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Last update 08 May 2025

ROBO4

Last update 08 May 2025

Basic Info

Synonyms

ECSM4, FLJ20798, Magic roundabout

+ [4]

Introduction

Receptor for Slit proteins, at least for SLIT2, and seems to be involved in angiogenesis and vascular patterning. May mediate the inhibition of primary endothelial cell migration by Slit proteins (By similarity). Involved in the maintenance of endothelial barrier organization and function (PubMed:30455415).

Drugs associated with ROBO4

WO2023156437

Patent Mining

Target

ROBO4

Mechanism-

Active Org.

Institut National de la Santé et de la Recherche Médicale [+3]

Originator Org.

Institut National de la Santé et de la Recherche Médicale [+3]

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

DS-7080a

Target

ROBO4

Mechanism

ROBO4 antagonists [+1]

Active Org.-

Originator Org.

Daiichi Sankyo Co., Ltd.

Active Indication-

Inactive Indication

Diabetic macular oedema [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with ROBO4

NCT02530918

/ CompletedPhase 1

Phase I Dose Escalation and Expansion Study of DS-7080a in Subjects With Neovascular Age-related Macular Degeneration or Diabetic Macular Edema

The purpose of this study is to test DS-7080a, a monoclonal antibody, as a new treatment for neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The hypothesis of the study is that DS-7080a is safe and shows preliminary efficacy in patients with these conditions either alone or in combination with ranibizumab. This study is organized into 3 Parts: Part 1 Dose Escalation in AMD participants, Part 2 Dose Expansion in AMD participants, and Part 3 Dose Expansion in DME participants.
In Part 1, participants will be enrolled into 3 sequential, ascending dose-level cohorts in non-randomized uncontrolled manner with the main purpose to determine the recommended dose.
In Part 2, participants will be randomized to 1 of 3 arms of either monotherapy with DS-7080a or monotherapy with ranibizumab, which is an active control, or combination therapy of DS-7080a plus ranibizumab (ranibizumab will be administered 30 minutes prior to DS-7080a).
In Part 3, subjects with DME will be assigned to 1 of 2 arms of either monotherapy with DS-7080a or monotherapy with ranibizumab. DS-7080a or ranibizumab will be administered 3 times: on Baseline/Day 1, Day 29, and Day 57.
Both Parts 2 and 3 will consist of 8 visits including a 14-day screening phase, an 84-day treatment period, and a 28-day follow-up period.

Start Date01 Jul 2015

Sponsor / Collaborator

Daiichi Sankyo, Inc.

100 Clinical Results associated with ROBO4

100 Translational Medicine associated with ROBO4

0 Patents (Medical) associated with ROBO4

267

Literatures (Medical) associated with ROBO4

01 May 2025·Current Opinion in Hematology

New mechanisms and therapeutic approaches to regulate vascular permeability in systemic inflammation

Review

Author: Puy, Cristina ; McCarty, Owen J.T. ; Vu, Helen H. ; Moellmer, Samantha A.

Purpose of reviewThis review summarizes mechanisms that regulate endothelial vascular permeability in health and disease. In systemic inflammation, the endothelial barrier integrity is disrupted, which exacerbates vascular permeability, leading to organ failure and death. Herein we provide an overview of emerging therapeutic targets to reverse barrier dysfunction and preserve vascular permeability in inflammatory diseases like sepsis.Recent findingsEndothelial barrier function is regulated in part by the endothelial cell-specific protein, Roundabout 4 (ROBO4), and vascular endothelial (VE)-cadherin, a critical adherens junction protein, which act in concert to suppresses vascular permeability by stabilizing endothelial cell-cell interactions. We recently discovered a pathway by which activation of coagulation factor XI (FXI) enhances the cleavage of VE-cadherin by the metalloproteinase ADAM10, contributing to sepsis-related endothelial damage and loss of barrier function. Targeting FXI improved survival and reduced sVE-cadherin levels in a baboon model of sepsis while enhancing Robo4 expression decreased mortality in LPS-treated mice.SummaryEndothelial cell barrier dysfunction is a hallmark of excessive immune responses characteristic of systemic inflammatory diseases such as sepsis. Advances in understanding the molecular mechanisms regulating vascular permeability, for instance the newly discovered roles of FXI or ROBO4, may help identify novel therapeutic targets for mitigating vascular hyperpermeability in septic patients.

01 Jan 2025·International Journal of Experimental Pathology

Perinatal exposure to lead alters male reproductive behaviour and immunoreactivity of androgen and oestrogen receptors in the brain

Article

Author: Arteaga‐Silva, Marcela ; Ríos, Camilo ; Contreras‐García, Itzel Jatziri ; Rojas‐Castañeda, Julio César ; Guillen‐Herrera, Gustavo ; Montes, Sergio ; Limón‐Morales, Ofelia ; Landero‐Huerta, Daniel Adrian ; Vigueras‐Villaseñor, Rosa María

AbstractLead (Pb) exposure during perinatal development alters testosterone (T) concentrations and delays puberty in children and laboratory rodents. In addition, exposure to the metal during adult life decreases T and libido in men and affects male reproductive behaviour (MRB) in rats. MRB is regulated by various brain nuclei including the medial preoptic area (MPOa) and the medial amygdala (MeA), in which T and oestradiol (E2) act through their respective androgen (AR) and oestrogen (ER) receptors. However, the mechanism by which MRB is affected by Pb exposure is not known. The objectives of the present study were to evaluate whether perinatal Pb exposure affects MRB and the number of cells immunoreactive to AR and ERα in the MPOa and the MeA. Male Wistar rats exposed to Pb (320 ppm) in drinking water from the beginning of pregnancy until weaning were used. The experimental group experienced significant alterations in MRB, an important decrease in T and E2 concentrations, and a significant increase in Pb concentrations in the blood, MPOa (hypothalamus) and MeA. In addition, in the studied areas the number of cells immunoreactive to AR and ERα, or detected using the Nissl technique, decreased significantly. These results show that perinatal exposure to Pb alters MRB. This event may be related to a decrease in both the concentrations of sex hormones and the number of cells that express their receptors as well as in the neuronal Nissl staining population. This ultimately affects the quality of life of the individual.

01 Dec 2024·Arteriosclerosis, Thrombosis, & Vascular Biology

Single-Cell Meta-Analysis Uncovers the Pancreatic Endothelial Cell Transcriptomic Signature and Reveals a Key Role for NKX2-3 in PLVAP Expression

Article

Author: Khan, Safwat T. ; Cleaver, Ondine ; Vohra, Shabana ; Taïb, Sonia ; Ahuja, Neha ; Nunes, Sara S.

BACKGROUND:The pancreatic vasculature displays tissue-specific physiological and functional adaptations that support rapid insulin response by β-cells. However, the digestive enzymes have made it difficult to characterize pancreatic endothelial cells (ECs), resulting in the poor understanding of pancreatic EC specialization.METHODS:Available single-nuclei/single-cell RNA-sequencing data sets were mined to identify pancreatic EC-enriched signature genes and to develop an integrated atlas of human pancreatic ECs. We validated the findings using independent single-nuclei/single-cell RNA-sequencing data, bulk RNA-sequencing data of isolated ECs, spatial transcriptomics data, immunofluorescence, and RNAScope of selected markers. The NK2 homeobox 3 (NKX2-3) TF (transcription factor) was expressed in HUVECs via gene transfection, and the expression of pancreatic EC-enriched signature genes was assessed via RT-qPCR.RESULTS:We defined a pancreatic EC-enriched gene signature conserved across species and developmental stages that included genes involved in ECM (extracellular matrix) composition (COL15A1 and COL4A1), permeability and barrier function (PLVAP, EHD4, CAVIN3, HSPG2, ROBO4, HEG1, and CLEC14A), and key signaling pathways (S1P [sphingosine-1-phosphate], TGF-β [transforming growth factor-β], RHO/RAC GTPase [guanosine triphosphatase], PI3K/AKT [phosphoinositide 3-kinase/protein kinase B], and PDGF [platelet-derived growth factor]). The integrated atlas revealed the vascular hierarchy within the pancreas. We identified and validated a specialized islet capillary subpopulation characterized by genes involved in permeability (PLVAP and EHD4), immune-modulation (FABP5, HLA-C, and B2M), ECM composition (SPARC and SPARCL1), IGF (insulin-like growth factor) signaling (IGFBP7), and membrane transport (SLCO2A1, SLC2A3, and CD320). Importantly, we identified NKX2-3 as a key TF enriched in pancreatic ECs. DNA-binding motif analysis found NKX2-3 motifs in ≈40% of the signature genes. Induction of NKX2-3 in HUVECs promoted the expression of the islet capillary EC-enriched genes PLVAP and SPARCL1.CONCLUSIONS:We defined a validated transcriptomic signature of pancreatic ECs and uncovered their intratissue transcriptomic heterogeneity. We showed that NKX2-3 acts upstream of PLVAP and provided a single-cell online resource that can be further explored by the community: https://vasconcelos.shinyapps.io/pancreatic_endothelial/.

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ROBO4

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