To function properly, our brain needs a tightly controlled environment. Toxic components circulating in the blood are detrimental to this homeostasis and need to be withheld. The blood-brain barrier, a network of specialized blood vessels separating the brain from the rest of the body, is a key determinant of this neuroprotection.
Blood-brain barrier (BBB) dysfunction is a hallmark of numerous severe brain disorders, generating inflammation and major dysfunctions. However, no treatment options are currently available to target this system. Research on the topic is emerging and has the potential to provide significant therapeutic benefits to patients.
The importance of Gpr124/Reck as new targets for BBB repair
Neuvasq’s scientific research is based on the groundbreaking discovery that the endothelial Wnt/β-catenin signaling pathway plays a crucial role in regulating the formation of blood vessels in the brain, including those of the BBB.
Recent studies have advanced our understanding of this pathway to the point where it appears possible to develop safe and effective therapeutic interventions. In particular, researchers have identified key components of this Wnt/β-catenin pathway, called Gpr124 and Reck, representing a prime therapeutic target for BBB therapy.
The in vivo validation of Gpr124/Reck activators
The team led by Benoit Vanhollebeke at Université libre de Bruxelles (ULB) recently developed a novel class of highly specific and fully active Gpr124/Reck agonists, inducing safe activation of the Gpr124/Reck complex at the BBB. In preclinical models of stroke and brain tumors, these activators showed good tolerance and clear signs of BBB normalization, leading to positive therapeutic effects.
This strong scientific evidence lead to the foundation of Neuvasq, where insights are translated into pioneering therapies that address different neurovascular, neurogenerative, and neuro-oncological disorders.
Scientific references
Liebner, S. et al. Wnt/beta-catenin signaling controls development of the blood-brain barrier. J. Cell Biol.183, 409–417 (2008).
Stenman, J. M. et al. Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247–1250 (2008).
Daneman, R. et al. Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl. Acad. Sci. U. S. A. 106, 641–646 (2009).
Vanhollebeke, B. et al. Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. eLife 4, (2015).
Eubelen, M. et al. A molecular mechanism for Wnt ligand-specific signaling. Science 361, (2018).
America, M. et al. An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates. Cell Rep. 39, 110902 (2022).
Kuhnert, F. et al. Essential Regulation of CNS Angiogenesis by the Orphan G Protein–Coupled Receptor GPR124. Science 330, 985–989 (2010).
Zhou, Y. & Nathans, J. Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Dev. Cell 31, 248–256 (2014).
Posokhova, E. et al. Gpr124 functions as a WNT7-specific coactivator of canonical β-catenin signaling. Cell Rep. 10, 123–130 (2015).
Cullen, M. et al. Gpr124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Proc. Natl. Acad. Sci. 108, 5759–5764 (2011).
Anderson, K. D. et al. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc. Natl. Acad. Sci. 108, 2807–2812 (2011).
Vallon, M. et al. A RECK-WNT7 Receptor-Ligand Interaction Enables Isoform-Specific Regulation of Wnt Bioavailability. Cell Rep. 25, 339-349.e9 (2018).
Cho, C., Smallwood, P. M. & Nathans, J. Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. Neuron 95, 1056-1073.e5 (2017).
Chang, J. et al. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat. Med. 23, 450–460 (2017).
Martin, M. et al. Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders. Science 375, eabm4459 (2022).
The central nervous system (CNS) is a tightly controlled environment, in which specialized endothelial cells restrict the exchange of substances between the blood and CNS tissue, such as the brain, neural retina and spinal cord.
Blood-CNS barriers include the blood-retina barrier (BRB) enabling normal vision, and the blood-brain barrier (BBB) favoring normal neurological functions.
Dysfunction of neurovascular barriers is a hallmark of numerous conditions:
BBB breakdown has been implicated in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and epilepsy, among other conditions.
BRB impairment is associated with vascular retinopathies such as diabetic macular edema (DME) and wet age-related macular degeneration (wAMD).
No treatment options are currently available to safeguard or rebuild Neurovascular barriers. Discovery and development of novel approaches targeting the BBB or the BRB has the potential to deliver significant therapeutic benefits to patients.
Neuvasq engineered several series of proprietary, first-in-class antibodies that target Gpr124 or Reck to selectively activate the Wnt/β-catenin pathway in CNS endothelial cells. These novel antibodies have the potential to ameliorate blood-CNS barrier properties, reduce leakage and improve blood vessel formation in neurological and retinal conditions.
Illustration: Gpr124 and Reck mediate Wnt signaling in CNS endothelial cells.
Gpr124 is a G protein-coupled receptor that regulates angiogenesis (the formation of new blood vessels) and vascular integrity. It is highly expressed in the endothelial cells of the blood-brain barrier (BBB) and blood-retina barrier (BRB).
Reck (Reversion Inducing Cysteine Rich Protein with Kazal Motifs) is a membrane-bound protein that helps maintain the integrity of the blood-brain barrier (BBB), support neuronal development, and regulate extracellular matrix remodeling.
Neuvasq Biotechnologies is pioneering the development
of first-in-class Gpr124- and Reck-targeting antibodies
for retinal and neurological diseases.
Wnt/beta-catenin signaling controls development of the blood-brain barrier. Liebner, S. et al. J. Cell Biol.183, 409–417 (2008).
Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Stenman, J. M. et al. Science 322, 1247–1250 (2008).
Wnt/beta-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Daneman, R. et al. Proc. Natl. Acad. Sci. U. S. A. 106, 641–646 (2009).
Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. Vanhollebeke, B. et al. eLife 4, (2015).
A molecular mechanism for Wnt ligand-specific signaling. Eubelen, M. et al. Science 361, (2018).
An integrated model for Gpr124 function in Wnt7a/b signaling among vertebrates. America, M. et al. Cell Rep. 39, 110902 (2022).
Essential Regulation of CNS Angiogenesis by the Orphan G Protein–Coupled Receptor GPR124. Kuhnert, F. et al. Science 330, 985–989 (2010).
Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Zhou, Y. & Nathans, J. Dev. Cell 31, 248–256 (2014).
Gpr124 functions as a WNT7-specific coactivator of canonical β-catenin signaling. Posokhova, E. et al. Cell Rep. 10, 123–130 (2015).
Gpr124, an orphan G protein-coupled receptor, is required for CNS-specific vascularization and establishment of the blood-brain barrier. Cullen, M. et al. Proc. Natl. Acad. Sci. 108, 5759–5764 (2011).
Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Anderson, K. D. et al. Proc. Natl. Acad. Sci. 108, 2807–2812 (2011).
A RECK-WNT7 Receptor-Ligand Interaction Enables Isoform-Specific Regulation of Wnt Bioavailability. Vallon, M. et al. Cell Rep. 25, 339-349.e9 (2018).
Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. Cho, C., Smallwood, P. M. & Nathans, J. Neuron 95, 1056-1073.e5 (2017).
Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Chang, J. et al. Nat. Med. 23, 450–460 (2017).
Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders. Martin, M. et al. Science 375, eabm4459 (2022).
Cookie policy