danegaptide (ZP1609) / Zealand Pharma - LARVOL DELTA

Preclinical and clinical evaluation of systemic danegaptide for the treatment of nonproliferative diabetic retinopathy. (PubMed, Sci Transl Med) - "No serious adverse events related to oral danegaptide were found in an early-stage phase 1b clinical trial in 24 patients with NPDR and mild center-involved macular edema. These findings support larger clinical trials to test efficacy."

Journal • Preclinical • Diabetic Retinopathy • Macular Edema • Ophthalmology • Retinal Disorders • CD40LG • TNFSF15

Roles of astrocytic Connexin 43 gap junctional deficit in alpha-synucleinopathy and inflammation relevant to Parkinson's. (PubMed, Exp Neurol) - "Causal rather than correlational roles of Cx43 dysfunction in PD pathology are suggested as experimental downregulation of Cx43 with shRNA dysregulates calcium signaling and exacerbates α-synuclein aggregation, while pharmacological preservation of GJs (and possible hemichannel closure) using a Cx43-modulating compounds danegaptide (GAP-134, ZP1609) reduces aspects of pathology induced by inflammation and α-synuclein in vitro and in vivo. Cx43 may therefore represent a new therapeutic target for disease modification in PD."

Journal • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease

Targeted Stabilization of Astrocytic Cx43 Gap Junctions Reverses Depression-like Behaviors via Dual Restoration of Syncytial Networks and Glutamatergic Homeostasis. (PubMed, Neurochem Int) - "Mechanistic investigation revealed ZP1609 exerts its effects through dual pathways: (ⅰ) stabilizing Cx43-GJs to maintain intercellular communication and reverse astrocyte structural atrophy, thereby restoring syncytial network integrity; and (ⅱ) normalizing astrocytic glutamate-glutamine cycling to mitigate synaptic excitotoxicity and protect glutamatergic synaptic function. Our findings suggest Cx43-GJ stabilization as a novel therapeutic strategy that simultaneously rectifies astrocyte network failure and glutamatergic synaptic impairment, providing preclinical evidence for Cx43-GJ-targeted antidepressants development."

Journal • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Psychiatry

Connexin 43 subcellular localization: From trafficking dynamics to pathophysiological outcomes and therapeutic opportunities. (PubMed, Cell Signal) - "We further discuss peptide-based inhibitors (e.g., Gap19, αCT1), small molecules (e.g., tonabersat, danegaptide), and natural product-derived modulators, highlighting challenges in specificity, bioavailability, and clinical translation. By linking compartment-specific functions to distinct disease entities, this review establishes subcellular localization as a central determinant of Cx43 biology and a promising axis for precision medicine."

Journal • Cardiomyopathy • Cardiovascular • Diabetes • Fibrosis • Immunology • Metabolic Disorders • Oncology • Reperfusion Injury • Retinal Disorders • Rheumatology • CDC37 • GJA1 • HSP90AA1

Effect of Danegaptide on Gap Junction Preservation at the Blood-Brain Barrier after Sudden Cardiac Arrest (ACEP 2023) - No abstract available

Cardiovascular

Scar border zone mass and presence of border zone channels assessed with cardiac magnetic resonance imaging are associated with ventricular arrhythmia in patients with ST-segment elevation myocardial infarction. (PubMed, Europace) - P=N/A, P2 | "Scar characterization with CMR indicates that a combination of ≥17.2 g BZ mass and the presence of BZ channels had the strongest association with subsequent VA in STEMI patients."

Journal • MRI • Atrial Fibrillation • Cardiovascular • Myocardial Infarction • Ventricular Tachycardia

Activating Connexin43 gap junctions primes adipose tissue for therapeutic intervention. (PubMed, Acta Pharm Sin B) - "Using an adipose tissue-specific Cx43 overexpression mouse model, we demonstrate effectiveness in connecting adipocytes to augment metabolic efficacy of the β -adrenergic receptor agonist Mirabegron and FGF21. Additionally, combing those molecules with the Cx43 gap junction channel activator danegaptide shows a similar enhanced efficacy. In light of these findings, we propose a model in which connecting adipocytes via Cx43 gap junction channels primes adipose tissue to pharmacological agents designed to engage it. Thus, Cx43 gap junction activators hold great potential for combination with additional agents targeting adipose tissue."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • FGF21

Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice. (PubMed, J Neuroinflammation) - "Our results reveal a novel mechanism of the GJ-Cx43-mediated astrocytic network involved in isoflurane-induced neuroinflammation and cognitive impairments, which provides new mechanistic insight into the pathogenesis of POCD and identifies potential targets for its treatment."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • Cognitive Disorders • Immunology • Inflammation • IL1B • IL6

Danegaptide Prevents TGFβ1-Induced Damage in Human Proximal Tubule Epithelial Cells of the Kidney. (PubMed, Int J Mol Sci) - "Furthermore, danegaptide inhibited TGFβ1-induced changes in the expression and secretion of key adipokines, cytokines, chemokines, growth factors and interleukins. The data suggest that as a gap junction modulator and hemichannel blocker, danegaptide has potential in the future treatment of CKD."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Renal Disease • TGFB1

Gap-134, a Connexin43 activator, prevents age-related development of ventricular fibrosis in Scn5a mice. (PubMed, Pharmacol Res) - "Chronic administration of a potent and selective gap junction modifier, Gap-134 (danegaptide), between 45 and 60 weeks, increased Cx43 expression and phosphorylation on serine 368 and prevented Cx43 delocalization...In conclusion, the present study demonstrates that the age-dependent decrease of Cx43 expression is involved in the ventricular fibrotic process occurring in Scn5a mice. Finally, our study suggests that gap junction modifier, such as Gap-134, could be an effective anti-fibrotic agent in the context of age-dependent fibrosis in progressive cardiac conduction disease."

Journal • Preclinical • Fibrosis • Immunology • GJA1

Danegaptide Enhances Astrocyte Gap Junctional Coupling and Reduces Ischemic Reperfusion Brain Injury in Mice. (PubMed, Biomolecules) - "Furthermore, administration of danegaptide in a novel mouse brain ischemia/reperfusion model showed significant decrease in infarct volume. Taken together, this study provides evidence for the therapeutic potential of danegaptide in ischemia/reperfusion stroke."

Journal • Preclinical

A human in vitro platform for the evaluation of pharmacology strategies in cardiac ischemia. (PubMed, APL Bioeng) - "ZP1609 significantly improved the drastic drop in conduction velocity and enabled a greater recovery. This model represents a new preclinical platform for studying cardiac ischemia with human cells, which does not rely on biomarker analysis and has the potential for screening novel cardioprotective drugs with readouts that are closer to the measured clinical parameters."

Biomarker • Journal • Preclinical