidney care professionals will attend the Spring Clinical Meetings in-person and virtually. Hundreds of the latest studies and kidney care advances will be unveiled. NKF Spring Clinical Meetings For the past 31 years, nephrology healthcare professionals from across the country have come to NKF's Spring Clinical Meetings to learn about the newest developments related to all aspects of nephrology practice; network with colleagues; and present their research findings. The NKF Spring Clinical Meetings are designed for meaningful change in the multidisciplinary healthcare teams' skills, performance, and patient health outcomes. It is the only conference of its kind that focuses on translating science into practice for the entire healthcare team. About Kidney Disease In the United States, more than 37 million adults are estimated to have kidney disease, also known as chronic kidney disease (CKD)—and approximately 90 percent don't know they have it. About 1 in 3 adults in the U.S. are at risk for kidney disease. Risk factors for kidney disease include: diabetes, high blood pressure, heart disease, obesity, and family history. People of Black or African American, Hispanic or Latino, American Indian or Alaska Native, Asian American, or Native Hawaiian or Other Pacific Islander descent are at increased risk for developing the disease. Black or African American people are about four times as likely as White people to have kidney failure. Hispanics experience kidney failure at about double the rate of White people. NKF Professional Membership Healthcare professionals can join NKF to receive access to tools and resources for both patients and professionals, discounts on professional education, and access to a network of thousands of individuals who treat patients with kidney disease. Media Contacts:

UNIONDALE, N.Y., May 16, 2022 (GLOBE NEWSWIRE) -- Angion Biomedica Corp. (NASDAQ:ANGN), a biopharmaceutical company focused on the discovery, development, and commercialization of novel small molecule therapeutics to address fibrotic diseases, today announced U.S. Food and Drug Administration’s (FDA) acceptance of an Investigational New Drug (IND) application supporting the clinical development of ANG-3070 in idiopathic pulmonary fibrosis (IPF) and clearance to begin a Phase 1b study of ANG-3070 in patients with IPF. ANG-3070 is an oral tyrosine kinase inhibitor targeting platelet-derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ, respectively) and Discoidin Domain Receptors 1 and 2 (DDR1 and DDR2), tyrosine kinase receptors linked to the development of fibrosis in the kidneys and lungs. The Phase 1b study is intended to start enrollment and report data in 2022. IPF patients eligible for this Phase 1b study of ANG-3070 include those who have discontinued nintedanib or pirfenidone, refused treatment with nintedanib or pirfenidone, or those who are treatment naïve. Approximately 20 IPF patients will be enrolled into a crossover design trial with four arms dosing for ten days each. One arm is ANG-3070 300mg twice per day, the second arm is 500mg once per day, plus placebo-to-match arms. Patients will be enrolled in two ten-day treatment periods with either ANG-3070 or placebo with a 5 day of washout period between treatments. The primary endpoint of the study is the frequency of treatment-emergent adverse events. Secondary endpoints include standard pharmacokinetic analyses. “The acceptance of this IND for ANG-3070 in patients with IPF is an important milestone for Angion,” stated Dr. John Neylan, Angion’s Executive Vice President and Chief Medical Officer. “The results from this study will assist us in designing and enrolling a Phase 2 trial in IPF, which we expect to initiate in 2023. IPF is a serious and ultimately fatal fibrotic disease where additional treatment options are needed.” Additionally, Angion has completed multiple preclinical studies demonstrating ANG-3070’s activity in IPF models. These studies include: An in vitro study exploring ANG-3070’s ability to inhibit proliferation of normal human lung fibroblasts, key components of the fibrotic pathway in IPF. ANG-3070 successfully inhibited fibroblast proliferation in the presence of PDGF, an important confirmation of ANG-3070’s ability to inhibit a known component of IPF pathophysiology. An in vitro study of ANG-3070’s ability to affect PDGF-mediated collagen secretion by normal human lung fibroblasts. Collagen secretion is part of the final pathway contributing to the pathology of fibrotic lung tissue in IPF and other progressive fibrotic diseases. ANG-3070 abrogated collagen secretion in this model, demonstrating activity against this pathway of progressive IPF. An in vitro study exposing ANG-3070 to normal human fibroblasts and human small airway epithelial cells, the latter cells being critical to healthy lung function. The ability of ANG-3070 to effectively inhibit fibroblast activation and collagen secretion while sparing small airway epithelial cells in this model suggests potentially increased clinical benefit via protection of the small airway epithelial cells and the alveolar epithelium from further damage. “These in vitro studies provide further demonstration of ANG-3070’s potential for clinical activity in IPF,” continued Dr. Neylan. “These data complement the significant body of existing in vivo studies showing activity of ANG-3070 in both kidney and lung fibrosis, enabling us to advance a robust clinical development program for ANG-3070 in both primary proteinuric kidney diseases in our Phase 2 JUNIPER trial as well as in IPF.” IPF is an aggressive form of fibrotic lung disease with a median survival for patients between two and three years. Approximately 140,000 patients in the U.S. have been diagnosed with IPF. While both nintedanib and pirfenidone are approved in the U.S. for IPF, approximately half of IPF patients discontinue their prescriptions within one year and fewer than one-third of IPF patients are currently prescribed either drug. Nevertheless, worldwide sales for nintedanib and pirfenidone are projected to be over $3.8 billion in 2021. About ANG-3070 ANG-3070 is a highly selective oral tyrosine kinase receptor inhibitor in development as a treatment for fibrotic diseases, particularly in the kidney and lung. ANG-3070 has demonstrated activity as an anti-fibrotic agent in a variety of animal models. A Phase 1 healthy volunteer study demonstrated ANG-3070 to have a favorable safety and PK profile, producing plasma concentrations which exceeded those demonstrating activity in animal models of proteinuric kidney diseases. Enrollment is ongoing in JUNIPER, a dose-finding Phase 2 trial of ANG-3070 in primary proteinuric kidney diseases (NCT04939116). A Phase 1b trial of ANG-3070 in patients with idiopathic pulmonary fibrosis is targeted to enroll and report data in 2022. About Angion Angion is committed to transforming the treatment paradigm for patients suffering from fibrotic diseases for which there are no approved medicines or where existing approved medicines have known limitations. Angion’s lead product candidate is ANG-3070, a highly-selective oral tyrosine kinase receptor inhibitor in development for the treatment of fibrotic kidney and lung diseases. Enrollment is ongoing in JUNIPER, a dose-finding Phase 2 trial of ANG-3070 in primary proteinuric kidney diseases (NCT04939116). A Phase 1b trial of ANG-3070 in patients with idiopathic pulmonary fibrosis is targeted to enroll and report data in 2022. Additionally, Angion has preclinical programs focused on a rho kinase 2 (ROCK2) inhibitor and a CYP11B2 (aldosterone synthase) inhibitor. For more information, please visit www.angion.com.