Rodent models for human diseases

Rodent models for human diseases

European Journal of Pharmacology 759 (2015) 84–89 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.e...

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European Journal of Pharmacology 759 (2015) 84–89

Contents lists available at ScienceDirect

European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Rodent models for human diseases Thierry F. Vandamme n Université de Strasbourg, Faculté de pharmacie, UMR 7199 CNRS, Laboratoire de Conception et Application de Molécules Bioactives, 74 Route du Rhin, B.P. 60024, 67401 Illkirch Cedex, France

art ic l e i nf o

a b s t r a c t

Article history: Received 26 January 2015 Received in revised form 3 February 2015 Accepted 12 March 2015 Available online 28 March 2015

One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. Except in the case of highly controlled and regulated clinical trials, geneticists and scientists do not use humans for their experimental investigations because of the obvious risk to life. Instead, they use various animal, fungal, bacterial, and plant species as model organisms for their studies. Amongst these model organisms, rodent models are the most used due to the easiness for the experiments and the possibility to modify genetically these model animals. Nevertheless, due to the fact that animal models typically do not contract the same genetic diseases as people, so scientists must alter their genomes to induce human disease states and to know what kind of mutation causes the disease. In this brief review, we will discuss the interests of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM) models, we will review some of the current genetic strategies for modeling diseases. & 2015 Elsevier B.V. All rights reserved.

Keywords: Rodent Animal models Diseases Xenografts model animals Genetically engineered model animals

1. Introduction A multi-disciplinary approach to improve medical treatments can catalyze scientific developments and enable clinical translation beyond what we currently utilize. Engineers, chemists, and physical scientists are teaming up with biologists, physiologists and clinical physicians to attack the vast array of human diseases using new drug developments, materials and conventional or targeted dosage forms. The challenge is not other than to identify new therapeutic targets in keeping with a pathology. Classically, they are receivers or enzymes on which are fixed the drugs in order to modify the cellular functions. Once the validated target, its biological operation should then be deciphered. Thanks to the exploration of the human genome, the potential of new targets increased these last years considerably and, in the future, the treatments will gain in specificity. The current challenge consists in identifying the embarrassments predisposing with such or such disease in the objective to find new ways of therapeutic. Even if bioinformatics, high-throughput screening, cell cultures, in vitro and ex vivo experiments are able to orientate the interests for a lead compound, a drug or a new formulation, it does not remain about it less than the animal experimentation remains necessary before considering the first human tests.

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http://dx.doi.org/10.1016/j.ejphar.2015.03.046 0014-2999/& 2015 Elsevier B.V. All rights reserved.

In many cases, while computers provide terrific resources for researchers all over the world, they do have limitations. For instance, computers are only able to provide informations or models known as “phenomena.” Because research consistently seeks answers to unknowns, a computer is unable to simulate how a particular cell might interact or react with a medical compound, or how a complex biological system such as the circulatory system will react to a new drug directed to improve organ function. A single living cell is many times more complex than even the most sophisticated computer program. There are an estimated 50–100 trillion cells in the human body, all of which communicate and interact using a complicated biochemical language – a language researchers have only just begun to learn. Studies using isolated cells or tissues almost always precede animal-based research, but researchers must study whole living systems to understand the effectiveness of treatments and, their potential benefits and dangers. Despite claims by animal rights activists, it is undeniable that animal-based research has contributed to significant improvement in the length and quality of human lives. Nevertheless, each species in the animal kingdom is unique. But just as there are differences, there are also key similarities. This is what comparative medicine is about: researchers use both similarities and differences to gain insight into the many complex human biological systems. Researchers often work with animal models that have biological systems similar to that of a human. For instance, swine and humans share similar cardiovascular and skin systems. By working

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with swine, researchers are better able to develop and study new heart medicines and treatments for skin diseases. To study genetic disorders such as Down Syndrome or Parkinson's Disease, researchers might study a mouse model which shares 94% of its DNA with humans. Organisms that look very different can be very similar genetically. Chimpanzees share 98.7% of their DNA with humans. Zebra fish share 75–80% of their DNA with humans. Bananas share 50%. The differences exhibited in a research model can also provide great insights. For instance, sharks and pigs rarely get cancer, cockroaches can regenerate damaged nerves, and some amphibians can regrow lost limbs. By studying these animals we may learn how they accomplish these remarkable feats and apply the principles to human medicine.

2. Animal models In vitro assays typically rely on simple interactions of (bio) chemicals with a drug target, such as receptor binding or enzyme activity inhibition. However, in vitro results often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro testing system. Although cellbased assays can provide some information, cultured cells still do not provide physiological conditions and complex interactions among different cell types and tissues. Moreover, cell lines are usually transformed, exhibiting different gene expression and cell cycle profiles than those of cells in the living organism. For these reasons, there is a growing trend of using human tissues for drug discovery research. Tissues, however, only provide an isolated ex vivo condition, which is not completely representative of in vivo response because drug action often involves metabolism and interplay among different tissues. For instance, the effects of a drug on muscle may involve absorption by the intestine and metabolism by the liver. Therefore, results in animal studies are essential to validate HTS (high-throughput screening) hits and exclude compounds with unfavorable ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, which are responsible for more than half of compound attrition in costly clinical trials. It is generally estimated that rodents and fish comprise well over 95% of all animals used in clinical research. When animal models are employed in the study of human disease, they are frequently selected because of their similarity to humans in terms of genetics, anatomy, and physiology. Also, animal models are often preferable for experimental disease research because of their unlimited supply and ease of manipulation (Simmons, 2008). For example, to obtain scientifically valid research results, the conditions associated with an experiment must be closely controlled. This often means manipulating only one variable while keeping others constant, and then observing the consequences of that change. In addition, to test hypotheses about how a disease develops, an adequate number of subjects must be used to statistically test the results of the experiment. Therefore, scientists cannot conduct research on just one animal or human, and it is easier for scientists to use sufficiently a large numbers of animals (rather than people) to attain significant results (Simmons, 2008). The advantages and limitations by using animal models are shown in Figs. 1 and 2. 2.1. Xenografts model animals Also called heterograft, xenograft is a graft obtained from a member of one species and transplanted to a member of another species. Investigating the metastatic behavior of cancer stem cells (CSCs) is critical for the development of more effective therapies to

Fig. 1. Main advantages of animal models used in preclinical studies.

Fig. 2. Limitations of animal models used in preclinical studies.

prevent or delay the progression of malignant diseases. Animal models have been developed to mimic the multistep process of metastasis to various target organs. To do this, several xenograft methods have been studied to introduce human cancer cells into nude mice in order to generate spontaneous and experimental metastases. By the past, numerous murine models have been developed to study human cancer. These models are used to investigate the factors involved in malignant transformation, invasion and metastasis, as well as to examine response to therapy. One of the most widely used models is the human tumor xenograft. In this model, human tumor cells are transplanted, either under the skin or into the organ type in which the tumor originated, into immunocompromised mice that do not reject human cells. For example, the xenograft will be readily accepted by athymic nude mice, severely compromised immunodeficient (SCID) mice, or other immunocompromised mice (Morton and Houghton, 2007). Depending upon the number of cells injected, or the size of the tumor transplanted, the tumor will develop over 1–8 weeks (or in some instances 1–4 months, or longer), and the response to appropriate therapeutic regimes can be studied in vivo (Richmond and Su, 2008). Even if heterotransplantation of human cancer cells or tumor biopsies into immunodeficient rodents (xenograft models) has, for the past two decades, constituted the major preclinical screen for the development of novel cancer therapeutics, at present time genetically engineered model animals are preferred. Despite limitations, these models have identified clinically efficacious agents, and remain

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the ‘workhorse’ of the pharmaceutical industry. However, if therapeutic approaches to treating tumors according to their molecular characteristics are to be achieved, additional new models of human cancer will be required to represent the genetic diversity that exists within tumor histologies. This protocol details a method for establishing xenografts from primary solid-tumor isolates or cells grown in culture. The procedure relies on immunodeficient mice to provide a host for the establishment of human xenografts. The procedure can be completed in 1–2 h with results being obtained in 1–4 months (Morton and Houghton, 2007).

2.2. Genetically engineered model animals They are animals that have had changes made to their DNA through molecular techniques. Changes in the DNA give these animals new characteristics. Transgenic animals are genetically modified animals which have had genes from another species inserted into their DNA. Jaenisch and Mintz, 1974 constructed the first genetically modified animal by inserting a DNA virus into an early-stage mouse embryo. These authors showed that the inserted genes were present in every cell (Jaenisch and Mintz, 1974). Unfortunately, the mice did not pass the transgene to their offspring, and the impact and applicability of this experiment were, therefore, limited. In 1981, the laboratories of Frank Constantini and Elizabeth Lacy from Oxford, Frank Ruddle from Yale, and Ralph Brinster and Richard Palmiter in collaboration from the University of Pennsylvania and the University of Washington injected purified DNA into a single-cell mouse embryo utilizing techniques developed by Brinster in the 1960s and 1970s. All of these authors showed the transmission of the genetic material to subsequent generations for the first time (Gordon and Ruddle, 1981; Costantini and Lacy, 1981; Brinster et al., 1981). During the early eighties, Palmiter and Brinster developed and led the field of transgenesis, refining methods of germline modification and using these techniques to elucidate the activity and function of genes in a way never possible before their unique approach (Hanahan et al., 2007). Since this time, further techniques have been developed. As well as inserting genes, it is now possible to ‘knock out’ specific genes, or to make larger-scale genetic alterations. Such animals are now generally referred to as GM animals. The most common method for producing GM animals is to inject the foreign gene into fertilized eggs through a process known as ‘microinjection’. For mammals, the injected eggs are placed into a ‘foster’ mother where they develop to term. If the foreign gene has been successfully incorporated into the egg's original DNA, the resultant offspring will carry the extra, foreign DNA. When this GM animal mates and produces offspring, the foreign gene is inherited in the same way as normal DNA. In this way, scientists can breed a line of GM animals that carries the extra DNA. The numbers of rats, mice and zebra fish have increased due to the ongoing development of genetic research tools. These methods allow researchers to modify the genome in animals to model common diseases in order to study potential cures. For instance, scientists have been able to insert the human genes responsible for a type of Alzheimer's disease into rodents, resulting in the rodents' developing the cognitive dysfunction and memory loss that people experience. Rodents are the most common type of mammal employed in experimental studies. Indeed, in the past, extensive research works have been conducted using rats, mice, gerbils, guinea pigs, and hamsters. Among these rodents, the majority of genetic studies, especially those involving disease, have employed mice, not only because their genomes are so similar to that of humans, but also because of their availability, ease of handling, high reproductive rates, and relatively low cost of use. Other common experimental organisms include fruit flies, zebra fish, and baker's yeast.

Genetically engineered mice and rats are animals that have had their genomes altered through the use of genetic engineering techniques to more precisely model human phenotypes and pathologies, giving researchers a better way to explore mechanisms and greater confidence in the translational potential of their findings. Transgenic models of oncology, cardiovascular disease, neurodegenerative and metabolic disorders, among others, are now available and described in the literature allowing to identify the transgenic mouse or rat model that will best meet the study needs. At present time, two basic technical approaches can be envisaged to produce genetically modified mice. The first approach, pioneered by Oliver Smithies and Mario Capecchi, involves modifying embryonic stem cells with a DNA construct containing DNA sequences homologous to the target gene. Embryonic stem cells that recombine with the genomic DNA are selected for and they are then injected into the mice blastocysts (Thomas and Capecchi, 1987). This method is used to manipulate a single gene, in most cases “knocking out” the target gene, although more subtle genetic manipulation can occur (e.g. only changing single nucleotides). The second involves pronuclear injection into a single cell of the mouse embryo, where it will randomly integrate into the mouse genome (Gordon et al., 1980). This method constructs a transgenic mouse and is used to insert new genetic information into the mouse genome or to over-express endogenous genes (Fig. 3). Different genetically engineered models animals have been developed to study different human diseases. Amongst them, for instance, we can cite:

2.3. Cancer The preclinical development of anticancer drugs has been based primarily on the transplantation of murine or human cancers into mice. Alternatives to these transplantation models are animals that naturally develop cancers with features relevant to the human disease. Mice are desirable as cancer models because of the discovery in 1981 that the mouse germline can be changed to accept the delivery and consistent expression of foreign genes. This followed the demonstration in 1976 that normal cells have proto-oncogenes

Fig. 3. Two methods to produce genetically engineered models animals.

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that are defective in tumor cells; these defective genes are called oncogenes, and many have now been associated with the development of human tumors. The first publications about transgenic cancer models appeared in 1984. One model of brain tumors was derived by delivering a viral oncogene called SV40 T-antigen into

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mouse eggs. The other was produced by delivering a mutant human oncogene called c-Myc by MMTV, a mouse virus that infects mouse mammary tissue; the mice developed mammary tumors that resemble human breast tumors. These first models were the impetus for development of a large number of transgenic

Table 1 Representative genetically engineered mouse models of prostate cancer. Type

Name

Description

Reference

Gain-offunction trangenic models

TRAMP(rPB-SV40)

SV40 large tumor antigen (Tag) driven by a minimal rat probassin promoter (rPB). Phenotype: PIN, adenocarcinoma, neuroendocrine differentiation, andmetastases, castration-resistant prostate cancer. SV40 large tumor antigen driven by large probastin promoter. Phenotype: PIN, adenocarcinoma, neuroendocrine differentiation, and metastases Truncated SV40 T antigen (without small t antigen) driven by minimal probassin promoter with androgen-regulated sites (ARR2PB). Phenotype: PIN and adenocarcinoma. Myristoylated Akt1 driven by the RPB promoter. Phenotype: PIN

Greenberg et al., 1995

A human mutantB-RAF (V600E) driven by the Tet promoter and crossed with mice having a tet-regulatable tyrosinase promoter. Phenotype: PIN and adenocarcinoma. Germline deletion of Nkx3.1 (or conditional deletion of Nkx3.1 in the germline). Phenotype: PIN.

Majumder et al., 2003 Jeong et al., 2008 Bhatia-Gaur et al., 1999; Abdulkadir et al., 2002; Kim et al., 2002. Di Cristofano et al., 1998; Podsypanina et al., 1999. Kim et al., 2002; Abate-Shen et al., 2003. Di Cristofano et al., 2001; Gao et al., 2004 Carver et al., 2009; King et al., 2009. Trotman et al., 2003; Wang et al., 2003

Lady (LPTB-Tag) TgAPT121 (ARR2PB-APT121)

Loss of function models

Hi-Myc/Low-MYc (ARR2PB-cMyc) MPAKT (rPB-myr-HAAkt1) iBraf (Tet-BRAFV600E; Tyr-rtTA; Ink4a/Arf  /  ) Nkx3.1 þ /  and Nkx3.1  /  and Nkx3.1flox/flox Pten þ/  Nkx3.1 þ /  ; Pten þ /  Pten þ /  ; p27  /  and Nkx3.1 þ /  ; Pten þ /  ; p27 þ /  TMPRS-Erg; Pten þ / 

Conditional loss-ofunction models

PB-Cre; Ptenflox/flox

PSA-Cre-ERt2; Ptenflox/flox PB-Cre; Ptenflox/flox; p53flox/flox

Masumori et al., 2001 Hill et al., 2005

Ellwood-Yen et al., 2003

Germline detection of Pten. Phenotype: PIN and high-grade PIN; castration-resistant prostate cancer. Phenotypes not restricted to prostate. Compound germline mutant mice; Phenotype: PIN, adenocarcinoma. Phenotypes not restricted to prostate. Compound germline.mutant mice. Phenotype: PIN, adenocarcinoma. Phenotypes not restricted to prostate. Germline loss of function of Pten combined with gain of function of the TMPRS-Erg transgene. Phenotype: PIN, adenocarcinoma Conditional deletion of Pten in the prostate driven by a minimal probasin promoter driving Cre recombinase. Phenotype: PIN, adenocarcinoma; castration-resistant prostate cancer. Condditional deletion of Pten in the prostate driven by a PSA promoter driving an Ratnacaram et al., 2008 inductible Cre-ERT2 recombinase. Phenotype: PIN, adenocarcinoma Conditional deletion of Pten and p53 in the prostate driven by a minimal probasin Chen et al., 2005 promoter driving Cre recombinase. Phenotype: PIN, adenocarcinoma

Table 2 Genetically engineered models. Models

Research applications

Cardiac hypertrophy. Triple n/i/eNOS  /  mice Transgenic (TG; FVB/N) mice engineered to express rat CRNK under control Heart failure of the α-myosin heavy chain promoter (11bHSD2) mice Heart failure Ptf1a þ/Cre;Kras þ/LSL-G12D;p53LoxP/LoxP mice Metabolism αERKO mice NOD-scid Il2rγnull or NSG NOD.Cg-PrkdcscidIl2rgtm1Sug BALB/c-Rag2nullIl2rγnull

Fertility Immunology

Der p2-sensitized mice Nonobese diabetic (NOD) mice ob/ob(lep  /  ) mouse IGF-1 knockout male mice Caps2/Cadps2 Variant Mice LsL-KrasG12D; Pdx1-Cre or LsL-KrasG12D;LsL-Trp53R172H;Pdx1-Cre mice

Allergy Immunity, autoimmunity Diabetes, glycogen regulation Cortisone regulation Neurology Cholesterol efflux, esterification and transport

Pgp-deficient mice IL-13 mice K-RasV14I-mutant mice

CNS, multiple drug sensitivity (MDS), toxicology, teratology, altered intestinal intraepithelial lymphocyte development Asthma Genetic disease

Tyrosine hydroxylase (TH)-MYCN, TH-MYCN/Trp53 þ /  , TH-MYCN/TH-Cre/ Casp8flox/flox, TH-MYCN/TH-ALKF1174L and DBH-iCre/CAG-LSL-Lin28b

Humanized models, gene knockdowns (siRNA expressing transgenes), reporter genes, gene overexpression

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cancer models, using oncogenes that many laboratories discovered to be associated with human cancers in a variety of organ systems. Therefore, since the eighties, a lot of different genetically engineered mice models have been developed. As example, if we focalize on the prostate cancer we can mention (Table 1): 2.4. Other applications Besides the genetically engineered rodents used for the study of oncology applications, other rodents models have been engineered to study other diseases. These genetically engineered mice and rats are constructed to more precisely model human phenotypes and pathologies, giving researchers a better way to explore mechanisms and greater confidence in the translational potential of their findings. To do this, transgenic models of oncology, cardiovascular disease, neurodegenerative and metabolic disorders, among others, are available. For instance, amongst them, we can cite Table 2.

3. Conclusion Among the many advantages to using the rodents as a model organisms, the most important is their striking similarity to humans in anatomy, physiology, and genetics. Over 95% of the mouse genome is similar to our own, making rodents genetic research particularly applicable to human disease. Practically, rodents are a cost-effective and efficient tool to speed research and the development of drug therapies. Rodents are small, have a short generation time and an accelerated lifespan (one mouse year equals about 30 human years), keeping the costs, space, and time required to perform research manageable. The natural variation among inbred strains provides an essential system to study complex diseases involving the interaction of multiple genes, a focal point of biomedical research and drug efficacy testing. Because many of the genes responsible for complex diseases such as cancer, metabolism disfunction, genetic diseases, asthma, etc. are shared between rodents and humans, research in rodents and especially in mice is crucial for the identification of genetic risk factors in the human population. Naturally occurring, spontaneous mutations also often cause afflictions in rodents that mimic similar human genetic diseases. References Abate-Shen, C., Banach-Petrosky, W.A., Sun, X., Economides, K.D., Desai, N., Gregg, J. P., Borowsky, A.D., Cardiff, R.D., Shen, M.M., 2003. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Res. 63 (14), 3886–3890. Abdulkadir, S.A., Magee, J.A., Peters, T.J., Kaleem, Z., Naughton, C.K., Humphrey, P.A., Milbrandt, J., 2002. Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. Mol. Cell. Biol. 22 (5), 1495–1503. Ai, C., Zhang, Q., Ren, C., Wang, G., Liu, X., Tian, F., Zhao, J., Zhang, H., Chen, Y.Q., Chen, W., 2014. Genetically engineered lactococcus lactis protect against house dust mite allergy in a BALB/c mouse model. PLoS One 9 (10), e109461, Article number. Bhatia-Gaur, R., Donjacour, A.A., Sciavolino, P.J., Kim, M., Desai, N., Young, P., Norton, C.R., Gridley, T., Cardiff, R.D., Cunha, G.R., Abate-Shen, C., Shen, M.M., 1999. Roles for Nkx3.1 in prostate development and cancer. Genes Dev. 13 (8), 966–977. Brinster, R., Chen, H.Y., Trumbauer, M., Senear, A.W., Warren, R., Palmiter, R.D., 1981. Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 27 (1 Pt 2), 223–231. Carver, B.S., Tran, J., Gopalan, A., Chen, Z., Shaikh, S., Carracedo, A., Alimonti, A., Nardella, C., Varmeh, S., Scardino, P.T., Cordon-Cardo, C., Gerald, W., Pandolfi, P. P., 2009. Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate. Nat. Genet. 41 (5), 619–624. Chapman, A.M., Malkin, D.J., Camacho, J., Schiestl, R.H., 2014. IL-13 overexpression in mouse lungs triggers systemic genotoxicity in peripheral blood. Mutat. Res./ Fundam. Mol. Mech. 769, 100–107. Chen, Z., Trotman, L.C., Shaffer, D., Lin, H.K., Dotan, Z.A., Niki, M., Koutcher, J.A., Scher, H.I., Ludwig, T., Gerald, W., Cordon-Cardo, C., Pandolfi, P.P., 2005. Crucial role of p53-

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