更新于：2024-05-01

PKD1

polycystin 1, transient receptor potential channel interacting

更新于：2024-05-01

基本信息

别名

Autosomal dominant polycystic kidney disease 1 protein、PBP、Pc-1

+ [5]

简介

Component of a heteromeric calcium-permeable ion channel formed by PKD1 and PKD2 that is activated by interaction between PKD1 and a Wnt family member, such as WNT3A and WNT9B (PubMed:27214281). Both PKD1 and PKD2 are required for channel activity (PubMed:27214281). Involved in renal tubulogenesis (PubMed:12482949). Involved in fluid-flow mechanosensation by the primary cilium in renal epithelium (By similarity). Acts as a regulator of cilium length, together with PKD2 (By similarity). The dynamic control of cilium length is essential in the regulation of mechanotransductive signaling (By similarity). The cilium length response creates a negative feedback loop whereby fluid shear-mediated deflection of the primary cilium, which decreases intracellular cAMP, leads to cilium shortening and thus decreases flow-induced signaling (By similarity). May be an ion-channel regulator. Involved in adhesive protein-protein and protein-carbohydrate interactions.

关联

项与 PKD1 相关的药物

H-1337

靶点

LRRK2 x PKA x PKD1 x PKN2

作用机制

LRRK2抑制剂 [+3]

在研机构

D. Western Therapeutics Institute, Inc.

原研机构

D. Western Therapeutics Institute, Inc.

在研适应症

开角型青光眼1A [+2]

非在研适应症-

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

VX-407

靶点

PKD1

作用机制

PKD1抑制剂

在研机构

Vertex Pharmaceuticals, Inc.

原研机构

Vertex Pharmaceuticals, Inc.

在研适应症

常染色体显性多囊肾病

非在研适应症-

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 PKD1 相关的临床试验

NCT06345755 / Recruiting临床1期

A Phase 1, Randomized, Double-blind, Placebo-controlled, First-in-human Study Evaluating the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of VX-407 in Healthy Subjects

The purpose of the study is to evaluate the safety, tolerability, and pharmacokinetic parameters of VX-407 in healthy participants.

开始日期2024-04-01

申办/合作机构

Vertex Pharmaceuticals, Inc.

NCT05913232 / Recruiting临床2期

A Phase 2b Randomized, Double-masked, Active-controlled, Dose-response Study of the Safety and Efficacy of H-1337 in Subjects With Primary Open Angle Glaucoma (POAG) or Ocular Hypertension

The trial will evaluate the safety and efficacy of 3 dose regimens of H-1337 [0.6% twice daily (b.i.d.), 1.0% b.i.d. and 1.0% once in the morning (q.a.m.), and timolol maleate (0.5%, b.i.d.) in both eyes for 28 days.

开始日期2023-08-28

申办/合作机构

D. Western Therapeutics Institute, Inc.

NCT03452033 / Completed临床1/2期

A Phase 1/2a Randomized, Double-masked, Placebo Controlled, Dose-ranging Study of the Safety and Efficacy of H-1337 in Subjects With Primary Open Angle Glaucoma (POAG) or Ocular Hypertension

The study will evaluate the safety, tolerability, and preliminary efficacy of three concentrations of H-1337 and vehicle administered twice daily in a parallel group, double-masked design for 28 days of dosing in patients with elevated intraocular pressure (IOP).

开始日期2018-03-15

申办/合作机构

Allysta Pharmaceuticals, Inc.初创企业

100 项与 PKD1 相关的临床结果

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100 项与 PKD1 相关的转化医学

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0 项与 PKD1 相关的专利（医药）

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2,292

项与 PKD1 相关的文献（医药）

2024-02-02·Cell and tissue research

Structure of putative epidermal sensory receptors in an acoel flatworm, Praesagittifera naikaiensis.

Article

作者: Tosuke Sakagami ; Kaho Watanabe ; Mayuko Hamada ; Tatsuya Sakamoto ; Toshimitsu Hatabu ; Motonori Ando

Acoel flatworms possess epidermal sensory-receptor cells on their body surfaces and exhibit behavioral repertoires such as geotaxis and phototaxis. Acoel epidermal sensory receptors should be mechanical and/or chemical receptors; however, the mechanisms of their sensory reception have not been elucidated. We examined the three-dimensional relationship between epidermal sensory receptors and their innervation in an acoel flatworm, Praesagittifera naikaiensis. The distribution of the sensory receptors was different between the ventral and dorsal sides of worms. The nervous system was mainly composed of a peripheral nerve net, an anterior brain, and three pairs of longitudinal nerve cords. The nerve net was located closer to the body surface than the brain and the nerve cords. The sensory receptors have neural connections with the nerve net in the entire body of worms. We identified five homologs of polycystic kidney disease (PKD): PKD1-1, PKD1-2, PKD1-3, PKD1-4, and, PKD2, from the P. naikaiensis genome. All of these PKD genes were implied to be expressed in the epidermal sensory receptors of P. naikaiensis. PKD1-1 and PKD2 were dispersed across the entire body of worms. PKD1-2, PKD1-3, and PKD1-4 were expressed in the anterior region of worms. PKD1-4 was also expressed around the mouth opening. Our results indicated that P. naikaiensis possessed several types of epidermal sensory receptors to convert various environmental stimuli into electrical signals via the PKD channels and transmit the signals to afferent nerve and/or effector cells.

2024-02-01·Kidney international reports

An Artificial Intelligence Generated Automated Algorithm to Measure Total Kidney Volume in ADPKD.

Article

作者: Jonathan Taylor ; Richard Thomas ; Peter Metherall ; Marieke van Gastel ; Emilie Cornec-Le Gall ; Anna Caroli ; Monica Furlano ; Nathalie Demoulin ; Olivier Devuyst ; Jean Winterbottom ; Roser Torra ; Norberto Perico ; Yannick Le Meur ; Sebastian Schoenherr ; Lukas Forer ; Ron T Gansevoort ; Roslyn J Simms ; Albert C M Ong

Introduction:

Accurate tools to inform individual prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD) are lacking. Here, we report an artificial intelligence (AI)-generated method for routinely measuring total kidney volume (TKV).

Methods:

An ensemble U-net algorithm was created using the nnUNet approach. The training and internal cross-validation cohort consisted of all 1.5T magnetic resonance imaging (MRI) data acquired using 5 different MRI scanners (454 kidneys, 227 scans) in the CYSTic consortium, which was first manually segmented by a single human operator. As an independent validation cohort, we utilized 48 sequential clinical MRI scans with reference results of manual segmentation acquired by 6 individual analysts at a single center. The tool was then implemented for clinical use and its performance analyzed.

Results:

The training or internal validation cohort was younger (mean age 44.0 vs. 51.5 years) and the female-to-male ratio higher (1.2 vs. 0.94) compared to the clinical validation cohort. The majority of CYSTic patients had PKD1 mutations (79%) and typical disease (Mayo Imaging class 1, 86%). The median DICE score on the clinical validation data set between the algorithm and human analysts was 0.96 for left and right kidneys with a median TKV error of -1.8%. The time taken to manually segment kidneys in the CYSTic data set was 56 (±28) minutes, whereas manual corrections of the algorithm output took 8.5 (±9.2) minutes per scan.

Conclusion:

Our AI-based algorithm demonstrates performance comparable to manual segmentation. Its rapidity and precision in real-world clinical cases demonstrate its suitability for clinical application.

2024-01-23·Journal of the American Society of Nephrology : JASN

Pkd2 Deficiency in Embryonic Aqp2+ Progenitor Cells Is Sufficient to Cause Severe Polycystic Kidney Disease.

Article

作者: Akaki Tsilosani ; Chao Gao ; Enuo Chen ; Andrea R Lightle ; Sana Shehzad ; Madhulika Sharma ; Pamela V Tran ; Carlton M Bates ; Darren P Wallace ; Wenzheng Zhang

BACKGROUND:

Most cases of autosomal dominant polycystic kidney disease (ADPKD) are caused by mutations in PKD1 or PKD2. Currently, the mechanism for renal cyst formation remains unclear. Aqp2+ progenitor cells (AP) (re)generate ≥5 cell types including principal cells (PC) and intercalated cells (IC) in the late distal convoluted tubules (DCT2), connecting tubules (CNT), and collecting ducts (CD).

METHODS:

Here, we tested whether Pkd2 deletion in AP and their derivatives at different developmental stages is sufficient to induce PKD. Aqp2Cre Pkd2f/f (Pkd2AC) mice were generated to disrupt Pkd2 in embryonic AP. Aqp2ECE/+Pkd2f/f (Pkd2ECE) mice were tamoxifen-inducted at P1 or P60 to inactivate Pkd2 in neonate or adult AP and their derivatives, respectively. All induced mice were sacrificed at P300. Immunofluorescence staining was done to categorize and quantify cyst-lining cell types. Four other PKD mouse models and ADPKD patients were similarly analyzed.

RESULTS:

Pkd2 was highly expressed in all CNT/CD cell types and weakly in all other tubular segments. Pkd2AC mice had obvious cysts by P6 and developed severe PKD and died by P17. The kidneys had reduced IC and increased transitional cells (TC). TC were negative for PC and IC markers examined. A complete loss of α-IC occurred by P12. Cysts extended from the distal renal segments to DCT1 and possibly to the loop of Henle, but not to the proximal tubules. The induced Pkd2ECE mice developed mild PKD. Cystic α-IC were found in the other PKD models. AQP2+ cells were found in cysts of only 13/27 ADPKD samples, which had the same cellular phenotype as Pkd2AC mice.

CONCLUSIONS:

Hence, Pkd2 deletion in embryonic AP, but unlikely in neonate or adult Aqp2+ cells (PC and AP), was sufficient to cause severe PKD with progressive elimination of α-IC, recapitulating a newly identified cellular phenotype of ADPKD patients. We proposed that Pkd2 is critical for balanced AP differentiation into, proliferation and/or maintenance of cystic IC, particularly α-IC.

项与 PKD1 相关的新闻（医药）

2024-03-31

·医药观澜

礼邦医药在研新药获FDA授予孤儿药资格，针对肾病！

▎药明康德内容团队编辑3月29日，礼邦医药宣布其在研创新药物AP303获得美国FDA授予孤儿药资格，用于治疗常染色体显性多囊肾病（ADPKD）。ADPKD是常见的单基因肾病，也是导致成人终末期肾病的主要原因之一。该病的主要表现为肾脏囊肿不断增大、增多，破坏正常的肾脏结构和功能。ADPKD最常见的致病原因有两个：一是多囊肾致病基因PKD1突变，约存在78%的疾病谱系中；二是PKD2突变，约存在15%的疾病谱系中。对于ADPKD患者的治疗，临床上建议包括抗高血压治疗、饮食限制以及仅适合部分患者的药物治疗。目前，ADPKD患者迫切需要可治疗更多患者且副作用更少的有效治疗药物，以减缓患者的肾功能衰退并改善肾脏结局。AP303是礼邦医药自主研发的一款创新药物。在ADPKD小鼠模型中，已观察到肾脏存活率提高。目前该药已完成其在健康受试者中的首次人体试验，并准备进行针对ADPKD的2期临床研究。礼邦医药成立于2018年初，致力于肾脏病以及其它相关慢性疾病创新药物的发现和开发，为慢性肾脏病及相关疾病患者提供更佳的临床治疗方案。目前，该公司已建立起包含多款肾脏病新药的产品管线，拟开发适应症涵盖慢性肾病/透析并发症、IgA肾病、糖尿病肾病、常染色体显性多囊肾病等产品。参考资料：[1]礼邦医药在研创新药物 AP303 获得美国食品药品监督管理局孤儿药资格认定, 用于治疗常染色体显性多囊肾病（ADPKD）. Retrieved Mar 29 , 2024, from https://mp.weixin.qq.com/s/LqsGIoaCQ_zKvPxDulcqVA本文由药明康德内容团队根据公开资料整理编辑，欢迎个人转发至朋友圈。转发授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

孤儿药临床2期快速通道

2024-03-29

·医药魔方Pro

礼邦医药：创新药AP303获FDA孤儿药资格认定，治疗常染色体显性多囊肾病

2024 年 3 月 29 日，礼邦医药宣布其在研创新药物 AP303 获得美国食品药品监督管理局（FDA）孤儿药资格认定，用于治疗常染色体显性多囊肾病（ADPKD）。ADPKD是最常见的单基因肾病，也是全球导致成人终末期肾病的主要原因之一，主要表现为肾脏囊肿不断增大、增多，破坏正常的肾脏结构和功能。ADPKD 最常见的原因是多囊肾致病基因PKD1（在78%的疾病谱系中）或 PKD2（在15%的疾病谱系中）突变。对于ADPKD患者的治疗建议包括抗高血压治疗、饮食限制以及仅适合部分患者的药物治疗。ADPKD患者迫切需要可治疗更多患者且副作用更少的有效治疗药物以减缓患者的肾功能衰退并改善肾脏结局。AP303是礼邦医药自主研发的创新药物，在ADPKD小鼠模型中观察到肾脏存活率的提高, 并已完成在健康受试者中的首次人体试验，即将进行II期临床研究。ADPKD 在新生儿中的患病率约为四百分之一到千分之一，该疾病是导致终末期肾病（ESKD）需接受肾脏替代治疗的重要原因[1]。此次孤儿药认定显示出治疗 ADPKD 的迫切临床需求，以及 AP303 未来为患者提供更多治疗手段的潜力。“我们非常高兴 AP303 被 FDA 授予孤儿药资格。”礼邦医药联合创始人、董事长兼首席执行官夏国尧博士评论道，“这对于礼邦医药以及我们为解决 ADPKD 疾病未满足的临床需求所做的努力而言都是一个重要里程碑。我们会努力推进AP303 项目，为 ADPKD 患者提供更多的治疗选择。”2018 年初，礼邦医药由顶尖的肾脏病领域行业领导者孵化于中国上海，主要致力于肾脏病以及其他相关慢性疾病创新药物的发现和开发，为慢性肾脏病及相关疾病患者提供更佳临床治疗方案。礼邦医药已经建立起了丰富且均衡的肾脏病新药产品管线，包括针对慢性肾病（CKD）/透析并发症、IgA 肾病、糖尿病肾病、常染色体显性多囊肾病（ADPKD）等产品，公司在研产品包括小分子药物和生物制剂，目前多个项目处于临床试验阶段。参考文献：[1]Bergmann, C., Guay-Woodford, L.M., Harris, P.C. et al. Polycystic kidney disease. Nat Rev Dis Primers 4, 50 (2018). https://doi.org/10.1038/s41572-018-0047-yCopyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

孤儿药

2024-03-29

·PRNewswire

Alebund's Innovative Investigational Drug AP303 Receives FDA Orphan Drug Designation (ODD) for the Treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD)

SHANGHAI, March 29, 2024 /PRNewswire/ -- Alebund Pharmaceuticals ("Alebund" or the "Company"), an integrated biopharmaceutical company focusing on developing innovative therapies for the treatment of renal diseases and related chronic conditions, announced today that the US Food and Drug Administration (FDA) has granted Orphan Drug Designation (ODD) to AP303 for the treatment of autosomal dominant polycystic kidney disease (ADPKD). "We are very excited that AP303 has been granted Orphan Drug Designation by the FDA", Dr. Gavin Xia, Co-founder, Chairman, and CEO of Alebund commented. "It is an important milestone for Alebund as well as our efforts to address the significant unmet medical needs with ADPKD. We look forward to advancing AP303 to improve future treatment options for patients in need." AP303, a novel drug candidate developed in-house by Alebund, has demonstrated a meaningful improvement of renal survival in an ADPKD mice model. AP303 has completed its first-in-human study in healthy subjects in Australia and is ready for a Phase II trial in ADPKD. The prevalence of ADPKD is reported to be between 1 in 400 and 1 in 1,000 live births; it is an important cause of end-stage kidney disease (ESKD) requiring renal replacement therapy [1]. This Orphan Drug Designation reflects the need for more new treatment options and the potential for AP303 to address the pressing needs of people living with ADPKD. The US FDA's ODD is a special status granted to support the development and evaluation of potential new medicines intended for the treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the US. The designation provides incentives to advance the development of treatments for rare diseases, including marketing exclusivity, tax credits for clinical research costs, and exemption from prescription drug user fees. About ADPKD ADPKD is the most common monogenic kidney disease and one of the leading causes of end-stage kidney disease in adults worldwide. Its course is characterized by the development and inexorable expansion of multiple cysts scattered throughout the kidney parenchyma. ADPKD is most caused by mutations in the genes PKD1 (in 78% of disease pedigrees) or PKD2 (in 15% of disease pedigrees). Treatment recommendation for patients with ADPKD includes anti-hypertensive treatment, dietary restrictions, and pharmacotherapy for a limited percentage of suitable patients. More broadly applicable treatment options with fewer side effects are needed to effectively slow the decline of kidney function and improve kidney outcomes in patients with ADPKD. About Alebund Pharmaceuticals Alebund is a biopharmaceutical company jointly incubated by a group of industry leaders in the field of nephrology in Shanghai in 2018. Alebund focuses on the discovery and development of novel therapies primarily for kidney diseases and their complications, as well as other chronic conditions. Alebund has built a diversified and balanced pipeline of drug candidates targeting a range of renal diseases, including chronic kidney disease (CKD)/dialysis complications, IgA nephropathy, diabetic kidney disease, and autosomal dominant polycystic kidney disease (ADPKD). Alebund's pipeline comprises both small-molecule and biological assets, in which many programs are in the clinical stage. [1] Bergmann, C., Guay-Woodford, L.M., Harris, P.C. et al. Polycystic kidney disease. Nat Rev Dis Primers 4, 50 (2018). SOURCE Alebund Pharmaceuticals

孤儿药临床2期