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Taking Aim at Target ID and Validation

Zebrafish models and new intracellular targets raise hopes for lowering drug attrition rates. Excerpt from a Genetic Engineering & Biotechnology News article by Kathy Liszewski featuring zebrafish in target ID and validation.

In The Hunger Games, Katniss Everdeen shocked the distracted gamemakers seated above her by shooting an arrow and blasting an apple out of the roasted pig’s mouth on the buffet table. Accuracy counts! Pharmaceutical and biotech firms are waging their own hunger games, albeit a bit less dramatic, as they attempt to hit the bullseye of identifying and validating therapeutic targets. New approaches are sorely needed as during the last several decades, drug discovery pipelines have suffered from high attrition rates for candidates entering clinical trials. The recently held Cambridge Healthtech Institute’s 15th Annual Target Identification and Validation conference focused on innovative chemical biology and phenotypic screening advances to overcome the challenges of pinpointing novel, druggable targets. Solutions discussed included a zebrafish platform for high-throughput screening, an innovative high-throughput genome engineering strategy to identify essential genes for cancer immunotherapy, a high-content autophagy screen to discover pathways in disease biology, and defining intracellular pathways that mediate lung fibrosis. Approximately 95% of compounds fail after Phases II and III, highlighting the need for fishing out innovative strategies to streamline the drug discovery pipeline. Zebrafish may be swimming to the rescue. “To date, the majority of animal testing is performed in mammals, making the whole process laborious, costly, and time-consuming,” declares Vincenzo Di Donato, PhD, project manager of the genome editing platform at ZeClinics. He adds, “We overcome these limitations by exploiting the advantages of zebrafish, a valuable alternative model for preliminary phases of drug screening pipelines.” Di Donato says that the high genetic and physiological homology between humans and fish enable a detailed study of the function of potential therapeutic targets as well as a deeper understanding of the mechanism of action of small molecules on those targets. “The elevated reproduction rate and fast organ development of zebrafish allow for high-throughput screenings resulting in a great time reduction,” he explains. “Low maintenance costs of fish colonies and reduced quantity of molecules required for assays have an enormous impact on the investment required for drug development. Importantly, drug screening on zebrafish larvae is performed at early developmental stages, before 120 hours post-fertilization, a time when they start being subject to regulations for animal experimentation.” The company’s ZeCardio® screening platform provides a tool for genetic association studies in cardiovascular disease. Di Donato, elaborates, “This methodology combines the advantages of the CRISPR- Cas9 system for generating somatic mutant larvae by using guide RNAs targeting candidate genes with high mutagenesis efficiency (up to 100%) and a high-throughput in vivo imaging system allowing for morphological and functional analysis of cardiovascular phenotypes.” Some therapeutic molecules identified in zebrafish-based screenings have already progressed to the clinical phase (e.g. PDE5A inhibitors for the treatment of Duchenne muscular dystrophy). However, challenges remain that Di Donato believes are solvable. He reveals, “To further improve the translatability of zebrafish in drug discovery, ZeClinics is actively working on the development of humanized zebrafish models.” About Zeclinics SL ZeClinics is an innovative biotech firm committed to streamlining discovery and preclinical development of novel compounds with zebrafish - an ideal vertebrate model for fast, cost-effective and highly predictive assessments. We combine in-house academic expertise with a diversified, cutting-edge portfolio: from CRISPR-licensed gene editing, high-throughput safety and efficacy assays to disease models. For more information, please visit and

Palabras clave

Target ID, Target validation, zebrafish, drug discovery, attrition, clinical trials, genome editing, cardiovascular


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