Institution
Vertex Pharmaceuticals
Company•Boston, Massachusetts, United States•
About: Vertex Pharmaceuticals is a company organization based out in Boston, Massachusetts, United States. It is known for research contribution in the topics: Ivacaftor & Hepatitis C virus. The organization has 2135 authors who have published 2022 publications receiving 134750 citations. The organization is also known as: Vertex Pharmaceuticals Inc. & Vertex.
Topics: Ivacaftor, Hepatitis C virus, Protease, Telaprevir, Protein kinase A
Papers published on a yearly basis
Papers
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TL;DR: In an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mice with genetic deletion of Piezo1 in T cells showed diminished disease severity as discussed by the authors.
Abstract: T lymphocytes encounter complex mechanical cues during an immune response. The mechanosensitive ion channel, Piezo1, drives inflammatory responses to bacterial infections, wound healing, and cancer; however, its role in helper T cell function remains unclear. In an animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we found that mice with genetic deletion of Piezo1 in T cells showed diminished disease severity. Unexpectedly, Piezo1 was not essential for lymph node homing, interstitial motility, Ca2+ signaling, T cell proliferation, or differentiation into proinflammatory T helper 1 (TH1) and TH17 subsets. However, Piezo1 deletion in T cells resulted in enhanced transforming growth factor-β (TGFβ) signaling and an expanded pool of regulatory T (Treg) cells. Moreover, mice with deletion of Piezo1 specifically in Treg cells showed significant attenuation of EAE. Our results indicate that Piezo1 selectively restrains Treg cells, without influencing activation events or effector T cell functions.
28 citations
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14 Mar 2003TL;DR: In this paper, the authors have proposed a method of using compounds usefull as inhibitors of protein kinases in the treatment of various diseases, conditions, or disorders, including cancer.
Abstract: The present invention relates to compounds usefull as inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositioins comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
28 citations
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TL;DR: The execution and reporting of experiments and the criteria recommended for the physiologically-relevant assessment of target engagement to identify viable new drug targets and facilitate the advancement of translational studies are discussed.
28 citations
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TL;DR: In this paper, the authors provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human, and demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species building confidence in the ability to extrapolate to human.
Abstract: Conjugation of oligonucleotide therapeutics, including small interfering ribonucleic acids (siRNAs) or antisense oligonucleotides (ASOs) to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI® (givosiran) for the treatment of acute hepatic porphyria, OXLUMOTM (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio® (inclisiran) for the treatment of hypercholesterolemia, the technology has been well-validated clinically. While much knowledge has been gained over decades of development there is a paucity of published literature on the DMPK properties of GalNAc-siRNA. With this in mind the goals of this mini-review are to provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human. Upon subcutaneous administration, GalNAc-conjugated siRNAs are quickly distributed to the liver, resulting in plasma pharmacokinetic (PK) properties that reflect rapid elimination through ASGPR-mediated uptake from circulation into hepatocytes. These studies confirm that liver PK, including half-life and, most importantly, siRNA levels in RNA-induced silencing complex (RISC) in hepatocytes are better predictors of pharmacodynamics (PD) than plasma PK. Several in vitro and in vivo nonclinical studies were conducted to characterize the absorption, distribution, metabolism and excretion (ADME) properties of GalNAc-conjugated siRNAs. These studies demonstrate that the PK/PD and ADME properties of GalNAc-conjugated siRNAs are highly conserved across species, largely predictable, and can be accurately scaled to human, allowing us to identify efficacious and safe clinical dosing regimens in the absence of human liver PK profiles. Significance Statement Several nonclinical ADME studies have been conducted in order to provide a comprehensive overview of the disposition and elimination of GalNAc-conjugated siRNAs and the PK/PD translation between species. These studies demonstrate that the ADME properties of GalNAc-conjugated siRNAs are well correlated and predictable across species building confidence in the ability to extrapolate to human.
28 citations
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30 Sep 2005TL;DR: In this paper, the NS3-NS4A protease inhibitor is used to prevent non-genotype 1 hepatitis C virus (HCV) NS3 NS4A activity.
Abstract: The present invention relates to inhibiting the activity of non-genotype 1 hepatitis C virus (HCV) NS3-NS4A protease activity. More particularly, the invention relates to inhibiting the activity of the protease from HCV genotype-2 or HCV genotype-3. The methods of the invention emply inhibitors that act by interfering with the life cycle of the HCV and are also useful as antiviral agents. The invention further relates to compositions comprising such compounds either for ex vivo use or for administration to a patient suffering from genotype-2 or genotype-3 HCV infection. The invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention.
28 citations
Authors
Showing all 2137 results
Name | H-index | Papers | Citations |
---|---|---|---|
David Altshuler | 162 | 345 | 201782 |
Richard J. Johnson | 137 | 880 | 72201 |
Gerhard Wagner | 116 | 589 | 50309 |
Paul I.W. de Bakker | 107 | 257 | 95323 |
Peter R. Mueller | 97 | 613 | 34457 |
Annamaria Vezzani | 85 | 285 | 26008 |
Mark D. Fleming | 81 | 433 | 36107 |
Santosh Kumar | 80 | 1196 | 29391 |
Thomas Helleday | 76 | 303 | 27757 |
Nicola J. Curtin | 68 | 228 | 18255 |
Susan J. Little | 62 | 276 | 17986 |
Jeremy S. Duffield | 58 | 124 | 16037 |
Edmund V. Capparelli | 54 | 281 | 10747 |
Roy A. Black | 54 | 99 | 16878 |
Murcko Mark A | 53 | 130 | 14347 |