A Phase 3, Open-label Study Evaluating the Long-term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Subjects 12 Months of Age and Older

The purpose of the study is to evaluate the long-term safety, tolerability, efficacy, and pharmacodynamics (PD) of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA).

开始日期2024-10-01

申办/合作机构

Vertex Pharmaceuticals, Inc.

ACTRN12624000146594 / RecruitingN/AIIT

Assessment of regional lung ventilation via X-ray velocimetry (XV) imaging following thecommencement of ETI (elexacaftor/tezacaftor/ivacaftor) treatment in children with cystic fibrosis

开始日期2024-08-26

申办/合作机构

WomenS & ChildrenS Hospital

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100 项与 P-gp x CFTR 相关的临床结果

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100 项与 P-gp x CFTR 相关的转化医学

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0 项与 P-gp x CFTR 相关的专利（医药）

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项与 P-gp x CFTR 相关的文献（医药）

2024-07-01·Journal of Cell Biology

HERC3 facilitates ERAD of select membrane proteins by recognizing membrane-spanning domains

Article

作者: Lukacs, Gergely L ; Okiyoneda, Tsukasa ; Fukuda, Ryosuke ; Tateishi, Hazuki ; Katoh, Saori ; Ohnishi, Yuko ; Terakawa, Mana ; Nakayamada, Uta ; Hirata, Noriaki ; Fujii, Aika ; Nakashima, Chikako ; Takahashi, Hirotaka ; Kamada, Yuka ; Hamano, Ikuto

Aberrant proteins located in the endoplasmic reticulum (ER) undergo rapid ubiquitination by multiple ubiquitin (Ub) E3 ligases and are retrotranslocated to the cytosol as part of the ER-associated degradation (ERAD). Despite several ERAD branches involving different Ub E3 ligases, the molecular machinery responsible for these ERAD branches in mammalian cells remains not fully understood. Through a series of multiplex knockdown/knockout experiments with real-time kinetic measurements, we demonstrate that HERC3 operates independently of the ER-embedded ubiquitin ligases RNF5 and RNF185 (RNF5/185) to mediate the retrotranslocation and ERAD of misfolded CFTR. While RNF5/185 participates in the ERAD process of both misfolded ABCB1 and CFTR, HERC3 uniquely promotes CFTR ERAD. In vitro assay revealed that HERC3 directly interacts with the exposed membrane-spanning domains (MSDs) of CFTR but not with the MSDs embedded in liposomes. Therefore, HERC3 could play a role in the quality control of MSDs in the cytoplasm and might be crucial for the ERAD pathway of select membrane proteins.

2024-06-01·BioMetals

Cadmium transport by mammalian ATP-binding cassette transporters

Review

作者: Thévenod, Frank ; Lee, Wing-Kee

AbstractCellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body—usually in epithelia—and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.

2023-12-01·Advanced Biology

Study Transportation of Drugs within Newly Established Murine Colon Organoid Systems

Article

作者: Atherly, Todd ; Davoudi, Zahra ; Barrett, Terrence A ; Wang, Qun ; Jergens, Albert E ; Wannemuehler, Michael ; Borcherding, Dana C

AbstractThe development of 3D organoids of the small intestine is a tremendous breakthrough in drug development and biological research. However, the development of colonic organoids (i.e., colonoids) is particularly challenging due to a lack of simple, cost‐effective protocols for colonoid cultivation. Here, intestinal homogenates are described as a supplement to the culture medium for maintaining and replicating colonic stem cells. Colonoids generated by this cultivation protocol demonstrate substantial proliferation and differentiation (3 months). There is a similarity between cultured colonoids and primary colon tissue regarding structure and functionality. To evaluate the functionality of colonoids, permeability testing is performed with suspensions of 4 and 40 kDa fluorescein isothiocyanate‐dextran (FITC‐DEX). It is observed that neither can permeate the healthy epithelial barrier. The P‐glycoprotein receptor, a vital drug efflux pump mitigating potential drug toxicity, is functionally manipulated, as evidenced by its inhibition function by verapamil and monitoring uptake of Rhodamin 123. In addition, Forskolin treatment which affects chloride transport results in organoid swelling; this confirms the functional expression of the CFTR transporter in the colonoids. This protocol to generate colonoids is promising for high‐throughput drug screening, toxicity testing, and oral drug development.