{"id":2584,"date":"2024-01-11T16:31:23","date_gmt":"2024-01-11T15:31:23","guid":{"rendered":"https:\/\/connected-pathology.com\/?p=2584"},"modified":"2024-01-11T16:33:22","modified_gmt":"2024-01-11T15:33:22","slug":"histopathology-as-a-quick-effective-and-complimentary-target-identification-and-validation-method","status":"publish","type":"post","link":"https:\/\/connected-pathology.com\/?p=2584","title":{"rendered":"Histopathology as a Quick, Effective and Complimentary Target Identification and Validation Method"},"content":{"rendered":"\n[et_pb_section fb_built=”1″ _builder_version=”4.20.2″ _module_preset=”default” da_disable_devices=”off|off|off” global_colors_info=”{}” da_is_popup=”off” da_exit_intent=”off” da_has_close=”on” da_alt_close=”off” da_dark_close=”off” da_not_modal=”on” da_is_singular=”off” da_with_loader=”off” da_has_shadow=”on”][et_pb_row _builder_version=”4.20.2″ _module_preset=”default” global_colors_info=”{}”][et_pb_column type=”4_4″ _builder_version=”4.20.2″ _module_preset=”default” global_colors_info=”{}”][et_pb_text _builder_version=”4.20.2″ _module_preset=”default” global_colors_info=”{}”]

Target identification and validation <\/span><\/b>represents a key first preclinical drug development phase leading up to clinical trials. In this case, target is used as a broad term, and represents a range of biological entities, including proteins, genes and different forms of RNA. A good, validated target is efficacious, safe and most importantly, is \u201c<\/span>druggable<\/span><\/i>\u201d. <\/span>Druggability <\/span><\/i>in this context refers to the target\u2019s intrinsic characteristic of<\/span> being amenable in eliciting a measurable biological response (i.e., suppression of a key player implicated in a pathophysiology a disease) in response to stimulation with a putative drug molecule (1)<\/a>. <\/span>\u00a0<\/span><\/p>\n

Before demonstrating efficacy and safety, drug developers need to be certain that their target has been thoroughly evaluated for its <\/span>therapeutic potential<\/span><\/b>. A target that cannot be thoroughly validated cannot proceed to the subsequent stages of drug development aiming to evaluate the efficacy, tolerability and safety of the putative test compounds. In fact, drug development experts argue that one of the main reasons of high attrition rates (around 90%) novel drug candidates is due to a lack of thorough target validation studies performed early in the clinical pipelines (2)<\/a>.\u00a0<\/span>\u00a0<\/span><\/p>\n

The journey of the drug development is exploratory and variable. The target identification and validation stages encompass multitude of experiments and approaches to ensure confidence in the target\u2019s biological and therapeutic potential. In this article, we provide a brief overview of how <\/span>histopathology<\/span><\/b> can be used as a quick and relatively efficient way to <\/span>obtain initial data during the target identification and validation phase.\u00a0<\/span><\/b>\u00a0<\/span><\/p>\n

\u00a0<\/span><\/p>\n

How can target identification and validation experiments using histopathology be conducted?<\/span><\/b>\u00a0<\/span><\/h2>\n

The target\u2019s role must be clearly identified before starting to develop a drug candidate against the disease and evaluate if the drug acts on the disease pathology (1<\/a>,3)<\/a>. Firstly, the target expression and distribution within all tissues and organs of interest can provide initial information about the disease-related pathways. Histopathology assessment can be performed to evaluate whether the <\/span>target is expressed<\/span><\/b> or active in the desired organ, tissue or a cell type using human organ and tissue samples. Similarly, histopathology evaluation can be done to evaluate whether the <\/span>target expression is<\/span><\/b> altered<\/span><\/b> in the diseased state using readily available human organ and tissue samples. This can be done using fluorescence in situ hybridization (FISH) using novel methods such as RNAscope<\/span>TM<\/span> and\/or BaseScope<\/span>TM<\/span>, and simple or multiplex fluorescent immunocytochemistry (IHC) approaches. <\/span>\u00a0<\/span><\/p>\n

However, it is not only the target\u2019s tissue expression and distribution that determines the target\u2019s drugabbility. Several other important target characteristics such as its regular function and its involvement and modulation in disease pathophysiology are important in determining whether the target can advance to the next stages of preclinical drug development. Further multi-validation approaches and techniques range from in vitro tools through in vivo animal models. Histopathology analyses, along with other analyses can be used to evaluate the <\/span>ex vivo tissue distribution<\/span><\/b> of the target following <\/span>in vivo target gene knockdown experiments<\/span><\/b> (small bioactive molecules, monoclonal antibodies, antisense oligonucleotides, iRNA, CRISPR\/Cas9, animal models with the targeted gene knockout or inducible gene knockout animal models) as well as <\/span>target overexpression<\/span><\/b> experiments. Similar to other high-throughput approaches applied in this phase, high-throughput histology using tissue microarrays can be a useful tool. <\/span>Target validation of therapeutic antibodies<\/span><\/b> can be evaluated using ex-vivo binding assays that make use of healthy and diseased (human and animal disease model) tissues, offering a quick and effective method to evaluate the antibody\u2019s binding potential, while also evaluating any off-target binding of the therapeutic antibody. For this purpose, each antibody binding assay is thoroughly optimised to ensure reliability of the results <\/span>(for a review of antibody optimisation steps click here). <\/span><\/a><\/span><\/p>\n

The advantage of outsourcing this relatively simple task to histopathology service providers lies in the fact that pathologists are familiar with working with different tissues and organs and can provide expert opinion on the (semi)qualitative results obtained which can guide the next stages of the iterative process of target validation. However, it is important to keep in mind that the drug development process is iterative, and a multitude of other techniques need to be performed to thoroughly validate the target. <\/span><\/p>\n

To conclude, histopathology can serve as a relatively quick complementary technique in addition to other high-throughput proteomic and genomic analyses, serving to gather initial, semi-quantitative or purely qualitative data regarding the target\u2019s expression during the target validation stage of preclinical drug development.\u00a0<\/span>\u00a0<\/span><\/p>\n

<\/span><\/p>\n

<\/span><\/p>[\/et_pb_text][\/et_pb_column][\/et_pb_row][et_pb_row _builder_version=”4.20.2″ _module_preset=”default” global_colors_info=”{}”][et_pb_column type=”4_4″ _builder_version=”4.20.2″ _module_preset=”default” global_colors_info=”{}”][et_pb_button button_url=”https:\/\/connected-pathology.com\/contact\/” button_text=”Contact Us To Inquire About Your Project Needs Now” _builder_version=”4.20.2″ _module_preset=”default” custom_margin=”-25px|||||” locked=”off” global_colors_info=”{}”][\/et_pb_button][\/et_pb_column][\/et_pb_row][\/et_pb_section]\n","protected":false},"excerpt":{"rendered":"

Target identification and validation represents a key first preclinical drug development phase leading up to clinical trials. In this case, target is used as a broad term, and represents a range of biological entities, including proteins, genes and different forms of RNA. A good, validated target is efficacious, safe and most importantly, is \u201cdruggable\u201d. Druggability […]<\/p>\n","protected":false},"author":7,"featured_media":2594,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_et_pb_use_builder":"on","_et_pb_old_content":"","_et_gb_content_width":"","_monsterinsights_skip_tracking":false,"footnotes":""},"categories":[3],"tags":[15,23,25],"class_list":["post-2584","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news","tag-digital-pathology","tag-histopathology-services","tag-outsourcing-histology"],"yoast_head":"\nTarget Identification and Validation - Connected-Pathology<\/title>\n<meta name=\"description\" content=\"Histopathology can be used as a quick and efficient way to obtain initial data during the target identification and validation phase.\" \/>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/connected-pathology.com\/?p=2584\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Target Identification and Validation - 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