
{"id":17045,"date":"2022-07-26T12:21:54","date_gmt":"2022-07-26T12:21:54","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/precision-cut-kidney-slices-pcks\/"},"modified":"2022-07-26T12:21:54","modified_gmt":"2022-07-26T12:21:54","slug":"precision-cut-kidney-slices-pcks","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/precision-cut-kidney-slices-pcks\/","title":{"rendered":"Precision Cut Kidney Slices (PCKS) in Chronic Kidney Disease (CKD) to Help Select Better Drug Candidates and Bridge the Translational Gap"},"content":{"rendered":"<p><span data-contrast=\"auto\">Chronic kidney disease (CKD) is a common and debilitating condition which affects an estimated 1 in 10 people worldwide. <\/span><span data-contrast=\"auto\">Individuals affected by CKD progressively lose kidney function as they are not diagnosed until the later stages of the disease due to the silent nature of this condition.<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><span data-contrast=\"auto\">Once diagnosed, control of blood pressure and inhibition of the renin angiotensin aldosterone system remains the cornerstone of the treatment of CKD. This slows disease progression but does not halt or reverse the condition. Consequently, biotech and large pharma are actively looking at improving their candidate screening cascades and testing platforms.\u00a0<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'> This includes the use of precision cut kidney slices (PCKS).<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"wp-image-13019 size-medium alignleft\" src=\"https:\/\/www.sygnaturediscovery.com\/wp-content\/uploads\/2025\/11\/Photo_Jul_15_22-04-27-38-pm-10-scaled.jpeg\" alt=\"Example of precision cut kidney slices (PCKS)\" width=\"225\" height=\"300\"><\/p>\n<p><b><span data-contrast=\"auto\">The challenges for biotechs and big pharma developing treatments for CKD<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">#1 Lack of a translational bridge between in vitro, in vivo studies and the patient<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">Typically, in the classic R&amp;D process before any lead candidate compounds are assessed in vivo, the properties of the drug and the mechanism of its possible mode of action are thoroughly evaluated using various vitro models. These in vitro assays often utilise one clonal cell type and thus fail to give any insight into the organ physiology and the greater translational response beyond the specific cellular cascade in question.<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">As the lead optimisation develops, animal models are increasingly used to evaluate the pathogenesis and underlying mechanisms of renal disease. Rodents (mice and rats) models are the most commonly used to study kidney injury and any potential therapeutic targets. Ethically the use of animals is carefully managed and utilised appropriately, aligning research with the 3r\u2019S, so that only the most likely drug candidates are dosed in-vivo.<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">#2 Speed of screening and compound Use<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">Compounds in late lead optimisation once passing the in-vitro screening stage gate would typically enter into in-vivo model assessments. This requires scale up of test compounds, appropriate form pre-formulation support and the relatively slow throughput of in-vivo models.\u00a0<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Precision cut kidney slices (PCKS) in the discovery cascade:<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">Precision cut tissue slices are three-dimensional (3D) tissue explants, usually derived from various human or animal organs, which can be cultured ex vivo for an extended period of time. All cell tissue (cortex, medulla) is present with intact inter-cellular and cell\u2013matrix interactions.\u00a0<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">These tissue slices, and in particular precision cut kidney slices (PCKS), represent a valid and robust platform to study the mechanism and efficacy of antifibrotic drug-candidates before <a href=\"https:\/\/www.sygnaturediscovery.com\/news-and-events\/webinars\/can-rodent-kidney-models-really-simulate-the-clinic\/\">moving into animal models<\/a>. <\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Utilising precision cut kidney slices (PCKS) has several clear benefits in drug discovery:<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<ol>\n<li><b><span data-contrast=\"auto\">Higher throughput of lead candidates saving time and money around test material preparation and scale up etc.<\/span><\/b><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<li><b><span data-contrast=\"auto\">Faster selection of the nominated drug candidate<\/span><\/b><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<li><b><span data-contrast=\"auto\">Reduction in the number of animal models needed to be performed in candidate selection<\/span><\/b><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<li><b><span data-contrast=\"auto\">Consistency of test material reducing batch to batch variation<\/span><\/b><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<li><b><span data-contrast=\"auto\">Better translation into in-vivo and man utilising appropriate biomarkers<\/span><\/b><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<\/ol>\n<p><span data-contrast=\"auto\">From one organ, researchers can obtain doses of the experimental units. And since they are more representative of the complex cell\u2013cell and cell\u2013matrix cross-talk than in vitro cultures, experimentation in slices offers a more reliable tool for drug candidate selection.\u00a0<\/span><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559685\":720,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Further applications: exploring the benefits of human PCKS<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><span data-contrast=\"auto\">The challenge with rodent tissue slices is that they are not human and theoretically do not fully translate into man. The use of kidney biopsy tissue from CKD patients as ex vivo disease models is a key addition or potentially in some cases an alternative to prolonged in vivo models. What\u2019s more, using human PCKS allows ex vivo culturing of renal tissues in stasis for several days without the loss of the phenotype. This is becoming a popular and valid method in the pre-clinical screening cascade, addressing key questions around possible drug mechanism of action and its potential therapeutic properties in human diseased tissue. Direct comparison of data generated in human versus animal diseased tissues can also serve as a robust way of validating animal models that precede initial clinical trials.<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Examples of potential biomarkers that can be used to bridge the translational gap from in-vitro, through ex-vivo tissue slices into man and in-vivo including rodents\u00a0<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<ul>\n<li data-leveltext=\"\uf0b7\" data-font=\"Symbol\" data-listid=\"6\" aria-setsize=\"-1\" data-aria-posinset=\"1\" data-aria-level=\"1\"><span data-contrast=\"auto\">Increase in collagen production at mRNA and protein level, e.g. Collagen 1a<\/span><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<li data-leveltext=\"\uf0b7\" data-font=\"Symbol\" data-listid=\"6\" aria-setsize=\"-1\" data-aria-posinset=\"2\" data-aria-level=\"1\"><span data-contrast=\"auto\">Increase in fibronectin production (extracellular matrix deposition)<\/span><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<li data-leveltext=\"\uf0b7\" data-font=\"Symbol\" data-listid=\"6\" aria-setsize=\"-1\" data-aria-posinset=\"2\" data-aria-level=\"1\"><span data-contrast=\"auto\">Increase in alpha-smooth muscle actin (fibroblast transdifferentiation)<\/span><\/li>\n<li data-leveltext=\"\uf0b7\" data-font=\"Symbol\" data-listid=\"6\" aria-setsize=\"-1\" data-aria-posinset=\"2\" data-aria-level=\"1\"><span data-contrast=\"auto\">Increase in inflammatory markers, cytokine release into media by PCKS and into plasma of kidney disease patients, e.g. IL6, TNF alpha<\/span><span data-ccp-props='{\"134233279\":true,\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/li>\n<\/ul>\n<p>\u00a0<\/p>\n<p><span data-contrast=\"auto\">If you would like to hear more about the use and benefits of PCKS in Chronic Kidney Disease research contact Sygnature Discovery, today.<\/span><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p>\u00a0<\/p>\n<p><b><span data-contrast=\"auto\">Additional reading material: <\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">* The Lancet, volume 395, issue 10225, p709-733, February 29, 2020<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Bigaeva, Emilia et al. \u201cTranscriptomic characterization of culture-associated changes in murine and human precision-cut tissue slices.\u201d Archives of toxicology vol. 93,12 (2019<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Bigaeva, Emilia et al. \u201cPredictive Value of Precision-Cut Kidney Slices as an Ex Vivo Screening Platform for Therapeutics in Human Renal Fibrosis.\u201d Pharmaceutics vol. 12,5 459. 18 May. 2020<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Stribos, Elisabeth G D et al. \u201cMurine Precision-Cut Kidney Slices as an ex vivo Model to Evaluate the Role of Transforming Growth Factor-\u03b21 Signaling in the Onset of Renal Fibrosis.\u201d Frontiers in physiology vol. 8 1026. 12 Dec. 2017<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">Graaf, Inge Am de et al. \u201cPrecision-cut tissue slices as a tool to predict metabolism of novel drugs.\u201d Expert opinion on drug metabolism &amp; toxicology vol. 3,6 (2007): 879-98.<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n<p><b><span data-contrast=\"auto\">https:\/\/nc3rs.org.uk\/who-we-are\/3rs<\/span><\/b><span data-ccp-props='{\"201341983\":0,\"335559739\":160,\"335559740\":259}'>\u00a0<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":17046,"template":"","category":[29],"class_list":["post-17045","blog","type-blog","status-publish","has-post-thumbnail","hentry","category-non-categorise"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.6 - 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