olitigaltin (GB0139) / Galecto - LARVOL DELTA

Pathways in the brain, heart and lung influenced by SARS-CoV-2 NSP6 and SARS-CoV-2 regulated miRNAs: an in silico study hinting cancer incidence. (PubMed, Cardiooncology) - "This study highlights probable hub genes, drugs targeting them, and associated pathways perturbed by SARS-CoV-2 NSP6. Galectin3 (LGALS3) upregulated in both heart and brain after COVID-19 infection is reported to be influencing all the ten hallmarks of cancer. Our bioinformatics and systems study hints probable effect of COVID-19 infection in cancer incidence and warrants in-depth studies for present scenario of long and recurrent COVID-19."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Infectious Disease • Lung Cancer • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Small Cell Lung Cancer • Solid Tumor • ATP6AP1 • ATP6V1D • CANX • CCNA1 • CCNB1 • CCND1 • CCNE1 • CDKN1B • EGF • LAMP2 • LGALS3 • TGFB1 • TGFBR2

Integration of single-cell and bulk RNA sequencing data to identify liquid-liquid phase separation-related prognostic biomarkers in hepatocellular carcinoma. (PubMed, Sci Rep) - "Ten LLPSRGs were identified as part of the LLPS-related risk signature, and potential agents were predicted: Olitigaltin and Lactose for LGALS3, and Sitamaquine, Phenazopyridine, Sulfanilamide, Pamaquine, Sodium ascorbate, and Co-trimoxazole for G6PD. Knockdown of LGALS3 inhibited HCC cell migration and invasion. LLPS-related molecular characteristics were identified, and an LLPS-related prognostic model was developed, offering novel insights into HCC research and providing potential therapeutic targets."

Biomarker • Journal • Hepatocellular Cancer • Oncology • Solid Tumor • CXCR4 • EGFR • LGALS3

Protocol for isolating patient-derived ascites cells and extracellular vesicles from gastric cancer peritoneal metastases. (PubMed, STAR Protoc) - "This protocol also includes TD-139 loading into exosomes for functional assays to evaluate their role in modulating the tumor microenvironment. For complete details on the use and execution of this protocol, please refer to Fan et al.1."

Journal • Gastric Cancer • Oncology • Peritoneal Cancer • Solid Tumor

Pleiotropic regulatory mechanisms and targeted therapeutic prospects of Galectin-3 in aging-related diseases. (PubMed, Neurotherapeutics) - "Preclinical studies demonstrate that Gal-3-targeted interventions-including small-molecule inhibitors (e.g., TD-139), natural compounds (e.g., modified citrus pectin), and other pharmacological agents-exert neuroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects by binding to Gal-3 and modulating its activity in animal models, offering promising avenues for multi-disease treatment. However, the dual roles and complex regulatory networks of Gal-3 present challenges for clinical translation, requiring context-specific therapeutic approaches tailored to distinct disease mechanisms. Future research should focus on elucidating tissue-specific mechanisms and optimizing combination therapies to enable precise targeting of aging-related pathologies."

Journal • Review • Age-related Macular Degeneration • Alzheimer's Disease • Atherosclerosis • Cardiovascular • CNS Disorders • Diabetes • Immunology • Inflammation • Macular Degeneration • Metabolic Disorders • Movement Disorders • Ophthalmology • Osteoarthritis • Pain • Parkinson's Disease • Retinal Disorders • Rheumatology • Type 2 Diabetes Mellitus • LGALS3

Intracellular Galectin-3 as a Crucial Regulator of Foam Cell Formation and Apoptosis Progression through the Modulation of Membrane Lipid Rafts. (PubMed, Arch Med Res) - "Gal-3 modulates lipid raft organization and oxLDL internalization, acting as a pro-inflammatory mediator in foam cell biology. These findings highlight Gal-3 as a potential therapeutic target for early atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Cholera • Inflammation • Metabolic Disorders • CD14 • CD36 • LGALS3 • SCARB1

DEFINE - Evaluating Therapies for COVID-19 (clinicaltrials.gov) - P1/2 | N=71 | Completed | Sponsor: University of Edinburgh | Recruiting ➔ Completed | N=200 ➔ 71

Enrollment change • Trial completion • Infectious Disease • Novel Coronavirus Disease

Inhibition of Galectin-3 Expression Could Preserve the Immunoregulatory Function of Mesenchymal Stem Cells During Cell Passaging. (PubMed, Front Biosci (Landmark Ed)) - "Gal-3 contributes to the decline in the immunomodulatory capabilities of MSCs. TD139, a Gal-3 inhibitor, has a potentially positive effect on rescuing the immunoregulation dysfunction of MSCs in late-passage and may represent a novel strategy to enhance the therapeutic potential of late-passage MSCs for GVHD treatment."

Journal • Acute Graft versus Host Disease • Bone Marrow Transplantation • Graft versus Host Disease • Immunology • Transplantation • LGALS3

Lectins and neurodegeneration: A glycobiologist's perspective. (PubMed, Adv Clin Exp Med) - "Overexpression of this lectin under inflammatory conditions activates TREM2 and TLR4 signaling pathways, enhances the phagocytic activity of microglia and leads to tissue damage. Blocking Gal-3 interactions with the thiodigalactoside inhibitor (TD-139) appears to be a promising novel approach to pharmacologically alleviating neuroinflammation."

Journal • Alzheimer's Disease • CNS Disorders • Inflammation • Movement Disorders • Parkinson's Disease • LGALS3

Binding free energy analysis of galectin-3 natural ligands and synthetic inhibitors. (PubMed, Protein Sci) - "Synthetic drug molecules GB0139, GB1107, and GB1211 were estimated to have binding free energies of -4.3, -6.7, and -9.5 kcal/mol respectively. We find that while the hydroxyl groups of the natural ligands interact reasonably well with residues in galectin-3's binding pocket, structural dynamics weaken the binding pose and favor interactions with water, sometimes yielding to dissociation. In contrast, the more favorable binding energy of GB1211, leading inhibitor in clinical studies, is associated with strong and constant electric fields across the bonds investigated, suggesting a stiffer binding pose with a stabilizing σ-hole interaction."

Journal

Targeting Galectin-3 to modulate inflammation in LAMA2-deficient congenital muscular dystrophy. (PubMed, bioRxiv) - "RNA sequencing of TD-139-treated dyW muscles showed upregulation of muscle contraction pathways and downregulation of fibrosis-related genes. These findings highlight Galectin-3 + macrophages as key contributors to LAMA2-CMD pathophysiology and support further exploration of TD-139 as a potential therapeutic strategy for LAMA2-CMD and other dystrophic conditions driven by chronic inflammation."

Journal • CNS Disorders • Fibrosis • Immunology • Inflammation • Muscular Dystrophy • LAMA2 • LGALS3 • PTPRC

Platelet glycoprotein VI promotes folic acid-induced acute kidney injury through interaction with tubular epithelial cell-derived galectin-3. (PubMed, Cell Commun Signal) - "These findings suggest that galectin-3, which is released from damaged cells during acute kidney injury (AKI), exacerbates renal inflammation and tissue damage by activating platelets through glycoprotein VI (GPVI). This activation enhances interactions between monocytes and platelets, ultimately leading to the formation of monocyte-platelet aggregates (MPA) and the polarization of M1 macrophages."

Journal • Acute Kidney Injury • Inflammation • Nephrology • Renal Disease • CD68 • ITGA2B

DEFINE - Evaluating Therapies for COVID-19 (clinicaltrials.gov) - P1/2 | N=200 | Recruiting | Sponsor: University of Edinburgh | Trial completion date: Dec 2024 ➔ Apr 2025 | Trial primary completion date: Dec 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

Intravitreal injection of the Galectin-3 inhibitor TD139 provides neuroprotection in a rat model of ocular hypertensive glaucoma. (PubMed, Mol Brain) - "The degeneration of retinal ganglion cells was prevented by TD139 injection, but gross glial markers remained unaffected. These data confirm that the intravitreal injection of TD139 is neuroprotective in a rat ocular hypertensive model of glaucoma, while suggesting that the inhibition of Galectin-3 is not sufficient to alter the gross inflammatory outcome."

Journal • Preclinical • Cardiovascular • CNS Disorders • Glaucoma • Inflammation • Ocular Inflammation • Ophthalmology

Galectin-3 inhibition reduces fibrotic scarring and promotes functional recovery after spinal cord injury in mice. (PubMed, Cell Biosci) - "Our finding underscores the pivotal role of macrophage-derived Galectin-3 in modulating the sustained internalized activation of PDGFRβ within fibroblasts, providing a novel mechanistic insight into fibrotic scarring post-SCI."

Journal • Preclinical • CNS Disorders • Fibrosis • Immunology • Orthopedics • LGALS3 • PDGFRB

In vitro and in vivo effects of Galectin-3 inhibitor TD139 on inflammation and ERK/JNK/p38 pathway in gestational diabetes mellitus. (PubMed, Kaohsiung J Med Sci) - "The study used TNF-α to mimic GDM in placental tissues and an STZ-induced GDM mouse model, which may not fully represent human GDM complexity. Future research should explore alternative models, and broader signaling pathways, and thoroughly evaluate TD139's safety in pregnancy."

Journal • Preclinical • Diabetes • Gestational Diabetes • Inflammation • Metabolic Disorders • Oncology • IL1B • IL6 • LGALS3 • MAPK8 • TNFA

Nebulizable Conjugates to Sustain Retention, Delivery, and Efficacy of Galectin-3 Inhibitory Drug TD139 in the Alveolar Space (ATS 2024) - "We incubated bleomycin-induced mouse precision-cut lung slices (PCLS) with TD139 to validate the model...Incubation of PCLS with TD139 (2 µM) resulted in a significant reduction in COL1A1 gene expression compared to Nintedanib (2 µM) treatment (Fig... We developed a method to increase solubility, nebulization, molecular size, and prolonged release of TD139 with the aim of increasing lung retention and single-dose effects. The release of the conjugates is being tested in PCLS to confirm its effects. Experiments to test the retention of the conjugates in mouse lungs and their effects are in progress."

Clinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases • COL1A1

GALACTIC-1: A Study to Test the Efficacy and Safety of Inhaled GB0139 in Subjects With Idiopathic Pulmonary Fibrosis (IPF) (clinicaltrials.gov) - P2 | N=172 | Completed | Sponsor: Galecto Biotech AB | Phase classification: P2b ➔ P2 | N=426 ➔ 172

Enrollment change • Phase classification • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Galectin-3 modulates microglial activation and neuroinflammation in early brain injury after subarachnoid hemorrhage. (PubMed, Exp Neurol) - "These findings suggest that regulating microglia polarization by galectin-3 after SAH to improve neuroinflammation may be a potential therapeutic target."

Journal • Cardiovascular • CNS Disorders • Hematological Disorders • Inflammation • Subarachnoid Hemorrhage • Vascular Neurology • LGALS3 • STAT3 • TLR4

Efficient O- and S-glycosylation with ortho-2,2-dimethoxycarbonylcyclopropylbenzyl thioglycoside donors by catalytic strain-release. (PubMed, Chem Sci) - "Because the activation conditions of conventional glycosyl donors and our CCPB thioglycoside are orthogonal, our novel donor is amenable to controlled one-pot glycosylation reactions with conventional donors for expeditious access to complex glycans. The strain-release glycosylation is applied to the assembly of a tetrasaccharide of O-polysaccharide of Escherichia coli O-33 in one pot and the synthesis of a 1,1'-S-linked glycoside oral galectin-3 (Gal-3) inhibitor, TD139, to demonstrate the versatility and effectiveness of the novel method for constructing both O- and S-glycosides."

Journal • LGALS3

Injured sensory neurons-derived galectin-3 contributes to neuropathic pain via programming microglia in the spinal dorsal horn. (PubMed, Brain Behav Immun) - "Gal3 knockout (Gal3 KO) mice showed a significant decrease in mechanical allodynia and Gal3 inhibitor TD-139 produced a significant anti-allodynia effect in the pSNL model...Finally, Gal3 enhances excitatory synaptic transmission in excitatory neurons in the SDH via microglia activation. Our findings reveal that injured sensory neurons-derived Gal3 programs microglia in the SDH and contribute to neuropathic pain."

Journal • Inflammation • Neuralgia • Pain • IL1B • LGALS3 • TNFA

DEFINE - Evaluating Therapies for COVID-19 (clinicaltrials.gov) - P1/2 | N=200 | Recruiting | Sponsor: University of Edinburgh | Trial completion date: Dec 2023 ➔ Dec 2024 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Infectious Disease • Novel Coronavirus Disease

Inhibition of galectin-3 in a rat model of epilepsy and kainate-activated BV-2 cells limits microglial activation through NLRP3/pyroptosis pathway. (PubMed, Neuroimmunomodulation) - "Galectin-3 activates the NLRP3/pyroptosis signaling pathway to promote microglial activation and neuroinflammation during epilepsy disease progression."

Journal • Preclinical • CNS Disorders • Epilepsy • Inflammation • LGALS3 • NLRP3

Population pharmacokinetic (pop-PK) model of GB0139 as a tool to characterise the biomarker response in patients with idiopathic pulmonary fibrosis (IPF) (ERS 2023) - "The derived pop-PK models quantified the dose-concentration relationship in HV & IPF patients & enabled simulation of plasma & lung PK, & ER analyses. AM surface Gal-3, the biomarker directly linked to the mode of action of GB0139, correlated with simulated Cavg at steady state.; Public health; Respiratory intensive care; Pulmonary function testing; Endoscopy and interventional pulmonology; Epidemiology; General respiratory patient care; Cell and molecular biology"

Biomarker • Clinical • PK/PD data • Critical care • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CHI3L1 • LGALS3

Epithelial Galectin-3 Induced the Mitochondrial Complex Inhibition and Cell Cycle Arrest of CD8 T Cells in Severe/Critical COVID-19. (PubMed, Int J Mol Sci) - "Importantly, the galectin-3 inhibitor, TD-139, promoted nuclear translocation of NRF1, thus enhancing the expression of the mitochondrial respiratory chain complex III/IV genes and the mitochondrial biogenesis of CD8 T cells. Our study provided new insights into the immunopathogenesis of COVID-19 and identified potential therapeutic targets for the prevention and treatment of severe/critical COVID-19 patients."

IO biomarker • Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CD8 • FASLG • NRF1

Galecto Announces Topline Results from Phase 2b GALACTIC-1 Trial of GB0139 for the Treatment of Idiopathic Pulmonary Fibrosis (GlobeNewswire) - P2b | N=426 | GALACTIC-1 (NCT03832946) | Sponsor: Galecto Biotech AB | "Galecto, Inc...today announced topline results from its Phase 2b GALACTIC-1 trial evaluating the safety and efficacy of inhaled GB0139 for the treatment of idiopathic pulmonary fibrosis (IPF). The GALACTIC-1 trial did not meet its primary endpoint of change from baseline in rate of decline in forced vital capacity (FVC). Based on the results of the GALACTIC-1 trial, Galecto plans to discontinue development of GB0139. Going forward, Galecto will focus on development opportunities for the treatment of severe liver diseases."

Discontinued • P2b data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Interstitial Lung Disease • Pulmonary Disease • Respiratory Diseases