更新于：2024-05-01

Norrie Disease

诺里病

更新于：2024-05-01

基本信息

别名

ATROPHIA BULBORUM HEREDITARIA、Anderson-Warburg Syndrome、Atrophia bulborum hereditaria

+ [31]

简介

A rare, X-linked recessive inherited syndrome caused by mutations in the NPD gene. It is characterized by developmental retinal abnormalities that result in blindness in male infants at birth or soon after birth. Additional manifestations include progressive hearing loss and developmental motor skills delays.

关联

项与诺里病相关的临床试验

NCT05004090 / RecruitingN/AIIT

Emotional-behavioral Regulation in Children With Neurodevelopmental Disabilities: an Exploratory Investigation of the Role of Genomic Variation, Proteomic Patterns, and Quality of Early Experience

Children with neurodevelopmental disabilities (ND) represent an heterogeneous population characterized by a wide range of clinical diagnoses (e.g., cerebral palsy, sensory impairment, psychomotor retardation), which are associated with various deficits that emerge early in the child's life. Although it has been broadly demonstrated that children with ND exhibit several differences in social-emotional skills and emotional-behavioral regulation, the underlying mechanisms that are associated with more or less impaired developmental trajectories remain still partially unexplored. While several studies have investigated the role of biological and environmental factors in the emotional behavioral regulation of typically developing children or children with risk conditions other than ND (e.g., children who are victims of maltreatment), little research has jointly explored the role of methylation, polymorphisms, and environmental experience in the emotional-behavioral regulation of children with ND during the first years of life. The aim of this project is to investigate biological (DNA methylation, polymorphic variants, and proteomics) and environmental (e.g., painful and/or invasive nursing procedures, proximity, and physical contact) factors that might be associated with the emotional behavioral regulation of children with ND.

开始日期2021-04-07

申办/合作机构-

100 项与诺里病相关的临床结果

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100 项与诺里病相关的转化医学

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0 项与诺里病相关的专利（医药）

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3,248

项与诺里病相关的文献（医药）

2024-03-01·Life science alliance

USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms.

Article

作者: Intisar Koch ; Maya Slovik ; Yuling Zhang ; Bingyu Liu ; Martin Rennie ; Emily Konz ; Benjamin Cogne ; Muhannad Daana ; Laura Davids ; Illja J Diets ; Nina B Gold ; Alexander M Holtz ; Bertrand Isidor ; Hagar Mor-Shaked ; Juanita Neira Fresneda ; Karen Y Niederhoffer ; Mathilde Nizon ; Rolph Pfundt ; Meh Simon ; Apa Stegmann ; Maria J Guillen Sacoto ; Marijke Wevers ; Tahsin Stefan Barakat ; Shira Yanovsky-Dagan ; Boyko S Atanassov ; Rachel Toth ; Chengjiang Gao ; Francisco Bustos ; Tamar Harel

Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.

2024-02-22·Neuroscience

Bioinformatics and Systems Biology Approaches to Identify the Synergistic Effects of Alcohol Use Disorder on the Progression of Neurological Diseases.

Article

作者: Md Jahangir Alam ; Md Habibur Rahman ; Md Arju Hossain ; Md Robiul Hoque ; Md Aktaruzzaman

Clinical investigations showed that individuals with Alcohol Use Disorder (AUD) have worse Neurological Disease (ND) development, pointing to possible pathogenic relationships between AUD and NDs. It remains difficult to identify risk factors that are predisposing between AUD and NDs. In order to fix these issues, we created the bioinformatics pipeline and network-based approaches for employing unbiased methods to discover genes abnormally stated in both AUD and NDs and to pinpoint some of the common molecular pathways that might underlie AUD and ND interaction. We found 100 differentially expressed genes (DEGs) in both the AUD and ND patient's tissue samples. The most important Gene Ontology (GO) terms and metabolic pathways, including positive control of cytotoxicity caused by T cells, proinflammatory responses, antigen processing and presentation, and platelet-triggered interactions with vascular and circulating cell pathways were then extracted using the overlapped DEGs. Protein-protein interaction analysis was used to identify hub proteins, including CCL2, IL1B, TH, MYCN, HLA-DRB1, SLC17A7, and HNF4A, in the pathways that have been reported as playing a function in these disorders. We determined several TFs (HNF4A, C4A, HLA-B, SNCA, HLA-DMB, SLC17A7, HLA-DRB1, HLA-C, HLA-A, and HLA-DPB1) and potential miRNAs (hsa-mir-34a-5p, hsa-mir-34c-5p, hsa-mir-449a, hsa-mir-155-5p, and hsa-mir-1-3p) were crucial for regulating the expression of AUD and ND which could serve as prospective targets for treatment. Our methodologies discovered unique putative biomarkers that point to the interaction between AUD and various neurological disorders, as well as pathways that could one day be the focus of therapeutic intervention.

2024-02-22·Scientific reports

Mechanism exploration and biomarker identification of glycemic deterioration in patients with diseases of the exocrine pancreas.

Article

作者: Zhen Wang ; Guolin Zhang ; Jixian Fu ; Guangxing Li ; Zhihao Zhao ; HyokChol Choe ; Kaiyue Ding ; Junnan Ma ; Jing Wei ; Dong Shang ; Lin Zhang

The damage to the endocrine pancreas among patients with diseases of the exocrine pancreas (DP) leads to reduced glycemic deterioration, ultimately resulting in diabetes of the exocrine pancreas (DEP). The present research aims to investigate the mechanism responsible for glycemic deterioration in DP patients, and to identify useful biomarkers, with the ultimate goal of enhancing clinical practice awareness. Gene expression profiles of patients with DP in this study were acquired from the Gene Expression Omnibus database. The original study defines DP patients to belong in one of three categories: non-diabetic (ND), impaired glucose tolerance (IGT) and DEP, which correspond to normoglycemia, early and late glycemic deterioration, respectively. After ensuring quality control, the discovery cohort included 8 ND, 20 IGT, and 12 DEP, while the validation cohort included 27 ND, 15 IGT, and 20 DEP. Gene set enrichment analysis (GSEA) employed differentially expressed genes (DEGs), while immunocyte infiltration was determined using single sample gene set enrichment analysis (ssGSEA). Additionally, correlation analysis was conducted to establish the link between clinical characteristics and immunocyte infiltration. The least absolute shrinkage and selection operator regression and random forest combined to identify biomarkers indicating glycemic deterioration in DP patients. These biomarkers were further validated through independent cohorts and animal experiments. With glycemic deterioration, biological processes in the pancreatic islets such as nutrient metabolism and complex immune responses are disrupted in DP patients. The expression of ACOT4, B2M, and ACKR2 was upregulated, whereas the expression of CACNA1F was downregulated. Immunocyte infiltration in the islet microenvironment showed a significant positive correlation with the age, body mass index (BMI), HbA1c and glycemia at the 2-h of patients. It was a crucial factor in glycemic deterioration. Additionally, B2M demonstrated a significant positive correlation with immunocyte infiltration and clinical features. Quantitative real-time PCR (qRT-PCR) and western blotting confirmed the upregulation in B2M. Immunofluorescent staining suggested the alteration of B2M was mainly in the alpha cells and beta cells. Overall, the study showed that gradually increased immunocyte infiltration was a significant contributor to glycemic deterioration in patients with DP, and it also highlighted B2M as a biomarker.

项与诺里病相关的新闻（医药）

2024-03-12

·CPHI制药在线

阿斯利康入局！让众多MNC折戟的CD123到底有何魅力？

关注并星标CPHI制药在线近日，中国国家药监局药品审评中心（CDE）官网公示，阿斯利康（AstraZeneca）1类新药AZD9829获得临床试验默示许可，拟开发治疗CD123阳性恶性血液疾病。公开资料显示，AZD9829是一款靶向CD123的拓扑异构酶1抑制剂（TOP1i）-抗体偶联药物（ADC）。AZD9829是一种靶向CD123的抗体与阿斯利康专有的拓扑异构酶1抑制剂（TOP1i）有效载荷连接而成的ADC。该药的主要作用机制是将TOP1i载荷递送到表达CD123的癌细胞中，导致DNA损伤和细胞凋亡。研究表明，AZD9829在体外显示出对CD123阳性的AML细胞系的强大杀伤能力。此外，AZD9829在第一次给药后第28天表现出持久的白血病母细胞减少，包括血液和骨髓中白血病母细胞的减少。据ClinicalTrials官网显示，阿斯利康在美国刚开展一项1/2期临床研究，评估AZD9829单独或联合疗法治疗CD123阳性血液恶性肿瘤患者的安全性、耐受性、药代动力学和初步抗肿瘤活性。预计招募79人，2026年2月份公布研究数据。 CD123：血液肿瘤潜力靶点大多数细胞因子受体是由两个或两个以上的亚单位组成的异源二聚体或多聚体，通常包括一个特异性配体结合α链和一个参与信号的β链。α链构成低亲和力受体，β链一般单独不能与细胞因子结合，但参与高亲和力受体的形成和信号转导。IL-3R、IL-5R 和 GM-CSFR都属于这一类，且都作用于造血系统，促进造血干细胞或定向干细胞的增殖。其中IL-3R的α链被命名为CD123，它是一种跨膜糖蛋白，能够以单体的低亲和力与IL-3特异结合，当与IL-3R的β链（CD131）形成异二聚体时，可以形成高亲和力的IL-3受体复合物，并以通过细胞膜激活细胞内受体级联下游信号，进而激活JAK/STAT, RAS-MAPK和磷脂酰肌醇3-激酶通路。图片来源：参考来源3 同时CD123 在各种血液恶性肿瘤中广泛过度表达，包括急性髓性白血病 (AML)、B 细胞急性淋巴细胞白血病、毛细胞白血病、霍奇金淋巴瘤和母细胞性浆细胞样树突状肿瘤（BPDCN）。更为重要的是，CD123 在白血病干细胞 (LSC) 和分化程度更高的白血病母细胞均表达。虽然CD123也在正常的造血干细胞上表达，但其表达水平低于LSC，这使得 CD123 成为非常有吸引力的治疗靶点。靶向CD123药物开发接连受挫，诸多Big Pharma折戟沉沙 CD123在许多血液系统恶性肿瘤中过表达，主要在CD34+/CD38- AML细胞中过表达，且CD123过表达意味着患者预后不良。因为CD123本身作为肿瘤细胞表面的一个特异性标记物所存在的潜在开发价值，诸多Big Pharma围绕该靶点也做了很多新药开发尝试，但无一例外，这些新的靶向疗法初步尝试都遭受了临床挫折。强生就曾在CD123靶点上摔了两跤。Talacotuzumab是强生旗下公司杨森研发的一款CD123单克隆抗体药物。2021年，一项评估Talacotuzumab联合地西他滨在不适合强化化疗的老年急性髓系白血病（AML）患者中疗效的多中心2/3期临床研究结果显示：联合治疗的完全缓解率和总生存率并不高于单独使用地西他滨。此外，与单独使用地西他滨相比，talacotuzumab联合使用地西他滨的严重治疗相关不良事件更高因此，由于缺乏疗效和高毒性率，强生最终决定停止整个talacotuzumab研究计划。另外，强生和Genmab合作开发的CD123/CD3双特异抗体JNJ63709178也因发生一例严重毒副反应，临床试验被FDA全面叫停。 CD123/CD3双抗方面，诺华也曾高调入局，低调退出。2016年，诺华与Xencor签订高达26亿美元的合作协议，获得用于治疗急性髓系白血病 (AML)的CD123/CD3候选药物XmAb14045（vibecotamab）及用于治疗B细胞恶性肿瘤CD123/CD3候选药物XmAb13676的开发权利。但合作时间不足三年，诺华（2019 年1月）在战略管线重排后放弃了其中一种候选药物XmAb13676，并把该药的商业化和开发权交还给Xencor（2019年6月生效）。彼时，诺华并未完全退出这场交易，双方继续合作开发XmAb14045。但在2019年12月，由于在临床试验中出现的安全性问题（一例患者在首次给药后出现了细胞因子释放综合征（CRS），另一例患者在数次给药后出现了急性肺水肿），FDA暂停了XmAb14045的临床试验。随后一年，诺华还是选择终止了对该药物的临床开发。Xencor似乎也对该候选药物丧失开发信心，Xencor在公告中表示，将完全放弃该药物的开发，公司内部没有未来的研究计划。 CD123在研药物一览 Elzonris（tagraxofusp）是全球首个针对母细胞性浆细胞样树突细胞肿瘤（BPDCN）的治疗药物，也是首个获批的靶向CD123的药物。该药由人IL-3与截短的白喉毒素（DT）进行重组融合而成，其中IL-3结构域能够将细胞毒性DT片段引导至表达CD123的肿瘤细胞，在被肿瘤细胞内化后，不可逆地抑制蛋白质合成并诱导靶细胞凋亡。除了治疗BPDCN，Elzonris还将开发用于治疗其他CD123阳性适应症，包括：慢性骨髓单核细胞性白血病（CMML）、骨髓纤维化（MF）及其他适应症。在tagraxofusp被成功开发并上市的影响下，在过去十多年的时间里，将靶向 CD123 作为治疗 CD123 过度表达的血液系统恶性肿瘤（特别是AML）作为潜在策略的药物开发如火如荼。尽管多款药物在临床中遭遇了重创，但CD123靶点在血液瘤领域的热度却依然不低，尤其对于该靶点在双抗、ADC、CAR-T细胞疗法中的开发，近几年吸引不少药企和研发机构投入。部分在研靶向CD123 药物 APVO436是Aptevo Therapeutics研发的一种创新双特异性重组蛋白，它像两个单克隆抗体连接在一起，可以同时靶向肿瘤细胞表面的CD123和T淋巴细胞表面的CD3，从而将宿主免疫系统的T细胞重定向到患者的肿瘤细胞上，以快速和完全摧毁表面表达CD123的肿瘤细胞。APVO436经改造后可在血液循环中停留足够长的时间，以发现、结合并破坏白血病细胞。 APVO436与维奈托克（venetoclax）和阿扎胞苷联用，在针对急性髓系白血病（AML）患者的1b期剂量递增试验中取得了积极结果。结果显示，患者对该三联疗法的缓解率达82%（9/11），27%（3/11）的患者缓解充分，可继续接受干细胞移植。此外，在有缓解的患者中，有一名患者持续完全缓解达8个周期（方案允许的最长周期），这意味着缓解持续时间（DOR）至少为8个月。目前，中位DOR尚未达到。图片来源：Aptevo Therapeutics官网 IMGN632（Pivekimab sunirine）是ImmunoGen研发的一款靶向CD123的ADC，该药物使用一种新型吲吲哚啉类苯并二氮（IGN）载荷DGN549，它能在不交联的情况下对DNA进行烷基化，导致单链DNA损伤。正在开发用于母细胞性浆样树突细胞肿瘤（BPDCN）和AML，处于临床II期阶段。此前，该药物被FDA授予用于治疗复发/难治性BPDCN的突破性治疗资格。 IMGN632与阿扎胞苷(Vidaza)、维奈克拉 (venetoclax)联合用于新诊断(ND)急性髓性白血病(AML)患者1b/2期也取得了积极结果，并在第 65 届美国血液学会 (ASH) 年会上公布。具体数据显示，在总体人群中，CCR率为68% (34/50)，CR率为54%(27/50)，可评估患者中MRD阴性率为76%(22/29)。图片来源：ImmunoGen官网从上述CD123在研药物表格中不难发现，针对该靶点，目前更多研究机构及企业将目光放在了CAR-T细胞疗法上。鉴于CAR-T疗法近几年在血液肿瘤中的优异表现，该靶点也许能获得新的突破。尽管目前CD123 CAR-T细胞疗法的研发项目颇多，进展也还不错，但临床数据公布的还不多，无法对其进行更多预测。国内有福建医科大学研发的CD123/CLL1 CAR-T，一款双靶点CAR-T细胞疗法，目前处于治疗复发和难治性急性髓细胞白血病的II/III期临床研究阶段。结语总的来说，CD123这个靶点有点邪乎，虽然作为肿瘤细胞表面的一个特异性标记物具有潜在的开发价值，不过临床试验中出现的一系列的不良安全事件说明，CD123在正常组织中存在的些许表达仍可能仍是它的一个致命缺陷。Tagraxofusp药物的成功至少说明CD123是个可成药靶点，但开发相应的靶向药物仍是一个需要长时间待定的验证问题，期待该靶点药物早日取得突破性进展结果。参考来源： 1. 各企业官网 2. Michael J. Slade, Geoffrey Uy，CD123 bi-specific antibodies in development in AML: What do we know so far?Best Practice & Research Clinical Haematology (2020), doi: https://doi.org/10.1016/j.beha.2020.101219. 3. Hanadi El Achi et al，CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies，Cancers 2020, 12, 3087 【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

抗体药物偶联物申请上市

2023-07-17

·BioSpace

Caeregen Therapeutics Receives $1.4 Million Phase 2 SBIR Grant from NIH/NEI to Advance Development of Regenerative Medicine Clinical Candidate CTR-107 (Noregen™) for Retinal Diseases

ROCHESTER, Mich.--(BUSINESS WIRE)-- Caeregen Therapeutics announced today that it has been awarded a $1.4 million Phase 2 Small Business Innovation Research (SBIR) grant from the National Institutes of Health (NIH) and National Eye Institute to advance the development of CTR-107 (Noregen™), a novel regenerative therapeutic for the treatment of retinal-related vision loss due to a wide range of inherited and age-related diseases. Caeregen is initially developing CTR-107 for the treatment of a rare inherited disorder of retinal blood vessel formation, Familial Exudative Vitreoretinopathy (FEVR). “The NIH grant will support the nonclinical development program of CTR-107 and accelerate our investigational new drug (IND) submission to begin clinical trials," said Walter Capone, CEO of Caeregen Therapeutics. “This award provides further, important validation for CTR-107 and our novel approach to retinal disease treatment, the first with the potential to restore retinal function and reverse vision loss,” said Dr. Kimberly Drenser, Chief Scientific Officer of Caeregen Therapeutics. Retinal disease is the leading cause of vision loss in developed countries and is the fastest growing cause of blindness globally. Currently, it is estimated that vision-depriving retinal diseases, such as macular degeneration, diabetic retinopathy, retinal vein occlusion, and ischemia affect more than 10 million people in the United States and Europe, respectively, and more than 50 million people worldwide1,2,3. Less common, but equally devastating causes of retina-related vision loss are driven by genetic alterations or mutations that impair normal cellular formation, or retinal structure or function, including Norrie Disease, Osteoporosis Pseudoglioma Syndrome, and FEVR. Both age-related and acquired retinal disorders share an underlying deterioration of the retinal vascular bed and related neurovascular structure. Current therapies slow the progression of vision loss but do not repair, nor reverse, retinal damage that has already occurred. CTR-107 is a synthetic targeted growth factor that mimics the properties of norrin, a naturally occurring human protein that promotes the development of organized blood vessels and neurons in the human eye, ear, and central nervous system. When injected into the eye, CTR-107 may regenerate retinal blood vessels and neurons, restoring retinal function and counteracting vision loss due to FEVR and other retinal diseases. The Phase 2 SBIR grant builds on prior research, including in a Phase 1 STTR grant, that demonstrated production feasibility, safety/tolerability, modulation of target gene expression in vitro, and in vivo functional activity. During Phase 2 SBIR grant-supported research, the company will optimize dosing through in vitro and in vivo studies, further develop analytical methods for product characterization, and conduct pharmacokinetic studies to support an IND submission. CTR-107 is the first program to obtain U.S. FDA Rare Pediatric Disease (RPD) Designation for treatment of FEVR, a designation that makes Caeregen eligible to obtain a Priority Review Voucher at the time of marketing approval. The RPD designation for CTR-107 (Noregen™) follows the Orphan Drug Designations by both the FDA and European Commission European Medicines Agency (EMA). About CTR-107 (Noregen™) CTR-107 (Noregen™) is a synthetic targeted growth-factor for retina-related vision loss modeled after norrin, a naturally occurring human protein that guides retinal formation in fetal development. CTR-107 may promote development of organized blood vessels and neurons in the human eye, ear, and central nervous system for individuals with inherited or acquired retinal diseases and potential applications in other neurosensory disorders. As a first-in-class therapeutic candidate to regenerate and repair the retinal vasculature to restore and preserve vision in patients with ischemic vitreoretinopathies, CTR-107 is currently being developed for Familial Exudative Vitreoretinopathy (FEVR), a rare disease of urgent, unmet medical need. About FAMILIAL EXUDATIVE VITREORETINOPATHY (FEVR) Familial Exudative Vitreoretinopathy, or ‘FEVR’ is a rare inherited disorder of retinal angiogenesis, leading to incomplete vascularization of the peripheral retinal and poor vascular differentiation. FEVR most often presents in childhood but may progress at any age with sight-threatening manifestations4 It is characterized by abnormal retinal vascular development with progressive vitreoretinal features, including retinal capillary dropout, vessel dragging; retinal folds, vessel leakage and exudation; hemorrhage, neovascularization, vitreoretinal interface changes, and serous, tractional, or combined retinal detachment5 - all contributing to or causing visual impairment and blindness. Currently there are no approved pharmacological therapies for FEVR. About Caeregen Therapeutics Caeregen Therapeutics, LLC, based in Rochester, MI with offices in Chapel Hill, N.C., is a regenerative medicines company developing therapeutics for neurosensory diseases. By exploiting biological pathways and signaling related to cellular and organ development, Caeregen is focused on advancing targeted therapies with the ability to repair, restore and protect neurosensory tissues affected by inherited or acquired diseases. Caeregen is currently developing Noregen, a unique, novel, recombinant protein mimetic of human norrin-derived growth factor for the potential treatment of retinal-related vision loss. For more information, visit: . 1Prevalence of Age-Related Macular Degeneration in the US in 2019”, JAMA Ophthalmology, Dec. 1, 2022 2Global epidemiology of retinal vein occlusion: a systematic review and meta-analysis of prevalence, incidence and risk factors”, Global Health, June 2019 3Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: A Systematic Review and Meta-Analysis,” Ophthalmology, November 2021 4Clinical presentation of Familial Exudative Vitreoretinopathy,” Ophthalmology, October 2011 5Symmetry of Folds in FEVR: a genotype-phenotype correlation study,” Experimental Eye Research, September 2019

孤儿药临床2期临床结果

2023-06-25

·生物谷

Nat Commun：科学家有望利用新型WNT信号通路来恢复机体大脑血脑屏障的功能

来自斯坦福大学医学院等机构的科学家们通过研究有望利用一种新型的WNT信号通路来恢复大脑的血脑屏障。每个人心中都有一个保镖，即血脑屏障，其是血管和大脑其它部分之间的一层细胞，能将毒素、病原体和其它可能破坏大脑珍贵灰质组织的不良物质“踢”出去；当保镖失去警惕，一种不良的因素穿过血脑屏障后就会发生多种情况，侵入血脑屏障的癌细胞就能发展成为肿瘤组织，而当太多白细胞滑过血脑屏障，导致对大脑神经的保护层发生自身免疫攻击，从而阻碍其与机体其它部分相互交流时，就会引发多发性硬化症。近日，一篇发表在国际杂志Nature Communications上题为“Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice”的研究报告中，来自斯坦福大学医学院等机构的科学家们通过研究有望利用一种新型的WNT信号通路来恢复大脑的血脑屏障。研究者表示，血脑屏障的渗漏是多种脑补疾病发生的共同途径，因此，能够封堵住渗透的血脑屏障一直是医学界科学家们长期追寻的目标，目前修复血脑屏障的方法仍未得到充分的研究，这篇文章中，研究人员就描述了一种有望恢复这一屏障正常功能的新型疗法。研究者Calvin Kuo说道，我们已经评估了一类新型治疗性分子用于治疗渗漏的血脑屏障，此前并没有专门针对血脑屏障的治疗性手段；文章中，研究人员通过研究WNT信号开始了他们的探索，WNT信号是细胞用来促进组织再生和伤口愈合的特殊交流通路，WNT信号能通过促进排列在血管中的细胞间的交流沟通从而维持血脑屏障的功能。有很多历史数据表明，WNT信号通路对于维持血脑屏障的功能非常重要，这样研究人员就能检测WNT信号通路，其能通过选择性地结合一种名为“卷曲受体”（frizzled receptor）的受体来开启血脑屏障中的特殊信号。长期以来，科学家们一直在关注卷曲受体，其是能开启WNT信号通路用于血脑屏障疗法的蛋白受体，因为小鼠机体中卷曲受体基因突变会诱发血脑屏障的功能异常。很多不同的分子都能与卷曲受体结合，因此为了缩小对潜在治疗性分子的寻找范围，研究人员仅选择了能特异性靶向作用位于大脑血管中的目标细胞的分子进行深入研究。科学家有望利用新型WNT信号通路来恢复机体大脑血脑屏障的功能。图片来源：Nature Communications (2023). DOI:10.1038/s41467-023-37689-1 研究者Chris Garcia指出，我们在实验室中开发了一种治疗性的WNT通路原型分子，其中包括一种能激活卷曲受体FZD4的分子，基于此前的研究，研究人员开发出了名为L6-F4-2的分子，其是一种FZD4结合分子，在激活WNT信号通路的效率是其它FZD4结合子的100倍。当研究人员以更高的速率激活WNT信号时，他们观察到了血脑屏障强度的增加。于是研究人员想通过研究当卷曲受体天然分子钥匙缺失时到底会发生什么，以及是否能利用L6-F4-2来成功替代它，随后他们转向了对诺里病(Norrie disease,ND)进行研究，其是一种导致血-视网膜屏障渗漏的遗传性异常疾病；血-视网膜屏障对眼睛的功能与血脑屏障对大脑的功能相同，在诺里病中，视网膜（眼睛后部的感光细胞层）中血管的发育会受阻，从而导致血管连接渗漏，发育不正常以及失明的发生。诺里病是由NDP基因的突变所致，该基因能提供指令来制造名为Norrin的蛋白，而该蛋白是配合FZD4受体的锁以及开启其表达的钥匙；在对小鼠的研究中，该基因处于失活状态，而且该钥匙的缺失会导致血-视网膜屏障渗漏以及患者失明，于是研究人员利用L6-F4-2来代替蛋白Norrin进行研究，当L6-F4-2代替了Norrin后，小鼠机体的血-视网膜层就能得到恢复，研究人员知道，由于其能对血管进行成像，且发现其要比治疗前更加密集而且渗漏更少，同时他们还表明，对于小鼠小脑周围的血脑屏障（负责肌肉协调的关键区域）而言，L6-F4-2就能取代Norrin并激活WNT信号通路。随后研究人员想研究一种更为常见的人类疾病—缺血性中风，在这种情况下，血管和血脑屏障的功能会被破坏，而参与细胞交流沟通的液体、血液和炎性蛋白会渗透到大脑中，研究者发现，相比中风未治疗的小鼠而言，L6-F4-2能降低机体中风的严重程度，并改善小鼠的生存情况，更为重要的是，L6-F4-2还能逆转中风后大脑血管的渗漏情况。与未进行治疗的小鼠相比，L6-F4-2治疗小鼠后会增加其中风后的存活率，这一研究结果表明，在小鼠机体中，血脑屏障的功能或许能通过激活FZD受体和WNT信号通路的药物来恢复，由于多种疾病都有血脑屏障功能异常的起源，研究者Kuo对于其它多种神经性疾病的治疗潜力表示非常兴奋，比如阿尔兹海默病、多发性硬化症和大脑肿瘤等。他表示，我们希望这将是开发新一代药物来修复大脑血脑屏障的第一步，我们所利用的策略和分子靶点或许与目前的药物会非常不同。综上，本文研究结果表明，在缺血性血脑屏障功能异常期间，一种生物工程化的FZD4选择性WNT替代物或许具有系统性的疗效，其或有望适用于以血脑屏障功能异常为主要特征的成年人中枢神经系统疾病的治疗。（生物谷Bioon.com）原始出处： Jie Ding,Sung-Jin Lee,Lukas Vlahos, et al. Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice, Nature Communications (2023). DOI:10.1038/s41467-023-37689-1