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TRANSGENIC ANIMALS AND THEIR APPLICATION IN MEDICINE

Article  in  Journal of Research in Health Sciences · January 2012

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 International Journal of Medical Research
&
Health Sciences
www.ijmrhs.com Volume 2 Issue 1Jan-Mar 2013 Coden: IJMRHS Copyright @2013 ISSN: 2319-5886
Received:2 nd Dec 2012 Revised: 20 th Dec 2012 Accepted: 25 th Dec 2012

Review article

TRANSGENIC ANIMALS AND THEIR APPLICATION IN MEDICINE

*Bagle TR1, Kunkulol RR2, Baig MS3, More SY4.

1
Assistant Professor, 2 Associate Professor, Department of Pharmacology, Pravara Institute of Medical
Sciences-Deemed University(PIMS-D), Loni, Maharashtra.-413736.
3
Assistant Professor, Government Medical College, Aurangabad, Maharashtra. 431001
4
Research Student, Department of Pharmaceutical Chemistry, Prin.K.M.Kundnani College of Pharmacy,
Colaba, Mumbai, Maharashtra.400005.

*Corresponding author email: [email protected]

ABSTRACT

Transgenic animals are animals that are genetically altered to have traits that mimic symptoms of specific
human pathologies. They provide genetic models of various human diseases which are important in
understanding disease and developing new targets. In early 1980 Gordon and co-workers described the first
gene addition experiment using the microinjection technology and since then the impact of transgenic
technology on basic research has been significant. Within 20 years of its inception, ATryn the first drug
approved by USFDA from transgenic animals was developed and it has opened door to drugs from
transgenic animals. In addition, they are looked upon as potential future donors for xenotransplantation.
With increasing knowledge about the genetics and improvements in the transgenetic technology numerous
useful applications like biologically safe new-generation drugs based on human regulatory proteins are
being developed.Various aspects of concern in the coming years are the regulatory guidelines, ethical issues
and patents related to the use of transgenic animals. This modern medicine is on the threshold of a
pharmacological revolution. Use of transgenic animals will provide solutions for drug research,
xenotransplantation, clinical trials and will prove to be a new insight in drug development.

Keywords: Transgenic animals, Xenotransplantation, Ethics, Patent.

INTRODUCTION

With the advent of transgenic technology and its development has been additionally accelerated by
application in many laboratories around the world, the decoding the genome of man, mouse and rat.1
there is an increase in the generation and use of Pharmaceutical companies are faced with the
genetically modified animals in biomedical, challenge that about 10% of compounds tested in
pharmaceutical research and safety testing. This clinical trials make to the market and, out of these,
a minority will generate significant profit. The cost
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Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
of identifying new drug is immense, about United Following sequence is generally adopted for the
States (US) $ 800 million and 80% of this cost is development of transgenic animals irrespective of
spent in clinical trials and development. species: 1, 9
Transgenic technology has potential to influence  Identification and construction of the foreign
the attrition rate in pharmaceutical research by gene and any promoter sequences
increasing the quality of both targets and  Introduction of DNA directly into the
compounds. 2 pronucleus of a single fertilized egg by various
To date most of the medicines are synthetically methods
produced and will continue in future. However, the  Implantation of these engineered cells into
challenge for the pharmaceutical industry is the surrogate mothers
development of ‘Biotech medicines’ which include  Bringing the developing embryo to term,
therapeutic proteins such as enzymes and proving that the foreign DNA has been stably
antibodies. 3 The global market for recombinant and heritably incorporated into the DNA of at
proteins from domestic animals is expected to least some of the newborn offspring.
exceed US$1 billion in 2008 and reach US$18. 6  Demonstrating that the gene is regulated well
billion in 2013.4 The two major animal systems of enough to function in its new environment.
production are pharmaceutical proteins in milk and The foreign DNA can be inserted into the
egg white from transgenic animals. 1 pronucleus or cytoplasm of the embryo using
Since the first transgenic mice were generated in microinjections or transposon. Other methods of
1982, transgenic animal models have been used DNA transfer are by lentivirus, sperms, pluripotent
extensively to investigate biomedical important cells and cloning. The last three methods allow
mechanisms underlying a variety of diseases, to random gene addition and targeted gene integration
develop and evaluate new therapies. 5 Thus via homologous recombination or gene
transgenic animals have the ability to fulfill the replacement thus causing mutation. 1,6
Targeted
needs of the pharmaceutical industry and in mutation refers to a process whereby a specific
coming years they are looked as potential gene (removal of a gene or part of a gene) is made
contributors to the drugs and research in medicine. nonfunctional (knocked-out) or less frequently
Making of Transgenic Animals made functional (knocked-in). 4, 7 A transgenic
There are three types of laboratory animal models organism carrying more than one transgenes is
mentioned in the literature. They are spontaneous, known as multiple transgenic. 4These methods do
induced and transgenic. Spontaneous models shape not create new species, but only offer tools for
up as a result of naturally occurring mutations. producing new strains of animals that carry novel
Induced models are produced by a laboratory genetic information. 10
procedure like administration of a drug or
Transgenic Animal models of various diseases
chemicals, feeding of special diets or surgical
An animal model is a living, non-human animal
procedure. The third category includes transgenic
used for research and investigation of human
models.6Transgenic refers to insertion of cDNA
disease, for the purpose of better understanding the
(complimentary deoxyribonucleic acid) made from
disease without the added risk of causing harm to a
specific mRNA (messenger ribonucleic acid) into
human being during the entire drug discovery and
cells.7 A transgenic animal is defined as an animal
development process. Transgenic animal models
which is altered by the introduction of recombinant
are created by the insertion of a particular human
DNA through human intervention. 8
DNA into fertilized oocytes which are then
allowed to develop to term by implantation into the
oviducts of pseudo pregnant females.6 There are
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Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
different models of transgenic animals for various secretion such as glucokinase, islet amyloid
diseases. polypeptide, and hepatic glucose production in
A. Human Immunodeficiency Virus/ Acquired type 2 diabetes are developed. 18A transgenic
Immunodeficiency Syndrome (HIV/AIDS): mouse model that expressed Insulin Dependent
Tg26 HIVAN Mouse Model was the first Diabetes Mellitus by inserting a viral gene in the
transgenic model developed in 1991 for HIV. animal egg stage is also developed.19 There are
Since than many models have developed, other models like beta receptor knockout mouse,
Rosenstiel et al gives summary of 32 transgenic uncoupling protein (UCP1) knockout mouse,acute
murine HIVAN models developed. 11 These and chronic models for the evaluation of
transgenic animals can express HIV-1 proteins; antidiabetic agents. 18, 20, 21, 22
develop symptoms and immune deficiencies E. Angiogenesis: Mouse models of
similar to the manifestations of AIDS in humans. 12 angiogenesis, arterial stenosis, atherosclerosis,
Other models are AIDS Mouse and Smart Mouse. 6 thrombosis, thrombolysis and bleeding addresses
B. Alzheimer’s disease: No animal models techniques to evaluate vascular development.23
existed for the disease before transgenic Inhibition of angiogenesis is currently one of the
technology was employed. Immunization of biggest opportunities for new cancer therapies.
Amyloid precursor protein A42 in transgenic mice With the help of angiogenesis transgenic animal
showed that vaccination against Alzheimer’s models inhibitors are identified which act on
disease could have potential as a therapeutic specific mechanisms of angiogenesis. 2
approach.2, 6 Different animal models like F. Cancer diseases: Oncomouse was first
Alzheimer’s mouse, amyloid pathology mouse transgenic animal to be patented. Its germ cells and
models like PDAPP mice, Tg2576 mice, 13, 14 TAU somatic cells contain an activated human oncogene
transgenic mouse models like ALZ7 mice, 7TauTg sequence introduced into the animal at an early
mice and presenilin transgenic models like ApoE embryonic stage to ensure that the oncogene is
knockout are developed to study Alzheimer’s present in all the animal cells.6 Mechanisms for
disease. 13, 15 tumor progression and metastasis via E-cadherin,
C. Cardiovascular disease: Various transgenic and other adhesion molecules is possible by
animal models for gain and or loss of function of various transgenic knockout models. 7
angiotensin, endothelin, natriuretic peptides, Transgenic animal models are used in the
catechoalmines, Calcium binding-signaling, assessment of mutagenicity, carcinogenicity and
sodium channel transporters, and nitric oxide tools for understanding metabolic enzymes and
synthesis involved in cardiovascular regulation are receptors. 24 There are transgenic animal models
used to study cardiovascular diseases.16 Transgenic for mutagenicity assays approved by the World
models of heart failure and hypertrophy like Gene Health organization like LACItransgenic model
overexpression of Calmodulin, Gene mutation of (Big Blue® construct) and LACZ transgenic
alpha cardiac myosin heavy chain and Knockout model (Muta™Mouse construct). 25Variety of
gene model of transforming growth factor are transgenic animals have been generated by
developed.17 Mutation of the ApoE gene that is different strategies in experimental immunotherapy
critical for uptake of chylomicrons and very low- of cancer, each aims to activate different immune
density lipoprotein particles, results in a model that system components. Some of them are transgenic
develops atherosclerotic lesions histologically rodent models expressing tumor associated
similar to those found in humans.2 antigens like MUC1 transgenic mice, Oncogene
D. Diabetes Mellitus: Transgenic models are transgenic mice to study immunotherapeutic
developed for studying the genes, and their role in strategies, transgenic mice expressing immune
peripheral insulin action. Models of insulin effector cell molecules like Fc-receptor transgenic
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Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
mice 5 The preclinical transgenic model of Matrix interleukin 2, tPA, alpha glucosidase, and human
Metalloproteinase (MMP) inhibitors studies the growth hormone. 9
bioactive products of MMP and their possible Sheep: sheep milk includes fibrinogen (major
effects on cell physiology. 26 Animal models for constituent, with thrombin and Factor XIII) human
Huntington’s disease, skeletal muscle disease and Factor VII, Factor IX, activated protein C and
other diseases are also developed.27, 28 alpha-1-antitrypsin. 9,31
Disease models are needed in medicine so that one Other Species: Frogs, nematodes, and marine
can discover the targets for drug development. invertebrates have been used to study various
Adding and deleting genes in these animals promoter elements and gene transfer technology. 9
provide them new properties that make them useful Currently in most pharmaceutical companies,
for better understanding of disease or relatively large numbers of targets are validated to
manufacturing a cure. It is not ethical or safe to varying extents and progressed to the high
perform the initial tests in humans, so transgenic throughput screening stage. The drugs acting on
animals are used. As the testing of new vaccines these targets are then used in clinical trials where
and drugs must first be performed on animals, the attrition rate is generally high, this makes it
these disease models are indispensable. 6 extremely costly. It is believed that the greater use
of transgenic models could reduce the required
Products from Transgenic Animals
throughput for achieving success and thereby
Most transgenic species are studied for research
significant impact on costs.10
applications as well as potential commercial
pharmaceutical productively. Here are some of the Drugs from Transgenic Animals and Other
transgenic animals and their products in Applications:
development. Proteins started being used as pharmaceuticals in
Goats: Monoclonal Antibodies (MAbs) , Ig fusion the 1920s with insulin extracted from pig pancreas.
proteins, tPA (tissue Plasminogen Activator), In the early 1980s, human insulin was prepared in
ATryn (recombinant human antithrombin III) is the recombinant bacteria and is now used by most of
first transgenic recombinant protein from the diabetic patients. This success was limited as
transgenic animal approved by the United States bacteria cannot synthesize complex proteins such
Food and Drug Administration (USFDA) in as monoclonal antibodies or coagulation blood
January 2009. 9,29 factors that must be matured by post-translational
Chickens and Eggs: vaccines; interferons, modifications to be active or stable in vivo. These
cytokines; Human Serum Albumin (HSA), insulin, can be fully achieved only in mammalian cells
MAbs. 9 which can be cultured in fermenters or used in
Pigs: organs for xenotransplantation, human living animals. Several transgenic animals can
hemoglobin, human protein C. 9,30,31 produce recombinant proteins but presently two
Cows: Factors VIII and IX, protein C, recombinant systems started being implemented. The first is
antithrombin III (rATIII), recombinant HSA, and milk of transgenic mammals and the second
human milk protein. 9 system are chicken egg white. A variety of
Mice: expression of malaria protein for vaccine recombinant proteins which includes antibodies,
development; MAbs, ATIII, beta interferon; cystic vaccines, blood factors, hormones, growth factors,
fibrosis transmembrane regulator; Factor X, HSA, cytokines, enzymes, milk proteins, collagen,
tPA, myelin basic protein; prolactin; fibrinogen fibrinogen and others are being developed in
and antineoplastic urinary protein. 9 transgenic animals. 1,3,31
Rabbits: recombinant human C1 inhibitor, human The mammary gland is the preferred production
erythropoietin, human alpha antitrypsin, human site, because of the quantities of protein that can
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Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
be produced in this organ and established methods porcine red blood cells contained human form of
for extraction and purification of these haemoglobin. 4
proteins.Products derived from the mammary
Xenotransplantation of porcine organs to human
gland of transgenic goats and sheep are ATIII, α-
patients
antitrypsin and tPA. ATIII is employed for the
Today more than 250,000 people are alive only
treatment of heparin-resistant patients undergoing
because of the successful transplantation of an
cardiopulmonary bypass. The enzyme α-
appropriate human organ (allotransplantation).
glucosidase from the milk of transgenic rabbits has
However, progress in organ transplantation
been successfully used for Pompe’s disease. 4, 31
technology has led to an acute shortage of
Blood, seminal plasma, urine, silk gland and insect
appropriate organs, and cadaveric or live organ
larvae haemolymph are other theoretically possible
donation does not meet the demand. To close the
systems. Blood most of the time cannot store high
growing gap between demand and availability of
levels of recombinant proteins which are naturally
appropriate human organs, porcine xenografts from
unstable also biologically active proteins in blood
domesticated pigs are considered to be the best
may alter the health of the animals. Milk avoids
alternative.4
essentially these problems and is presently the
Essential prerequisites for a successful
most mature systems to produce recombinant 4, 34
xenotransplantation are:
proteins from transgenic organisms. Now
1. Prevention of transmission of zoonoses
experiments validate egg white as a source of
2. Compatibility of the donor organs in anatomy
foreign proteins including recombinant vaccines. 1,
31 and physiology
3. Overcoming the immunological rejection of the
Blood replacement
transplanted organ.
The current production system for blood products The immunological hurdles are:
is donated human blood, and this is limiting (a) Hyperacute rejection response (HAR) occurs
because of disease concerns, lack of qualified within seconds or minutes.
donors, and regulatory issues. Genetically (b) Acute vascular rejection occurs within days.
engineered animals, such as cattle carrying human (c) Cellular rejection occurs within weeks after
antibody genes which are able to produce human transplantation.
polyclonal antibodies, have the potential to (d) Chronic rejection is a complex immunological
provide a steady supply of polyclonal antibodies process resulting in the rejection of the
for treatment of various infectious and medical transplanted organ after several years.
conditions like organ transplant rejection, cancer, Due to demand and unavailability of appropriate
and autoimmune diseases and other diseases. 32 organs, xenotransplantation is considered as the
There are currently at least 33 different drugs in solution of choice. The pig seems to be the optimal
clinical testing including several in pivotal trials donor animal because their organs have a similar
that contain variable regions from transgenic mice size as human organs, porcine anatomy and
encoded by human sequences. Also there are 17 physiology is same and maintenance is possible at
therapeutic MAbs approved by the USFDA which high hygienic standards at relatively low costs. 34, 35
are in different phases of drug development. 33 Two main strategies have been successfully
Functional human haemoglobin has been produced explored for long-term suppression of HAR, the
in transgenic swine. The transgenic protein knockout of α-gal epitopes which are the antigenic
purified from the porcine blood showed oxygen- structures on the surface of the porcine cells that
binding characteristics similar to natural human cause HAR and synthesis of human complement
haemoglobin but only a small proportion of regulatory proteins in transgenic pigs. 31, 34, 36

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Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
Problems with drugs from transgenic animals: increase rather than reduced because of a wider
Erythropoietin could not be expressed in the range of diseases and conditions. 38
mammary gland of transgenic cattle. The recovery Ethical concern with oncomouse is that it usually
rates of Factor VIII protein were low. 34 Another suffers in order to collect relevant information,
concern is leakage of a target protein into the which contradict the principles of animal
circulation by way of the mammary epithelial cells rights.6Adenopolyposis coli knock-out mutant
and as measured by increased plasma levels of the mice are clinically normal until the intestinal
protein designed to be expressed only in the polyps develop, after which mice become anemic
animal’s milk. 9 There is also a risk of transmission and lose weight. Each newly created transgenic
of infection from animal to man. 31 There are some strain has the potential to cause poor health and
unique concerns such as premature lactational shut suffering in the animals hence measures need to be
down observed in some animals expressing undertaken to minimize animal suffering. 39
recombinant proteins in their mammary gland. 37 Other ethical concerns are breaching species
While there are problems associated with barriers and animal life should not be regarded as a
transgenic animals, the benefit derived from them chemical product subject to genetic alteration and
is far superior and with the increase in technology patentable for economic benefit. Also genetic
this could be solved. engineering of animals interferes with the integrity
or telos of the animal. Telos is defined as the set of
Drugs from Transgenic Animals in Clinical
needs and interests which are genetically based,
Trials
environmentally expressed, and which collectively
The approval of ATryn (rATIII) by USFDA has
constitute or define the form of life or way of
opened gates for other drugs from transgenic
living exhibited by that animal, and whose
animals. 29 Recombinant C1 inhibitor produced in
fulfillment or thwarting matter to that animal. 37
the milk of transgenic rabbits has completed phase
In India attitude towards animals is tinged with
III trials and is expected to receive registration. 4, 31
religious and ethical colour which makes religious
A topical antibiotic against Streptococcus mutans,
sentiments and public awareness necessary to be
for prevention and treatment of dental caries, has
taken in consideration.40 The 3R (Reduction,
completed phase III trials. 34 Vaccine used in
Refinement, Replacement) aim to minimize pain
Alzheimers disease has restored neurological
experienced by the animals used in
performance in the mice, and is currently in phase 29
experiments. Inspite of the problems listed above,
II human clinical trials. 6α-Glucosidase from the
transgenic animals may represent a “refinement” in
rabbit is in clinical trial phase II/III for Pompe’s
comparison to some other traditional experimental
disease. 31, 34 Products such as α-anti-trypsinused
models of disease where animals bear a heavy load
for cystic fibrosis, α-AT deficiency and tPA used
of suffering. A genotype is an excellent model of
for coronary clots are currently in phase II/III
disease for selected body functions at the
clinical trials and are expected to be on the market
molecular or cellular level while the corresponding
within the next few years. 34
phenotype is completely healthy. Thus it becomes
Ethics in Transgenic Animals
necessary to consider the moral implications of
Genetic modification of micro-organisms and
producing such a species as well as measures of
plants has least concern with regards to ethics but
reducing animal suffering. 39
when it comes to genetic modification of animals
and particularly humans, more objections are Patents on Transgenic animals
registered. There remains concern that with Patenting of animal models is the need of hour,
advances in transgenic animal technologies the because it is an indispensable tool for screening of
number of animals used for research may actually novel molecule to various diseases. A human

112
Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
pathological condition in animals is most important process of drug discovery. 6 The Indian regulatory
to determine the therapeutic efficacy of novel authorities need to be prepared for such challenges
molecule. They allow facilitation of the screening of ethics, regulation and patents in transgenic
process to eliminate inactive moieties and assess animals.
the pharmacologist to identify the therapeutic
Future prospects
potential and characterize the toxicological profile
Xenogenic cells, in particular from the pig, hold
of novel chemical or biological entities. 6
great promise with regard to successful cell
The two major aspects in granting patents to
therapy for human patients. Porcine islet cells
animal model are morality and reproducibility. 6
transplanted to diabetic patients has shown to be
Other concerns like restrictive licensing of the
partially functional over a period of time. Porcine
patents can hinder transfer of knowledge. 41
fetal neural cells have been transplanted into the
Preclinical animal models are important in drug
brain of patients suffering from Parkinson’s
discovery, because they lay the fundamental for
disease, Huntington’s disease, stroke and focal
human trials. Patents remain one of the important
epilepsy. The advantages of porcine neural cells
ways of recovery of the investments made by the
over their human counterparts are the abundant
Pharmaceutical companies in research. The Indian
availability. 34The pig could be a useful model for
Patent Law section 3i and 3 j states that all the
studying defects of growth-hormone releasing
surgical processes and animals are not patentable,
hormone, which are implicated in conditions such
hence animal models are not patentable in India. If
as Turner syndrome, hypochrondroplasia, and
the suitable amendments are made then animal
intrauterine growth retardation.4
models can be patentable in India and it would
Eggs provide other non-invasive harvesting
open novel vistas in the research arena in India. 6
medium. Significant quantities of two human
Regulation in Transgenic Animals proteins, interferon beta-1a and a humanized
Pharmaceutical research on animals in India monoclonal antibody (miR24) were expressed in
depends on Department of Biotechnology, the whites of eggs laid by transgenic hens. miR24
National Institute of Immunology and is being developed for malignant melanoma. 3
Environment Protection Act. An Animal Welfare There are transgenic animals for the development
Board is constituted, with a Committee for the of unique biological materials like polymers based
Control and Supervision of Experiments Animals on spider silks that may be useful as suture or
(CPCSEA) which is in charge of legal and ethical plastic materials in facial and orthopedic
aspects or animal research. General Guidelines on restorative surgery. 43,37 It is impractical to obtain
caring for animals in research are in accordance sufficient quantities of plasma butylcholinesterase
with the International Committee for Laboratory (BChE) to treat humans exposed to
Animal Science (ICLAS) Guidelines. However organophosphorus agents in agriculture and
there is no specific law or guidelines for cloned chemical warfare, the production of recombinant
and transgenic animals. In 2000, Indian Council of BChE in milk of transgenic animals is under
Medical Research Report promotes transgenic investigation. 44 It is proven that the amount of
animal research as long as it would pursue a higher human antithrombin III obtained per year from
scientific goal. 40, 42 transgenic goats is equivalent to this resulting from
With changes in the overall process of drug 90,000 human blood samplings. 1 Thus transgenic
discovery, US patents of animal models encourage animals have the capacity of mass production and
scientists in America and Europe to produce an effective alternative to various human
animal models which are very close to human byproducts. Improvements in transgenic
disease and hence contribute significantly to the technology include inducible gene expression,
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Bagle TR et al., Int J Med Res Health Sci. 2012;2(1):107-116
artificial chromosomes and advancement in in medicine and is now a necessity rather than a
nuclear transfer. 34, 45, 36 matter of choice.
Emerging transgenic technologies: 4, 31, 45
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