RARE DISEASE
Norrie disease
Norrie disease
Norrie disease
Synonyms: Atrophia bulborum hereditaria, Episkopi blindness, Norrie-Warburg disease
Synonyms: Atrophia bulborum hereditaria, Episkopi blindness, Norrie-Warburg disease
Synonyms: Atrophia bulborum hereditaria, Episkopi blindness, Norrie-Warburg disease
Drug discovery
2
drugs
With orphan designations
Overview
Norrie disease is a rare X-linked recessive disorder caused by pathogenic NDP gene mutations, leading to congenital blindness, progressive sensorineural hearing loss (30-50%), and neurodevelopmental/psychiatric manifestations (20-50%) [1][5][9][10]. It disrupts retinal vascularization and cochlear function through impaired Wnt signaling [5][9]. Multisystem involvement may include peripheral vascular disease and endocrine dysfunction [1][9].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare otorhinolaryngological diseases
Research Papers
66 drug discovery papers about Norrie disease. Recent publications:
66 drug discovery papers about Norrie disease. Recent publications:
categories:
Small molecules
small molecules
2024-11-25 | Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease.
Variants in the gene NDP cause Norrie disease, a severe dual-sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death. NDP encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood. We investigated whether the Norrie disease cochlear pathology can be ameliorated in an Ndp-knockout (Ndp-KO) mouse model by conditional activation of stabilized β-catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, β-catenin is the primary downstream intracellular effector of norrin binding to endothelial cell surface receptors and that restoration of this signaling pathway is sufficient to prevent sensory hair cell death and hearing loss. We show that tamoxifen induction of Cdh5CreERT2;Ctnnb1flex3/+;Ndp-KO mice stabilizing β-catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers (Cldn5, Abcb1a, Slc7a1, and Slc7a5), and prevented progressive outer hair cell death and hearing loss. Single-cell transcriptome profiling of human cochleas showed NDP expression by fibrocytes and glial cells while receptor gene expression (FZD4, TSPAN12, LRP5, and LRP6) coincided in vascular endothelial cells. Our findings support the conclusion that vascular endothelial cells are a primary target of norrin signaling in the cochlea of mice and humans and restoration of β-catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival.
2023-08-24 | The role of PLVAP in endothelial cells.
Endothelial cells play a major part in the regulation of vascular permeability and angiogenesis. According to their duty to fit the needs of the underlying tissue, endothelial cells developed different subtypes with specific endothelial microdomains as caveolae, fenestrae and transendothelial channels which regulate nutrient exchange, leukocyte migration, and permeability. These microdomains can exhibit diaphragms that are formed by the endothelial cell-specific protein plasmalemma vesicle-associated protein (PLVAP), the only known protein component of these diaphragms. Several studies displayed an involvement of PLVAP in diseases as cancer, traumatic spinal cord injury, acute ischemic brain disease, transplant glomerulopathy, Norrie disease and diabetic retinopathy. Besides an upregulation of PLVAP expression within these diseases, pro-angiogenic or pro-inflammatory responses were observed. On the other hand, loss of PLVAP in knockout mice leads to premature mortality due to disrupted homeostasis. Generally, PLVAP is considered as a major factor influencing the permeability of endothelial cells and, finally, to be involved in the regulation of vascular permeability. Following these observations, PLVAP is debated as a novel therapeutic target with respect to the different vascular beds and tissues. In this review, we highlight the structure and functions of PLVAP in different endothelial types in health and disease.
2022-03-14 | LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling
Precise Norrin and β-catenin (Norrin/β-catenin; encoded by NDP and CTNNB1, respectively) signaling is critical for proper angiogenesis. Dysregulation of this signaling leads to various diseases, of which retinal exudative vitreoretinopathy is the most prevalent. Here, we used a global knockout mouse model to show that limb development membrane protein 1 like (LMBR1L), a transmembrane protein of unknown function in angiogenesis, is essential for retinal vascular development. In vitro experiments revealed that LMBR1L depletion results in aberrant activation of the Norrin/β-catenin signaling pathway via decreased ubiquitylation of FZD4 and increased Norrin co-receptor LRP5 and p-GSK3β-Ser9 expression levels, which cause accumulation of β-catenin. Moreover, inhibition of LMBR1L in human retinal microvascular endothelial cells (HRECs) caused increased proliferation ability and defective cell migration, which might have occurred as a result of upregulated expression levels of the apical junction components. Treatment with p-GSK3β-Ser9 inhibitor AR-A014418 restored the phenotypes in LMBR1L-null HRECs, which further demonstrated the important regulatory role of LMBR1L in the Norrin/β-catenin signaling pathway. Taken together, our data reveal an essential role for LMBR1L in angiogenesis. This article has an associated First Person interview with the first author of the paper.
2021-02-05 | Faculty Opinions recommendation of Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier.
Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss.We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis.Mice lacking either the Wnt co-receptor low-density lipoprotein receptor-related protein 5 (Lrp5 -/-) or the Wnt ligand Norrin (Ndp y/-) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis.Wnt signaling directly controls the transcription of an endotheliumspecific transcytosis inhibitor, major facilitator superfamily domain-containing protein 2a (MFSD2A), in a -catenin-dependent manner.MFSD2A overexpression reverses Wnt deficiency-induced transcytosis in endothelial cells and in retinas.Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)-positive caveolae pathway.In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling-deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter.Our findings uncovered the Wnt/-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.
2019-06-25 | Extracellular Vesicles from Activated Dermal Fibroblasts Stimulate Hair Follicle Growth Through Dermal Papilla-Secreted Norrin
Abstract Dermal papilla cells (DPCs) play a pivotal role in the regulation of hair follicle (HF) growth, formation, and cycling, mainly through paracrine mechanisms. In the last decade, extracellular vesicles (EVs) have been recognized as a new paracrine mechanism that can modify the physiological state of recipient cells by transferring biological material. Herein, we investigated the effect of EVs isolated from stimulated human dermal fibroblasts (DFs) on DPC activation and HF growth. We found that these EVs (st-EVs) enhanced HF growth ex vivo. Comparative transcriptomic analysis on DPCs identified specific activation of the NDP gene, encoding the non-Wnt ligand Norrin. We found that Norrin was secreted by st-EVs-stimulated DPCs activating in a noncell autonomous manner β-catenin pathway in follicular keratinocytes (human HF keratinocyte [HHFK]) and hair growth ex vivo. Although Norrin-specific receptor Frizzled4 was barely detected in HHFK, we found its presence in DF-EVs. Accordingly, DF-EVs provided Frizzled4 to potentiate Norrin effects ex vivo. Our study identifies DF-EVs as efficient activators of DPCs and Norrin as a novel modulatory player in HF physiopathology. Stem Cells 2019;37:1166–1175
proteins
2023-06-02 | Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice
Abstract Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer’s disease. The Norrin/FZD 4 /TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD 4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD 4 -selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD 4 -specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout ( Ndp KO ) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD 4 -selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
2022-10-14 | Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate
Abstract Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer’s disease. The Norrin/FZD 4 /TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD 4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD 4 -selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD 4 -specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout ( Ndp KO ) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD 4 -selective WNT surrogate during ischemic BBB dysfunction, with general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
2022-08-15 | Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease.
We previously reported that planned preterm delivery at 34 weeks gestational age provided an opportunity to treat Norrie disease in the vasoproliferative phase, prevented infantile retinal detachment, and preserved functional vision without further treatment after infancy. Although retinal vascularization did not proceed postnatally, after 8 years of follow-up, the retinas remained attached, and rudimentary foveal development was observed by optical coherence tomography. Best corrected visual acuity gradually improved to 20/80 with both eyes, and visual fields and real-world visual performance were remarkably functional. Global development progressed appropriately, and no long-term sequelae of premature delivery were observed. [Ophthalmic Surg Lasers Imaging Retina 2022;53:464-467.].
2020-03-17 | Norrin mediates tumor-promoting and -suppressive effects in glioblastoma via Notch and Wnt
Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on ASCL1lo and ASCL1hi GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in ASCL1lo GSCs. In contrast, in ASCL1hi GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in ASCL1lo GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype–restricted cancer stem cells.
2020-02-07 | Wnt Signaling in vascular eye diseases.
The Wnt signaling pathway plays a pivotal role in vascular morphogenesis in various organs including the eye. Wnt ligands and receptors are key regulators of ocular angiogenesis both during the eye development and in vascular eye diseases. Wnt signaling participates in regulating multiple vascular beds in the eye including regression of the hyaloid vessels, and development of structured layers of vasculature in the retina. Loss-of-function mutations in Wnt signaling components cause rare genetic eye diseases in humans such as Norrie disease, and familial exudative vitreoretinopathy (FEVR) with defective ocular vasculature. On the other hand, experimental studies in more prevalent vascular eye diseases, such as wet age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), and corneal neovascularization, suggest that aberrantly increased Wnt signaling is one of the causations for pathological ocular neovascularization, indicating the potential of modulating Wnt signaling to ameliorate pathological angiogenesis in eye diseases. This review recapitulates the key roles of the Wnt signaling pathway during ocular vascular development and in vascular eye diseases, and pharmaceutical approaches targeting the Wnt signaling as potential treatment options.
antibodies
2025-07-08 | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling.
The Wnt/β-catenin pathway requires precise regulation for proper development and tissue homeostasis, yet the structural mechanisms enabling its fine-tuned control remain incompletely understood. Here, we reveal how LGR4 achieves differential signaling outcomes through distinct recognition of two key modulators: Norrin and R-spondins (RSPOs). Using cryo-electron microscopy, we determined the structure of full-length LGR4 bound to Norrin in a 2:2 stoichiometry, revealing a molecular bridging mechanism where Norrin dimer connect two LGR4 protomers in a spatial arrangement fundamentally distinct from the LGR4-RSPO2-ZNRF3 complex. Notably, Norrin binding to LGR4 sterically hinders simultaneous interaction with the Frizzled4 receptor, establishing a regulatory checkpoint in Wnt signaling. The partially overlapping binding sites for Norrin and RSPOs on LGR4 enable mutually exclusive interactions that drive distinct signaling outcomes. Disease-linked mutations map to distinct functional regions: those disrupting LGR4 interaction are associated with familial exudative vitreoretinopathy (FEVR), while others impairing Frizzled4 binding are linked to Norrie disease. Furthermore, we developed a high-affinity nanobody that blocks both Norrin and RSPO binding to LGR4, providing a potential tool for therapeutic intervention. These findings elucidate the structural basis of LGR4's dual signaling roles and lay the groundwork for therapeutic strategies targeting Wnt-related diseases.
2018-09-25 | A synthetic anti-Frizzled antibody engineered for broadened specificity exhibits enhanced anti-tumor properties
Secreted Wnt ligands play a major role in the development and progression of many cancers by modulating signaling through cell-surface Frizzled receptors (FZDs). In order to achieve maximal effect on Wnt signaling by targeting the cell surface, we developed a synthetic antibody targeting six of the 10 human FZDs. We first identified an anti-FZD antagonist antibody (F2) with a specificity profile matching that of OMP-18R5, a monoclonal antibody that inhibits growth of many cancers by targeting FZD7, FZD1, FZD2, FZD5 and FZD8. We then used combinatorial antibody engineering by phage display to develop a variant antibody F2.A with specificity broadened to include FZD4. We confirmed that F2.A blocked binding of Wnt ligands, but not binding of Norrin, a ligand that also activates FZD4. Importantly, F2.A proved to be much more efficacious than either OMP-18R5 or F2 in inhibiting the growth of multiple RNF43-mutant pancreatic ductal adenocarcinoma cell lines, including patient-derived cells.
2013-07-16 | LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling
Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-β1 (TGF-β1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-β accessory receptor endoglin, which, in the presence of TGF-β1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-β signalling. LRG1 is identified as a new regulator of TGF-β signalling that promotes angiogenesis via a TβRII–ALK1–ENG–Smad1/5/8 signalling pathway; antibody-mediated inhibition of LRG1 reduces pathogenic neovascularization in a mouse model of retinal injury. Defective angiogenesis is a common feature in many diseases including age-related macular degeneration, atherosclerosis, rheumatoid arthritis and cancer. Here John Greenwood and colleagues identify a novel angiogenic glycoprotein of previously unknown function — leucine-rich-alpha-2-glycoprotein 1 (LRG1) — that exerts its effect through modifying TGF-β signalling. LRG1, upregulated in vitreous samples from humans with proliferative diabetic retinopathy, activates an angiogenic switch by binding to the receptor endoglin and promoting pro-angiogenic TGF-β signalling. Antibody-mediated inhibition of LRG1 reduces pathogenic neovascularization in a mouse model of retinal injury, which suggests that LRG1 is a possible therapeutic target for controlling pathological angiogenesis in ocular disease.
oligonucleotides
2026-04-01 | Norrie Disease
Abstract This chapter provides clinical details of Norrie Disease, an XLID with a progressive ophthalmopathy (iris atrophy, uveal ectropion, anterior and posterior synechiae, cataract, hyperplastic vitreous, and retrolental mass) and adult-onset hearing loss. The gene, NDP, codes for a cysteine knot-containing growth factor. Missense mutations, especially in the C-terminal portion of the gene, result in a less severe phenotype. Ocular dysplasia and degeneration dominate the physical phenotype. Apart from the ocular findings, major malformations and facial manifestations do not occur. Moderate to severe sensorineural hearing loss appears in the second or third decade in about one-third of patients. Cognitive impairment of varying severity affects the majority of patients. Aside from blindness and deafness, neurological abnormalities do not occur.
2026-01-18 | Norrie Disease - An Overview
Norrie disease is a rare, severe inherited neurodevelopmental disorder primarily affecting the eye. It was first described by the Danish ophthalmologist Gordon Norrie in 1927, and later, Dr. Mette Warburg established its X-linked recessive inheritance pattern in 1961. The condition is caused by mutations in the NDP gene located on chromosome Xp11.3, which encodes the protein norrin. Norrin is a secreted protein that acts as a ligand for the Wnt/β-catenin signalling pathway (binding to the Frizzled-4 receptor), playing a critical role in the vascular development of the retina and the stria vascularis of the cochlea.
2022-04-18 | Endolymphatic Hydrop Phenotype in Familial Norrie Disease Caused by Large Fragment Deletion of NDP
Norrie disease (ND; OMIM 310600), a rare X-linked recessive genetic disorder, is characterized by congenital blindness and occasionally, sensorineural hearing loss, and developmental delay. The congenital blindness of ND patients is almost untreatable; thus, hearing is particularly important for them. However, the mechanism of hearing loss of ND patients is unclear, and no good treatment is available except wearing hearing-aid. Therefore, revealing the mechanism of hearing loss in ND patients and exploring effective treatment methods are greatly important. In addition, as a serious monogenic genetic disease, convenient gene identification method is important for ND patients and their family members, as well as prenatal diagnosis and preimplantation genetic diagnosis to block intergenerational transmission of pathogenic genes. In this study, a Norrie family with two male patients was reported. This pedigree was ND caused by large fragment deletion of NDP (norrin cystine knot growth factor NDP) gene. In addition to typical severe ophthalmologic and audiologic defects, the patients showed new pathological features of endolymphatic hydrops (EH), and they also showed acoustic nerves abnormal as described in a very recent report. PCR methods were developed to analyze and diagnose the variation of the family members. This study expands the understanding of the clinical manifestation and pathogenesis of ND and provides a new idea for the treatment of patients in this family and a convenient method for the genetic screen for this ND family.
2022-03-11 | A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes
While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. The potential occurrence of protein-altering variants in two different genes has been documented in a very small percentage of patients, but potential multigenic contributions to FEVR remain unclear. Genes involved in these orphan pediatric retinal diseases are not universally included in available IRD targeted-sequencing panels, and cost is also a factor limiting multigenic-sequence-based testing for these rare conditions. To provide an accurate solution at lower cost, we developed a targeted-sequencing protocol that includes seven genes involved in Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie disease. Seventy-six DNA samples from persons refered to clinic with possible FEVR and some close relatives were sequenced using a novel Oakland-ERI orphan pediatric retinal disease panel (version 2) providing 900 times average read coverage. The seven genes involved in FEVR/ND were: NDP (ChrX), CTNNB1 (Chr3); TSPAN12 (Chr7); KIF11 (Chr10), FZD4 (Chr11), LRP5 (Chr11), ZNF408 (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: LRP5 13/33 (40%), FZD4 9/33 (27%), ZNF408 6/33 (18%), (KIF11 3/33 (9%), NDP 1/33 (3%), CTNNB1 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: FZD4, LRP5, and ZNF408. Four previously known pathogenic variants were detected in five families and two unrelated individuals. Two novel, likely pathogenic variants were detected in one family (FZD4: Cys450ter), and a likely pathogenic frame shift termination variant was detected in one unrelated individual (LRP5: Ala919CysfsTer67). The average number of genes with protein-altering variants was greater in subjects with confirmed FEVR (1.46, n = 30) compared to subjects confirmed unaffected by FEVR (0.95, n = 20), (p = 0.009). Thirty-four percent of persons sequenced had digenic and trigenic protein-altering variants within this set of FEVR genes, which was much greater than expected in the general population (3.6%), as derived from GnomAD data. While the potential contributions to FEVR are not known for most of the variants in a multigenic context, the high multigenic frequency suggests that potential multigenic contributions to FEVR severity warrant future investigation. The targeted-sequencing format developed will support such exploration by reducing the testing cost to $250 (US) for seven genes and facilitating greater access to genetic testing for families with this very rare inherited retinal disease.
small molecules
2024-11-25 | Rescue of cochlear vascular pathology prevents sensory hair cell loss in Norrie disease.
Variants in the gene NDP cause Norrie disease, a severe dual-sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death. NDP encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood. We investigated whether the Norrie disease cochlear pathology can be ameliorated in an Ndp-knockout (Ndp-KO) mouse model by conditional activation of stabilized β-catenin in vascular endothelial cells. We hypothesized that in the cochlea microvasculature, β-catenin is the primary downstream intracellular effector of norrin binding to endothelial cell surface receptors and that restoration of this signaling pathway is sufficient to prevent sensory hair cell death and hearing loss. We show that tamoxifen induction of Cdh5CreERT2;Ctnnb1flex3/+;Ndp-KO mice stabilizing β-catenin in vascular endothelial cells alone rescued defects in cochlear vascular barrier function, restored dysregulated expression of endothelial cell disease biomarkers (Cldn5, Abcb1a, Slc7a1, and Slc7a5), and prevented progressive outer hair cell death and hearing loss. Single-cell transcriptome profiling of human cochleas showed NDP expression by fibrocytes and glial cells while receptor gene expression (FZD4, TSPAN12, LRP5, and LRP6) coincided in vascular endothelial cells. Our findings support the conclusion that vascular endothelial cells are a primary target of norrin signaling in the cochlea of mice and humans and restoration of β-catenin regulation of target gene expression within cochlear endothelial cells is sufficient to maintain a cochlear microenvironment critical for hair cell survival.
2023-08-24 | The role of PLVAP in endothelial cells.
Endothelial cells play a major part in the regulation of vascular permeability and angiogenesis. According to their duty to fit the needs of the underlying tissue, endothelial cells developed different subtypes with specific endothelial microdomains as caveolae, fenestrae and transendothelial channels which regulate nutrient exchange, leukocyte migration, and permeability. These microdomains can exhibit diaphragms that are formed by the endothelial cell-specific protein plasmalemma vesicle-associated protein (PLVAP), the only known protein component of these diaphragms. Several studies displayed an involvement of PLVAP in diseases as cancer, traumatic spinal cord injury, acute ischemic brain disease, transplant glomerulopathy, Norrie disease and diabetic retinopathy. Besides an upregulation of PLVAP expression within these diseases, pro-angiogenic or pro-inflammatory responses were observed. On the other hand, loss of PLVAP in knockout mice leads to premature mortality due to disrupted homeostasis. Generally, PLVAP is considered as a major factor influencing the permeability of endothelial cells and, finally, to be involved in the regulation of vascular permeability. Following these observations, PLVAP is debated as a novel therapeutic target with respect to the different vascular beds and tissues. In this review, we highlight the structure and functions of PLVAP in different endothelial types in health and disease.
2022-03-14 | LMBR1L regulates the proliferation and migration of endothelial cells through Norrin/β-catenin signaling
Precise Norrin and β-catenin (Norrin/β-catenin; encoded by NDP and CTNNB1, respectively) signaling is critical for proper angiogenesis. Dysregulation of this signaling leads to various diseases, of which retinal exudative vitreoretinopathy is the most prevalent. Here, we used a global knockout mouse model to show that limb development membrane protein 1 like (LMBR1L), a transmembrane protein of unknown function in angiogenesis, is essential for retinal vascular development. In vitro experiments revealed that LMBR1L depletion results in aberrant activation of the Norrin/β-catenin signaling pathway via decreased ubiquitylation of FZD4 and increased Norrin co-receptor LRP5 and p-GSK3β-Ser9 expression levels, which cause accumulation of β-catenin. Moreover, inhibition of LMBR1L in human retinal microvascular endothelial cells (HRECs) caused increased proliferation ability and defective cell migration, which might have occurred as a result of upregulated expression levels of the apical junction components. Treatment with p-GSK3β-Ser9 inhibitor AR-A014418 restored the phenotypes in LMBR1L-null HRECs, which further demonstrated the important regulatory role of LMBR1L in the Norrin/β-catenin signaling pathway. Taken together, our data reveal an essential role for LMBR1L in angiogenesis. This article has an associated First Person interview with the first author of the paper.
2021-02-05 | Faculty Opinions recommendation of Wnt signaling activates MFSD2A to suppress vascular endothelial transcytosis and maintain blood-retinal barrier.
Breakdown of the blood-retinal barrier (BRB) causes retinal edema and vision loss.We investigated the role of Wnt signaling in maintaining the BRB by limiting transcytosis.Mice lacking either the Wnt co-receptor low-density lipoprotein receptor-related protein 5 (Lrp5 -/-) or the Wnt ligand Norrin (Ndp y/-) exhibit increased retinal vascular leakage and enhanced endothelial transcytosis.Wnt signaling directly controls the transcription of an endotheliumspecific transcytosis inhibitor, major facilitator superfamily domain-containing protein 2a (MFSD2A), in a -catenin-dependent manner.MFSD2A overexpression reverses Wnt deficiency-induced transcytosis in endothelial cells and in retinas.Moreover, Wnt signaling mediates MFSD2A-dependent vascular endothelium transcytosis through a caveolin-1 (CAV-1)-positive caveolae pathway.In addition, levels of omega-3 fatty acids are also decreased in Wnt signaling-deficient retinas, reflecting the basic function of MFSD2A as a lipid transporter.Our findings uncovered the Wnt/-catenin/MFSD2A/CAV-1 axis as a key pathway governing endothelium transcytosis and inner BRB integrity.
2019-06-25 | Extracellular Vesicles from Activated Dermal Fibroblasts Stimulate Hair Follicle Growth Through Dermal Papilla-Secreted Norrin
Abstract Dermal papilla cells (DPCs) play a pivotal role in the regulation of hair follicle (HF) growth, formation, and cycling, mainly through paracrine mechanisms. In the last decade, extracellular vesicles (EVs) have been recognized as a new paracrine mechanism that can modify the physiological state of recipient cells by transferring biological material. Herein, we investigated the effect of EVs isolated from stimulated human dermal fibroblasts (DFs) on DPC activation and HF growth. We found that these EVs (st-EVs) enhanced HF growth ex vivo. Comparative transcriptomic analysis on DPCs identified specific activation of the NDP gene, encoding the non-Wnt ligand Norrin. We found that Norrin was secreted by st-EVs-stimulated DPCs activating in a noncell autonomous manner β-catenin pathway in follicular keratinocytes (human HF keratinocyte [HHFK]) and hair growth ex vivo. Although Norrin-specific receptor Frizzled4 was barely detected in HHFK, we found its presence in DF-EVs. Accordingly, DF-EVs provided Frizzled4 to potentiate Norrin effects ex vivo. Our study identifies DF-EVs as efficient activators of DPCs and Norrin as a novel modulatory player in HF physiopathology. Stem Cells 2019;37:1166–1175
proteins
2023-06-02 | Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice
Abstract Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer’s disease. The Norrin/FZD 4 /TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD 4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD 4 -selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD 4 -specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout ( Ndp KO ) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD 4 -selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
2022-10-14 | Therapeutic modulation of the blood-brain barrier and ischemic stroke by a bioengineered FZD4-selective WNT surrogate
Abstract Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer’s disease. The Norrin/FZD 4 /TSPAN12 pathway activates WNT/β-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD 4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD 4 -selective ligand Norrin. Here, we developed L6-F4-2, a non-lipidated, FZD 4 -specific surrogate with significantly improved sub-picomolar affinity versus native Norrin. In Norrin knockout ( Ndp KO ) mice, L6-F4-2 not only potently reversed neonatal retinal angiogenesis deficits, but also restored BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduced BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD 4 -selective WNT surrogate during ischemic BBB dysfunction, with general applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.
2022-08-15 | Long-Term Anatomic and Visual Outcomes of Planned Preterm Delivery and Treatment of Norrie Disease.
We previously reported that planned preterm delivery at 34 weeks gestational age provided an opportunity to treat Norrie disease in the vasoproliferative phase, prevented infantile retinal detachment, and preserved functional vision without further treatment after infancy. Although retinal vascularization did not proceed postnatally, after 8 years of follow-up, the retinas remained attached, and rudimentary foveal development was observed by optical coherence tomography. Best corrected visual acuity gradually improved to 20/80 with both eyes, and visual fields and real-world visual performance were remarkably functional. Global development progressed appropriately, and no long-term sequelae of premature delivery were observed. [Ophthalmic Surg Lasers Imaging Retina 2022;53:464-467.].
2020-03-17 | Norrin mediates tumor-promoting and -suppressive effects in glioblastoma via Notch and Wnt
Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on ASCL1lo and ASCL1hi GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in ASCL1lo GSCs. In contrast, in ASCL1hi GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in ASCL1lo GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype–restricted cancer stem cells.
2020-02-07 | Wnt Signaling in vascular eye diseases.
The Wnt signaling pathway plays a pivotal role in vascular morphogenesis in various organs including the eye. Wnt ligands and receptors are key regulators of ocular angiogenesis both during the eye development and in vascular eye diseases. Wnt signaling participates in regulating multiple vascular beds in the eye including regression of the hyaloid vessels, and development of structured layers of vasculature in the retina. Loss-of-function mutations in Wnt signaling components cause rare genetic eye diseases in humans such as Norrie disease, and familial exudative vitreoretinopathy (FEVR) with defective ocular vasculature. On the other hand, experimental studies in more prevalent vascular eye diseases, such as wet age-related macular degeneration (AMD), diabetic retinopathy (DR), retinopathy of prematurity (ROP), and corneal neovascularization, suggest that aberrantly increased Wnt signaling is one of the causations for pathological ocular neovascularization, indicating the potential of modulating Wnt signaling to ameliorate pathological angiogenesis in eye diseases. This review recapitulates the key roles of the Wnt signaling pathway during ocular vascular development and in vascular eye diseases, and pharmaceutical approaches targeting the Wnt signaling as potential treatment options.
antibodies
2025-07-08 | Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling.
The Wnt/β-catenin pathway requires precise regulation for proper development and tissue homeostasis, yet the structural mechanisms enabling its fine-tuned control remain incompletely understood. Here, we reveal how LGR4 achieves differential signaling outcomes through distinct recognition of two key modulators: Norrin and R-spondins (RSPOs). Using cryo-electron microscopy, we determined the structure of full-length LGR4 bound to Norrin in a 2:2 stoichiometry, revealing a molecular bridging mechanism where Norrin dimer connect two LGR4 protomers in a spatial arrangement fundamentally distinct from the LGR4-RSPO2-ZNRF3 complex. Notably, Norrin binding to LGR4 sterically hinders simultaneous interaction with the Frizzled4 receptor, establishing a regulatory checkpoint in Wnt signaling. The partially overlapping binding sites for Norrin and RSPOs on LGR4 enable mutually exclusive interactions that drive distinct signaling outcomes. Disease-linked mutations map to distinct functional regions: those disrupting LGR4 interaction are associated with familial exudative vitreoretinopathy (FEVR), while others impairing Frizzled4 binding are linked to Norrie disease. Furthermore, we developed a high-affinity nanobody that blocks both Norrin and RSPO binding to LGR4, providing a potential tool for therapeutic intervention. These findings elucidate the structural basis of LGR4's dual signaling roles and lay the groundwork for therapeutic strategies targeting Wnt-related diseases.
2018-09-25 | A synthetic anti-Frizzled antibody engineered for broadened specificity exhibits enhanced anti-tumor properties
Secreted Wnt ligands play a major role in the development and progression of many cancers by modulating signaling through cell-surface Frizzled receptors (FZDs). In order to achieve maximal effect on Wnt signaling by targeting the cell surface, we developed a synthetic antibody targeting six of the 10 human FZDs. We first identified an anti-FZD antagonist antibody (F2) with a specificity profile matching that of OMP-18R5, a monoclonal antibody that inhibits growth of many cancers by targeting FZD7, FZD1, FZD2, FZD5 and FZD8. We then used combinatorial antibody engineering by phage display to develop a variant antibody F2.A with specificity broadened to include FZD4. We confirmed that F2.A blocked binding of Wnt ligands, but not binding of Norrin, a ligand that also activates FZD4. Importantly, F2.A proved to be much more efficacious than either OMP-18R5 or F2 in inhibiting the growth of multiple RNF43-mutant pancreatic ductal adenocarcinoma cell lines, including patient-derived cells.
2013-07-16 | LRG1 promotes angiogenesis by modulating endothelial TGF-β signalling
Aberrant neovascularization contributes to diseases such as cancer, blindness and atherosclerosis, and is the consequence of inappropriate angiogenic signalling. Although many regulators of pathogenic angiogenesis have been identified, our understanding of this process is incomplete. Here we explore the transcriptome of retinal microvessels isolated from mouse models of retinal disease that exhibit vascular pathology, and uncover an upregulated gene, leucine-rich alpha-2-glycoprotein 1 (Lrg1), of previously unknown function. We show that in the presence of transforming growth factor-β1 (TGF-β1), LRG1 is mitogenic to endothelial cells and promotes angiogenesis. Mice lacking Lrg1 develop a mild retinal vascular phenotype but exhibit a significant reduction in pathological ocular angiogenesis. LRG1 binds directly to the TGF-β accessory receptor endoglin, which, in the presence of TGF-β1, results in promotion of the pro-angiogenic Smad1/5/8 signalling pathway. LRG1 antibody blockade inhibits this switch and attenuates angiogenesis. These studies reveal a new regulator of angiogenesis that mediates its effect by modulating TGF-β signalling. LRG1 is identified as a new regulator of TGF-β signalling that promotes angiogenesis via a TβRII–ALK1–ENG–Smad1/5/8 signalling pathway; antibody-mediated inhibition of LRG1 reduces pathogenic neovascularization in a mouse model of retinal injury. Defective angiogenesis is a common feature in many diseases including age-related macular degeneration, atherosclerosis, rheumatoid arthritis and cancer. Here John Greenwood and colleagues identify a novel angiogenic glycoprotein of previously unknown function — leucine-rich-alpha-2-glycoprotein 1 (LRG1) — that exerts its effect through modifying TGF-β signalling. LRG1, upregulated in vitreous samples from humans with proliferative diabetic retinopathy, activates an angiogenic switch by binding to the receptor endoglin and promoting pro-angiogenic TGF-β signalling. Antibody-mediated inhibition of LRG1 reduces pathogenic neovascularization in a mouse model of retinal injury, which suggests that LRG1 is a possible therapeutic target for controlling pathological angiogenesis in ocular disease.
oligonucleotides
2026-04-01 | Norrie Disease
Abstract This chapter provides clinical details of Norrie Disease, an XLID with a progressive ophthalmopathy (iris atrophy, uveal ectropion, anterior and posterior synechiae, cataract, hyperplastic vitreous, and retrolental mass) and adult-onset hearing loss. The gene, NDP, codes for a cysteine knot-containing growth factor. Missense mutations, especially in the C-terminal portion of the gene, result in a less severe phenotype. Ocular dysplasia and degeneration dominate the physical phenotype. Apart from the ocular findings, major malformations and facial manifestations do not occur. Moderate to severe sensorineural hearing loss appears in the second or third decade in about one-third of patients. Cognitive impairment of varying severity affects the majority of patients. Aside from blindness and deafness, neurological abnormalities do not occur.
2026-01-18 | Norrie Disease - An Overview
Norrie disease is a rare, severe inherited neurodevelopmental disorder primarily affecting the eye. It was first described by the Danish ophthalmologist Gordon Norrie in 1927, and later, Dr. Mette Warburg established its X-linked recessive inheritance pattern in 1961. The condition is caused by mutations in the NDP gene located on chromosome Xp11.3, which encodes the protein norrin. Norrin is a secreted protein that acts as a ligand for the Wnt/β-catenin signalling pathway (binding to the Frizzled-4 receptor), playing a critical role in the vascular development of the retina and the stria vascularis of the cochlea.
2022-04-18 | Endolymphatic Hydrop Phenotype in Familial Norrie Disease Caused by Large Fragment Deletion of NDP
Norrie disease (ND; OMIM 310600), a rare X-linked recessive genetic disorder, is characterized by congenital blindness and occasionally, sensorineural hearing loss, and developmental delay. The congenital blindness of ND patients is almost untreatable; thus, hearing is particularly important for them. However, the mechanism of hearing loss of ND patients is unclear, and no good treatment is available except wearing hearing-aid. Therefore, revealing the mechanism of hearing loss in ND patients and exploring effective treatment methods are greatly important. In addition, as a serious monogenic genetic disease, convenient gene identification method is important for ND patients and their family members, as well as prenatal diagnosis and preimplantation genetic diagnosis to block intergenerational transmission of pathogenic genes. In this study, a Norrie family with two male patients was reported. This pedigree was ND caused by large fragment deletion of NDP (norrin cystine knot growth factor NDP) gene. In addition to typical severe ophthalmologic and audiologic defects, the patients showed new pathological features of endolymphatic hydrops (EH), and they also showed acoustic nerves abnormal as described in a very recent report. PCR methods were developed to analyze and diagnose the variation of the family members. This study expands the understanding of the clinical manifestation and pathogenesis of ND and provides a new idea for the treatment of patients in this family and a convenient method for the genetic screen for this ND family.
2022-03-11 | A Survey of Multigenic Protein-Altering Variant Frequency in Familial Exudative Vitreo-Retinopathy (FEVR) Patients by Targeted Sequencing of Seven FEVR-Linked Genes
While Inherited Retinal Diseases (IRDs) are typically considered rare diseases, Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie Disease (ND) are more rare than retinitis pigmentosa. We wanted to determine if multigenic protein-altering variants are common in FEVR subjects within a set of FEVR-related genes. The potential occurrence of protein-altering variants in two different genes has been documented in a very small percentage of patients, but potential multigenic contributions to FEVR remain unclear. Genes involved in these orphan pediatric retinal diseases are not universally included in available IRD targeted-sequencing panels, and cost is also a factor limiting multigenic-sequence-based testing for these rare conditions. To provide an accurate solution at lower cost, we developed a targeted-sequencing protocol that includes seven genes involved in Familial Exudative Vitreo-Retinopathy (FEVR) and Norrie disease. Seventy-six DNA samples from persons refered to clinic with possible FEVR and some close relatives were sequenced using a novel Oakland-ERI orphan pediatric retinal disease panel (version 2) providing 900 times average read coverage. The seven genes involved in FEVR/ND were: NDP (ChrX), CTNNB1 (Chr3); TSPAN12 (Chr7); KIF11 (Chr10), FZD4 (Chr11), LRP5 (Chr11), ZNF408 (Chr11). A total of 33 variants were found that alter protein sequence, with the following relative distribution: LRP5 13/33 (40%), FZD4 9/33 (27%), ZNF408 6/33 (18%), (KIF11 3/33 (9%), NDP 1/33 (3%), CTNNB1 1/33 (3%). Most protein-altering variants, 85%, were found in three genes: FZD4, LRP5, and ZNF408. Four previously known pathogenic variants were detected in five families and two unrelated individuals. Two novel, likely pathogenic variants were detected in one family (FZD4: Cys450ter), and a likely pathogenic frame shift termination variant was detected in one unrelated individual (LRP5: Ala919CysfsTer67). The average number of genes with protein-altering variants was greater in subjects with confirmed FEVR (1.46, n = 30) compared to subjects confirmed unaffected by FEVR (0.95, n = 20), (p = 0.009). Thirty-four percent of persons sequenced had digenic and trigenic protein-altering variants within this set of FEVR genes, which was much greater than expected in the general population (3.6%), as derived from GnomAD data. While the potential contributions to FEVR are not known for most of the variants in a multigenic context, the high multigenic frequency suggests that potential multigenic contributions to FEVR severity warrant future investigation. The targeted-sequencing format developed will support such exploration by reducing the testing cost to $250 (US) for seven genes and facilitating greater access to genetic testing for families with this very rare inherited retinal disease.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Norrie disease.
2 orphan drug designations for Norrie disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adeno-associated viral vector serotype ShH10 containing a codon-optimised human NDP gene | gene therapies | EMA | — | UCL Research Limited |
Adeno-associated virus serotype 9 vector containing the human NDP gene | gene therapies | EMA | — | UCL Research Limited |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.