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Oct 1, 2013 (Vol. 33, No. 17)

Human Disease Models Move Underwater

  • Fish Tools for the Future of Comparative Medicine

    Click Image To Enlarge +
    Zebrafish-human oncogenomics was pioneered at Purdue University, where researchers realized the rapid breeding, cost effectiveness, and broad availability of the zebrafish made this species attractive as an animal model. One Purdue-based group is mutating either ribosomal proteins or p53 to develop tumors in this aquarium fish.

    Dr. Postlethwait and many other investigators subsequently turn to zebrafish as an in-lab model for examining the functions of potential disease-related genes.

    One burgeoning domain for this popular aquarium fish is as an in vivo model for aneuploidy in cancer. Aneuploidy—or an abnormal number of chromosomes—is universally observed in all types of human cancer, yet genetic mouse models of these diseases rarely feature aneuploidy.

    This chromosomal phenomenon is relatively easy to replicate in zebrafish, according to Guang Jun Zhang, Ph.D., assistant professor of genetic epidemiology and comparative medicine at Purdue University, whose lab mutates either ribosomal proteins or p53 to develop tumors in zebrafish.

    Dr. Zhang has pioneered zebrafish-human oncogenomics, a comparative approach that can reveal novel cancer driver genes. The zebrafish genome shares about 70% identity with the human genome, but through evolutionary synteny, many of the genetic loci have moved to different chromosomal locations.

    Oncogenomics allows Dr. Zhang to illuminate patterns in the aneuploidy of human cancers and contrast those with genetic arrangements in zebrafish tumors. Cancer is an automatic evolution process, so the technique reflexively selects for chromosome-related growth advantages.

    This investigation has yielded a plethora of gene candidates that may function as oncogenes or tumor suppressors, which Dr. Zhang’s team is now using to build new zebrafish lines that model cancer.

    “You cannot explore 100 new genes in mice; it would cost a fortune. But in zebrafish, it is very possible,” said Dr. Zhang, who cites their rapid breeding, cost effectiveness, and broad availability as benefits of the model.

    He added that the Sanger Institute’s comprehensive Zebrafish Mutation Project, which aims to create a knockout allele in every protein-coding gene in the animal’s genome, should be completed in the next two years, providing an exceptional resource for comparative medicine studies within the model.

    Moreover, recently developed technologies for gene editing—zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), CRISP/CAS-9—are rapidly moving into fish models.

    “These innovative tools are opening two types of doors,” said molecular physiologist Aron Geurts, Ph.D., of the Medical College of Wisconsin, who specializes in gene targeting with rat models of cardiovascular disease but was invited to attend the conference as a guest lecturer.

    “First, gene-editing technology is enabling very elegant experiments that were previously restricted only to the mouse,” remarked Dr. Geurts. “In addition, these tools are empowering precision editing of genomes for the assessment of specific disease-linked alleles.”

    This will move animal models away from the realm of simple knockouts and knock-in breeding and will allow future investigators to ask very specific questions about the role of particular single-nucleotide polymorphisms (SNPs) in pathogenic phenotypes.

    GWAS and large-scale genetic investigations, like the Encyclopedia of DNA Elements (ENCODE) Consortium and the 1000 Genomes Project, are really driving this research, according to Dr. Geurts, who is a big proponent of using aquatic models in scenarios where biological questions are not easily answered by mammalian systems.

    “We’re going to see more people working with genetic engineering in these models, which may be better than mice in some areas of translational medicine,” concluded Dr. Geurts. “That’s where the field is going.”

  • New Animal Model Introductions

    Charles River Labs reports that it will introduce four pain models (rat) for translational disease research this fall.

    According to Mike Luther, corporate vp, scientists using a glycolytic inhibitor (monoiodoacetate) will be able to observe behavioral, histological, and biochemical changes that resemble human osteoarthritis and its associated joint pain with the Monoiodoacetate Chronic Joint Pain Model.

    Luther also pointed out that the Formalin Model of Spontaneous Behavioral Pain is widely utilized as an acute and rapid in vivo screening assay for evaluating the potential analgesic effects of novel chemical entities.

    The Spinal Nerve Ligation (SNL) or Chung Model of Neuropathic Pain is considered one of the most suitable models for analgesia screening against neuropathic pain, noted Luther, adding that the rat paw Complete Freund’s Adjuvant Model of Inflammatory Pain is well characterized in the literature and is routinely used for screening novel compounds targeted for inflammatory pain.

    “We have implemented a set of pain models and assays that are robust and reproducible and which provide translational endpoints that allow our clients to make the appropriate decisions regarding progress for their projects and pipelines,” explained Luther.

    “These new models are part of our integrated approach to support the lead to candidate process in drug discovery from early PK and PD to efficacy as well as mechanism of action studies, including early safety and toxicology studies for candidate selection.”

    Oncology Models

    Taconic says it will expand its oncology portfolio later this year with the inclusion of four new mouse models from the Netherlands Cancer Institute.

    The Brca1-Associated Breast Cancer Model is a conditional mouse mutant with somatic deletion of Brca1 and Trp53 in several epithelial tissues including mammary epithelium. This model may be helpful in predicting responses of human BRCA1-deficient tumors to therapies, according to Taconic.

    The Invasive Lobular Breast Cancer Model was developed to serve as a tissue-specific conditional knockout of Cdh1 (E-cadherin) and Trp53 in mice. It induces metastatic mammary carcinomas that resemble human invasive lobular carcinoma, the second most common type of primary breast cancer. The model is intended to serve as a tool for the development of therapies for the treatment of lobular breast cancer.

    The Floxed Ink4a/Arf Mouse contains a targeted mutation of Cdkn2a (Ink4a/Arf), which introduced LoxP sites upstream of exon 2 and downstream of exon 3. It can be crossed with the tissue-specific cre of a researcher’s choice to develop a tumor model.

    Floxed p53 Mouse contains a targeted mutation of Trp53, which introduced LoxP sites flanking exons 2 through 10. It can be crossed with a tissue-specific cre to generate a conditional disruption of the Trp53 tumor suppressor gene, the most commonly mutated gene in human cancers. Taconic says it will be useful for studying Trp53 gene function or screening potential cancer intervention therapies.

    “Taconic’s newest transgenic oncology mouse models can help researchers accelerate drug discovery by providing better predictability of outcomes in the clinical lab setting and by offering a more reliable screening tool for use in target selection,” said Megan McBride, Ph.D., associate director, scientific marketing. “By using tumor cell lines that correlate well with the tumors they were derived from, these models can also accelerate the target validation process by helping investigators determine early on which targets are best pursued in later-stage drug development efforts for oncology therapeutics.”

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