Skip to main content
SpringerLink
Log in

In Vivo Target Validation Using Biological Molecules in Drug Development

  • Chapter
New Approaches to Drug Discovery

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 232))

Abstract

Drug development is a resource-intensive process requiring significant financial and time investment. Preclinical target validation studies and in vivo testing of the therapeutic molecules in clinically relevant disease models can accelerate and significantly de-risk later stage clinical development. In this chapter, we will focus on (1) in vivo animal models and (2) pharmacological tools for target validation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Bahou WF, Bowie EJ, Fass DN, Ginsburg D (1988) Molecular genetic analysis of porcine von Willebrand disease: tight linkage to the von Willebrand factor locus. Blood 72:308–313

    CAS  PubMed  Google Scholar 

  • Bi L, Lawler AM, Antonarakis SE, High KA, Gearhart JD, Kazazian HH Jr (1995) Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A. Nat Genet 10:119–121

    Article  CAS  PubMed  Google Scholar 

  • Bogue MA, Grubb SC (2004) The mouse phenome project. Genetica 122:71–74

    Article  CAS  PubMed  Google Scholar 

  • Booth CJ, Brooks MB, Rockwell S et al (2010a) WAG-F8(m1Ycb) rats harboring a factor VIII gene mutation provide a new animal model for hemophilia A. J Thromb Haemost 8:2472–2477

    Article  CAS  PubMed  Google Scholar 

  • Booth CJ, Brooks MB, Rockwell S (2010b) Spontaneous coagulopathy in inbred WAG/RijYcb rats. Comp Med 60:25–30

    CAS  PubMed  PubMed Central  Google Scholar 

  • Brinkhous KM, Graham JB (1950) Hemophilia in the female dog. Science 111:723–724

    Article  CAS  PubMed  Google Scholar 

  • Brooks AR, Sim D, Gritzan U et al (2013) Glycoengineered factor IX variants with improved pharmacokinetics and subcutaneous efficacy. J Thromb Haemost 11:1699–1706

    Article  CAS  PubMed  Google Scholar 

  • C. elegans Sequencing Consortium (1998) Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282:2012–2018

    Article  Google Scholar 

  • Cook N, Jodrell DI, Tuveson DA (2012) Predictive in vivo animal models and translation to clinical trials. Drug Discov Today 17:253–260

    Article  PubMed  Google Scholar 

  • Crudele JM, Finn JD, Siner JI et al (2015) AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice. Blood 125:1553–1561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Denis C, Methia N, Frenette PS et al (1998) A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis. Proc Natl Acad Sci U S A 95:9524–9529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Drummond IA (2005) Kidney development and disease in the zebrafish. J Am Soc Nephrol 16:299–304

    Article  CAS  PubMed  Google Scholar 

  • Dumont JA, Liu T, Low SC et al (2012) Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood 119:3024–3030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elm T, Karpf DM, Ovlisen K et al (2012) Pharmacokinetics and pharmacodynamics of a new recombinant FVIII (N8) in haemophilia A mice. Haemophilia 18:139–145

    Article  CAS  PubMed  Google Scholar 

  • Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA (1989) Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci U S A 86:10095–10099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fass DN, Bowie EJ, Owen CA Jr, Zollman PE (1979) Inheritance of porcine von Willebrand’s disease: study of a kindred of over 700 pigs. Blood 53:712–719

    CAS  PubMed  Google Scholar 

  • Felix MA, Braendle C (2010) The natural history of Caenorhabditis elegans. Curr Biol 20:050

    Article  Google Scholar 

  • Furth PA, St Onge L, Boger H et al (1994) Temporal control of gene expression in transgenic mice by a tetracycline-responsive promoter. Proc Natl Acad Sci U S A 91:9302–9306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaj T, Gersbach CA, Barbas CF 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31:397–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garza JC, Kim CS, Liu J, Zhang W, Lu XY (2008) Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity. J Endocrinol 197:471–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giles AR, Tinlin S, Greenwood R (1982) A canine model of hemophilic (factor VIII:C deficiency) bleeding. Blood 60:727–730

    CAS  PubMed  Google Scholar 

  • Gordon JW, Scangos GA, Plotkin DJ, Barbosa JA, Ruddle FH (1980) Genetic transformation of mouse embryos by microinjection of purified DNA. Proc Natl Acad Sci U S A 77:7380–7384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graham JB, Buckwalter JA et al (1949) Canine hemophilia; observations on the course, the clotting anomaly, and the effect of blood transfusions. J Exp Med 90:97–111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grubb SC, Churchill GA, Bogue MA (2004) A collaborative database of inbred mouse strain characteristics. Bioinformatics 20:2857–2859

    Article  CAS  PubMed  Google Scholar 

  • Grubb SC, Bult CJ, Bogue MA (2014) Mouse phenome database. Nucleic Acids Res 42:D825–D834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haberichter SL, Merricks EP, Fahs SA, Christopherson PA, Nichols TC, Montgomery RR (2005) Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 105:145–152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J (2014) Clinical development success rates for investigational drugs. Nat Biotechnol 32:40–51

    Article  CAS  PubMed  Google Scholar 

  • Heinzel FP, Sadick MD, Holaday BJ, Coffman RL, Locksley RM (1989) Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J Exp Med 169:59–72

    Article  CAS  PubMed  Google Scholar 

  • Howe K, Clark MD, Torroja CF et al (2013) The zebrafish reference genome sequence and its relationship to the human genome. Nature 496:498–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsieh CS, Macatonia SE, O’Garra A, Murphy KM (1995) T cell genetic background determines default T helper phenotype development in vitro. J Exp Med 181:713–721

    Article  CAS  PubMed  Google Scholar 

  • Kashiwakura Y, Mimuro J, Onishi A et al (2012) Porcine model of hemophilia A. PLoS One 7:28

    Article  Google Scholar 

  • Kirienko NV, Mani K, Fay DS (2010) Cancer models in Caenorhabditis elegans. Dev Dyn 239:1413–1448

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kistner A, Gossen M, Zimmermann F et al (1996) Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice. Proc Natl Acad Sci U S A 93:10933–10938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koller BH, Hagemann LJ, Doetschman T et al (1989) Germ-line transmission of a planned alteration made in a hypoxanthine phosphoribosyltransferase gene by homologous recombination in embryonic stem cells. Proc Natl Acad Sci U S A 86:8927–8931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kucherlapati R (2012) Genetically modified mouse models for biomarker discovery and preclinical drug testing. Clin Cancer Res 18:625–630

    Article  CAS  PubMed  Google Scholar 

  • Leong L, Sim D, Patel C et al (2015) Noncovalent stabilization of the factor VIII A2 domain enhances efficacy in hemophilia A mouse vascular injury models. Blood 125:392–398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Le W (2013) Modeling neurodegenerative diseases in Caenorhabditis elegans. Exp Neurol 250:94–103

    Article  CAS  PubMed  Google Scholar 

  • Li TT, Larrucea S, Souza S et al (2004) Genetic variation responsible for mouse strain differences in integrin alpha 2 expression is associated with altered platelet responses to collagen. Blood 103:3396–3402

    Article  CAS  PubMed  Google Scholar 

  • Lin HF, Maeda N, Smithies O, Straight DL, Stafford DW (1997) A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90:3962–3966

    CAS  PubMed  Google Scholar 

  • Lin CN, Kao CY, Miao CH et al (2010) Generation of a novel factor IX with augmented clotting activities in vitro and in vivo. J Thromb Haemost 8:1773–1783

    Article  CAS  PubMed  Google Scholar 

  • Liu S, Leach SD (2011) Zebrafish models for cancer. Annu Rev Pathol 6:71–93

    Article  CAS  PubMed  Google Scholar 

  • Mauser AE, Whitlark J, Whitney KM, Lothrop CD Jr (1996) A deletion mutation causes hemophilia B in Lhasa Apso dogs. Blood 88:3451–3455

    CAS  PubMed  Google Scholar 

  • McIntosh J, Lenting PJ, Rosales C et al (2013) Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant. Blood 121:3335–3344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mei B, Pan C, Jiang H et al (2010) Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment. Blood 116:270–279

    Article  CAS  PubMed  Google Scholar 

  • Menoret S, Fontaniere S, Jantz D et al (2013) Generation of Rag1-knockout immunodeficient rats and mice using engineered meganucleases. FASEB J 27:703–711

    Article  CAS  PubMed  Google Scholar 

  • Metzner HJ, Weimer T, Kronthaler U, Lang W, Schulte S (2009) Genetic fusion to albumin improves the pharmacokinetic properties of factor IX. Thromb Haemost 102:634–644

    CAS  PubMed  Google Scholar 

  • Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173

    Article  CAS  PubMed  Google Scholar 

  • Mustard JF, Rowsell HC, Robinson GA, Hoeksema TD, Downie HG (1960) Canine haemophilia B (Christmas disease). Br J Haematol 6:259–266

    Article  CAS  PubMed  Google Scholar 

  • Neuenschwander S, Kissling-Albrecht L, Heiniger J, Backfisch W, Stranzinger G, Pliska V (1992) Inherited defect of blood clotting factor VIII (haemophilia A) in sheep. Thromb Haemost 68:618–620

    CAS  PubMed  Google Scholar 

  • Novoa B, Figueras A (2012) Zebrafish: model for the study of inflammation and the innate immune response to infectious diseases. Adv Exp Med Biol 946:253–275

    Article  CAS  PubMed  Google Scholar 

  • Ostergaard H, Bjelke JR, Hansen L et al (2011) Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide. Blood 118:2333–2341

    Article  PubMed  PubMed Central  Google Scholar 

  • Pastoft AE, Lykkesfeldt J, Ezban M, Tranholm M, Whinna HC, Lauritzen B (2012) A sensitive venous bleeding model in haemophilia A mice: effects of two recombinant FVIII products (N8 and Advate((R))). Haemophilia 18:782–788

    Article  CAS  PubMed  Google Scholar 

  • Pastoft AE, Ezban M, Tranholm M, Lykkesfeldt J, Lauritzen B (2013) Prolonged effect of a new O-glycoPEGylated FVIII (N8-GP) in a murine saphenous vein bleeding model. Haemophilia 19:913–919

    Article  CAS  PubMed  Google Scholar 

  • Peng A, Straubinger RM, Balu-Iyer SV (2010) Phosphatidylinositol containing lipidic particles reduces immunogenicity and catabolism of factor VIII in hemophilia a mice. AAPS J 12:473–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peters RT, Low SC, Kamphaus GD et al (2010) Prolonged activity of factor IX as a monomeric Fc fusion protein. Blood 115:2057–2064

    Article  CAS  PubMed  Google Scholar 

  • Platt RJ, Chen S, Zhou Y et al (2014) CRISPR-Cas9 knockin mice for genome editing and cancer modeling. Cell 159:440–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Porada CD, Sanada C, Long CR et al (2010) Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A. J Thromb Haemost 8:276–285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubinson DA, Dillon CP, Kwiatkowski AV et al (2003) A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 33:401–406

    Article  CAS  PubMed  Google Scholar 

  • Scott P, Natovitz P, Coffman RL, Pearce E, Sher A (1988) Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med 168:1675–1684

    Article  CAS  PubMed  Google Scholar 

  • Spence R, Gerlach G, Lawrence C, Smith C (2008) The behaviour and ecology of the zebrafish, Danio rerio. Biol Rev Camb Philos Soc 83:13–34

    Article  PubMed  Google Scholar 

  • Stennicke HR, Kjalke M, Karpf DM et al (2013) A novel B-domain O-glycoPEGylated FVIII (N8-GP) demonstrates full efficacy and prolonged effect in hemophilic mice models. Blood 121:2108–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart D, Fulton WB, Wilson C et al (2002) Genetic contribution to the septic response in a mouse model. Shock 18:342–347

    Article  PubMed  Google Scholar 

  • Sun N, Zhao H (2013) Transcription activator-like effector nucleases (TALENs): a highly efficient and versatile tool for genome editing. Biotechnol Bioeng 110:1811–1821

    Article  CAS  PubMed  Google Scholar 

  • Tang K, Rossiter HB, Wagner PD, Breen EC (2004) Lung-targeted VEGF inactivation leads to an emphysema phenotype in mice. J Appl Physiol 97:1559–1566, discussion 1549

    Article  CAS  PubMed  Google Scholar 

  • Urnov FD, Rebar EJ, Holmes MC, Zhang HS, Gregory PD (2010) Genome editing with engineered zinc finger nucleases. Nat Rev Genet 11:636–646

    Article  CAS  PubMed  Google Scholar 

  • Ventura A, Meissner A, Dillon CP et al (2004) Cre-lox-regulated conditional RNA interference from transgenes. Proc Natl Acad Sci U S A 101:10380–10385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Zoppe M, Hackeng TM, Griffin JH, Lee KF, Verma IM (1997) A factor IX-deficient mouse model for hemophilia B gene therapy. Proc Natl Acad Sci U S A 94:11563–11566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Bayer HealthCare, 455 Mission Bay Blvd. South, Suite 493, San Francisco, CA, 94158, USA

    Derek S. Sim & Katalin Kauser

Authors
  1. Derek S. Sim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katalin Kauser
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Derek S. Sim .

Editor information

Editors and Affiliations

  1. Drug Discovery-Cross Indication Platform, Bayer Pharma AG, Wuppertal, Germany

    Ulrich Nielsch

  2. Drug Discovery-Cross Indication Platform, Bayer Pharma AG, Berlin, Berlin, Germany

    Ulrike Fuhrmann

  3. Drug Discovery-Global External Innovation & Alliances, Bayer Pharma AG, Berlin, Berlin, Germany

    Stefan Jaroch

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Sim, D.S., Kauser, K. (2015). In Vivo Target Validation Using Biological Molecules in Drug Development. In: Nielsch, U., Fuhrmann, U., Jaroch, S. (eds) New Approaches to Drug Discovery. Handbook of Experimental Pharmacology, vol 232. Springer, Cham. https://doi.org/10.1007/164_2015_17

Download citation

Publish with us

Policies and ethics

Search

Navigation