Human disease models in drug development

Nature Reviews Bioengineering, Год журнала: 2023, Номер 1(8), С. 545 - 559

Опубликована: Май 11, 2023

Язык: Английский

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Membrane transporters in drug development and as determinants of precision medicine

Nature Reviews Drug Discovery, Год журнала: 2024, Номер 23(4), С. 255 - 280

Опубликована: Янв. 24, 2024

Язык: Английский

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Pharmacogenomics: Driving Personalized Medicine

Pharmacological Reviews, Год журнала: 2023, Номер 75(4), С. 789 - 814

Опубликована: Март 16, 2023

Abstract

Personalized medicine tailors therapies, disease prevention, and health maintenance to the individual, with pharmacogenomics serving as a key tool improve outcomes prevent adverse effects. Advances in genomics have transformed pharmacogenetics, traditionally focused on single gene-drug pairs, into pharmacogenomics, encompassing all "-omics" fields (e.g., proteomics, transcriptomics, metabolomics, metagenomics). This review summarizes basic principles relevant translation assessing pharmacogenomics' central role converging diverse elements of personalized medicine. We discuss genetic variations pharmacogenes (drug-metabolizing enzymes, drug transporters, receptors), their clinical relevance biomarkers, legacy decades research pharmacogenetics. All types including proteins, nucleic acids, viruses, cells, genes, irradiation, can benefit from genomics, expanding across Food Drug Administration approvals therapeutics involving biomarkers increase rapidly, demonstrating growing impact pharmacogenomics. A beacon for therapeutic approaches, molecularly targeted cancer therapies highlight trends discovery applications. To account human complexity, multicomponent biomarker panels genetic, personal, environmental factors guide diagnosis increasingly artificial intelligence cope extreme data complexities. However, application encounters substantial hurdles, such unknown validity ethnic groups, underlying bias care, real-world validation. address science technologies germane medicine, integrated economic, ethical, regulatory issues, providing insights current status future direction care.

Significance Statement

aims optimize care individual patients use predictive Pharmacogenomics drives guides development therapeutics. addresses large-scale repositories accelerating medical advances. The is discussed, along hurdles impeding broad implementation, context ethics, economics, affairs.

Язык: Английский

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The future of cystic fibrosis treatment: from disease mechanisms to novel therapeutic approaches

The Lancet, Год журнала: 2023, Номер 402(10408), С. 1185 - 1198

Опубликована: Сен. 1, 2023

Язык: Английский

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Cystic fibrosis

Nature Reviews Disease Primers, Год журнала: 2024, Номер 10(1)

Опубликована: Авг. 8, 2024

Язык: Английский

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Molecular glues and bifunctional compounds: Therapeutic modalities based on induced proximity

Cell chemical biology, Год журнала: 2024, Номер 31(6), С. 1050 - 1063

Опубликована: Июнь 1, 2024

Язык: Английский

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Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants

PLoS ONE, Год журнала: 2024, Номер 19(1), С. e0297560 - e0297560

Опубликована: Янв. 25, 2024

Variants in the cystic fibrosis transmembrane conductance regulator gene (CFTR) result fibrosis-a lethal autosomal recessive disorder. Missense variants that alter a single amino acid CFTR protein are among most common variants, yet tools for accurately predicting molecular consequences of missense have been limited to date. AlphaMissense (AM) is new technology predicts pathogenicity based on dual learned structure and evolutionary features. Here, we evaluated ability AM predict variants. predicted high residues overall, resulting false positive rate fair classification performance CF from CFTR2.org database. score correlated modestly with metrics persons including sweat chloride level, pancreatic insufficiency rate, Pseudomonas aeruginosa infection rate. Correlation was also modest trafficking folding competency vitro. By contrast, well channel function vitro-demonstrating training approach learns important functional information despite lacking such data during training. Different across indicated may determine if polymorphisms cannot differentiate mechanistic effects or nature pathophysiology. Finally, predictions offered utility inform pharmacological response i.e., theratype. Development approaches biochemical properties therefore still needed refine targeting emerging precision therapeutics.

Язык: Английский

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Protein dynamics underlying allosteric regulation

Current Opinion in Structural Biology, Год журнала: 2024, Номер 84, С. 102768 - 102768

Опубликована: Янв. 11, 2024

Allostery is the mechanism by which information and control are propagated in biomolecules. It regulates ligand binding, chemical reactions, conformational changes. An increasing level of experimental resolution over allosteric mechanisms promises a deeper understanding molecular basis for life powerful new therapeutics. In this review, we survey literature an up-to-date biological theoretical protein allostery. By delineating five ways energy landscape or kinetics system may change to give rise allostery, aim help reader grasp its physical origins. To illustrate framework, examine three systems that display these forms allostery: inhibitors beta-lactamases, thermosensation TRP channels, role kinetic allostery function kinases. Finally, summarize growing power computational tools available investigate different presented review.

Язык: Английский

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Gathering real-world compassionate data to expand eligibility for elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with N1303K or other rareCFTRvariants: a viewpoint

European Respiratory Journal, Год журнала: 2024, Номер 63(1), С. 2301959 - 2301959

Опубликована: Янв. 1, 2024

Elexacaftor-tezacaftor-ivacaftor (ETI) was approved in 2019 by the United States Food and Drug Administration (FDA) 2020 European Medicines Agency (EMA) for people with cystic fibrosis (pwCF). It is a combination of small molecules that bind to defective transmembrane conductance regulator (CFTR) protein, thus allowing rescue CFTR structure function [1]. Footnotes This manuscript has recently been accepted publication Respiratory Journal . published here its form prior copyediting typesetting our production team. After these processes are complete authors have resulting proofs, article will move latest issue ERJ online. Please open or download PDF view this article. Conflict interest: Pierre-Régis Burgel reports support present from Association Vaincre la Mucoviscidose, Société Française de Filière Maladie Rare Muco CFTR. In addition, grants Vertex Pharmaceuticals, GSK; consulting fees Astra Zeneca, Chiesi, GSK, Insmed, Vertex, Viatris, Zambon; travel Chiesi; outside submitted work. Isabelle Sermet-Gaudelus Therapeutics, Tavanta. Tavanta; Durieu Jeanne Languepin report Mylan, Anne Guillaumot Asten, Boehringer Ingelheim, LFB, CSL Behring, Roche, Menarini; Camille Audousset Zambon, Viatris; advisory board participation Pharmaceuticals; Raphaël Chiron ECFC; Vertex; Laurence Weiss Fajac AbbVie, Bayer, Kither Biotech, leadership role Cystic Fibrosis Society; Clémence Martin lecture honoraria AstraZeneca, Boehringer, GSL; Boehringer; All other nothing disclose.

Язык: Английский

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mRNA therapies: Pioneering a new era in rare genetic disease treatment

Journal of Controlled Release, Год журнала: 2024, Номер 369, С. 696 - 721

Опубликована: Апрель 13, 2024

Язык: Английский

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