Cracking the Egg: Potential of the Developing Chicken as a Model System for Nonclinical Safety Studies of Pharmaceuticals

Abstract

The advance of perinatal medicine has improved the survival of extremely premature babies, thereby creating a new and heterogeneous patient group with limited information on appropriate treatment regimens. The developing fetus and neonate have traditionally been ignored populations with regard to safety studies of drugs, making medication during pregnancy and in newborns a significant safety concern. Recent initiatives of the Food and Drug Administration and European Medicines Agency have been passed with the objective of expanding the safe pharmacological treatment options in these patients. There is a consensus that neonates should be included in clinical trials. Prior to these trials, drug leads are tested in toxicity and pharmacology studies, as governed by several guidelines summarized in the multidisciplinary International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use M3 (R2). Pharmacology studies must be performed in the major organ systems: cardiovascular, respiratory, and central nervous system. The chicken embryo and fetus have features that make the chicken a convenient animal model for nonclinical safety studies in which effects on all of these organ systems can be tested. The developing chicken is inexpensive, accessible, and nutritionally self-sufficient with a short incubation time and is ideal for drug-screening purposes. Other high-throughput models have been implemented. However, many of these have limitations, including difficulty in mimicking natural tissue architecture and function (human stem cells) and obvious differences from mammals regarding the respiratory organ system and certain aspects of central nervous system development (Caenorhabditis elegans, zebrafish).This minireview outlines the potential and limitations of the developing chicken as an additional model for the early exploratory phase of development of new pharmaceuticals.

Niclosamide rescues microcephaly in a humanized in vivo model of Zika infection using human induced neural stem cells

“…In addition, some mouse models to date have had to specifically utilize immunocompromised strains to allow for ZIKV infection, as common strains systemically infected with ZIKV have no microcephalic phenotype ( Cugola et al, 2016 ). The innate immune system of the chick embryo does not function until around E14 ( Kain et al, 2014 ) suggesting that this in vivo system provides a naturally immunodeficient model system suitable for both human xenografts as well as viral infection ( Bjornstad et al, 2015 ). We intracranially injected hiNSCs into developing chick embryos, subjected them to systemic ZIKV infection and found that humanized ZIKV-infected embryos developed severe microcephaly consisting of significantly reduced cranial size, decreased forebrain volume and enlarged ventricles.…”

Hampered Lung Maturation in Methimazole-Induced Hypothyroidism in Fetal Chicken: Morphological and Molecular Correlates to Human Fetal Development

“…MMI treatments were initiated at E14, during the pseudoglandular stage of lung development, when several developmental steps, including most of the proximal-distal differentiation and preparabronchial vascularization, have already taken place [16]. Our model is therefore most relevant in exploring regulatory mechanisms involved in developmental events in the atrioinfundibular (equivalent to human canalicular, 16-24 weeks of gestation) and air-capillary (equivalent to human saccular, 24 weeks of gestation to term) [7] stages of lung development, including distal epithelial and vascular differentiation.…”

“…The chicken has a long history as a developmental model system [7]. Verhoelst et al [8] demonstrated that methimazole (MMI) administration to developing chicken fetuses at embryonic day (E)14 at doses of 2.0 mg/egg induces hypothyroidism.…”

High resolution, label‐free photoacoustic imaging of live chicken embryo developing in bioengineered eggshell

“…Chicken embryo has been a model organism for developmental biology for a very long time . It is expansively studied in fields of developmental biology , cardiovascular studies , and angiogenesis .…”