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10 Drug Design Models forHuman Diseases by Transgenic Animals
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10.7 Blood Replacement
The existing blood product-producing process relies on donated human blood,
which is constrained by concerns related to diseases, a shortage of eligible
donors, and regulatory challenges. Animals that have been genetically modied,
such as cattle that possess human antibody genes and can produce human polyclonal antibodies that offer the possibility of a consistent source of polyclonal
antibodies for treating different medical and infectious conditions, including
cancer, autoimmune diseases, organ transplant rejection, and other ailments (Van
Eenennaam 2008). Currently, there are a minimum of 33 medications undergoing
clinical testing. Some of these treatments are in pivotal trials and incorporate
changeable sections from transgenic mice that are encoded by human sequences.
Furthermore, the USFDA has authorized a total of 17 therapeutic MAbs that are
now undergoing various stages of pharmacological development (Lonberg 2005).
Transgenic pigs have successfully developed functional human hemoglobin. The
transgenic protein isolated from pig blood had oxygen-binding properties comparable to those of native human hemoglobin. However, only a minuscule fraction of swine red blood cells carried the human variant of hemoglobin (Niemann
and Kues 2007).
10.7.1 Transplanting Pig Organs into
Humans (Xenotransplantation)
Presently, almost 250,000 individuals owe their survival only to the successful allotransplantation of a suitable human organ. Nevertheless, advancements in organ
transplanting technology have resulted in a severe scarcity of suitable organs, and
both deceased and living organ donations are insufcient to satisfy the need. In
order to address the increasing disparity between the need for suitable human organs
and their limited availability, porcine xenografts derived from farmed pigs are
regarded as the most optimal option (Niemann and Kues 2007).
The necessary requirements for a successful xenotransplantation are (Niemann
and Kues 2007; Niemann and Kues 2003):
1. Zoonotic transmission prevention
2. Compatibility of the donated organs in terms of their anatomical and physiologi-
cal characteristics
3. Resolving the immunologic rejections of the transplanted organs
Xenotransplantation is regarded as the preferred approach due to the high
demand and limited supply of suitable organs. The pig is considered an ideal candidate for organ donation due to the similarity in size between pig and human organs,
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as well as the comparable architecture and physiology. Additionally, pigs can be
maintained at high sanitary standards at very low costs (Niemann and Kues 2003;
Fung etal. 1997). The long-term suppression of hyperacute rejection (HAR) has
been effectively researched using two basic ways. Antigenic features on swine cells
called gal epitopes are removed in order to prevent HAR, and transgenic pigs that
generate human complement regulating proteins are created (Niemann and Kues
2003; Cooper 2003).
Issues pertaining to medications derived from transgenic animals include the
inability to produce erythropoietin in transgenic animal’s mammary glands. The
retrieval rates of Factor-VIII protein were suboptimal (Niemann and Kues 2003).
Another worry arises from the potential leaking of a specic protein into the bloodstream via the mammary epithelial cells. This may be assessed by seeing elevated
levels of the protein in the animal’s plasma, which is intended to be exclusively
expressed in its milk. There is also a potential for infection to be transmitted from
animals to humans (Hunter etal. 2005). Some animals that produce recombinant
proteins in their mammary gland may have a premature lactational shutdown,
which is a distinct problem (Van Eenennaam 2008). Although transgenic animals
present some challenges, the advantages they provide far outweigh these issues.
Furthermore, with advancements in technology, these challenges may be effectively addressed.
S. Banerjee et al.
10.8 Clinical Trials ofMedications Derived
fromTransgenic Animals
The USFDA’s clearance of ATryn has paved the way for the introduction of additional pharmaceuticals derived from transgenic animals (Ormandy etal. 2011).
The transgenic rabbits have effectively produced the recombinant C1 inhibitor in
their milk. This inhibitor has passed phase III trials and is expected to get registration (Hunter etal. 2005; Niemann and Kues 2003). A successful phase III clinical
trial has been conducted for a topical antibiotic that specically targets
Streptococcus mutans, a bacterium responsible for causing dental caries. This antibiotic is intended for both preventing and treating dental caries (Niemann and
Kues 2003). The vaccine administered in mice with Alzheimer’s disease has successfully improved their neurological function. Currently, the vaccine is undergoing phase II clinical trials in humans. The clinical study phase II/III for Pompe’s
illness is now evaluating the effectiveness of α-Glucosidase derived from rabbits
(Hunter etal. 2005; Niemann and Kues 2003). α-antitrypsin, which is used in the
treatment of cystic brosis and α-AT deciency, together with tPA, which is utilized for coronary clotting, are now completing clinical trial phase II or III.These
goods are expected to become commercially accessible in the next years (Niemann
and Kues 2003).
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10.9 Transgenic Animals andEthical Considerations
The ethical concerns surrounding genetic alteration are often less prominent when
it comes to microorganisms and plants. Nevertheless, when it pertains to the genetic
alteration of animals and especially humans, a greater number of concerns are
raised. There is a concern that advancements in transgenic animal technology may
actually result in an increase, rather than a reduction, in the number of animals utilized for research. This is due to the fact that medical conditions and diseases may
be studied with the help of new technology (Einsiedel 2005). The oncomouse presents a moral conundrum since it is routinely subjected to discomfort for the sake of
collecting useful data, which goes against the ideals of animal rights (Gupta and
Maurya 2018). The Adenomatous polyposis coli knockout mutant mice display conventional clinical features until the development of intestinal polyps, at which juncture they manifest anemia and endure a decline in body weight. Every new transgenic
strain has the ability to provoke detrimental health issues and discomfort in the
animals. Hence, it is essential to use strategies focused on mitigating animal distress
(Mertens and Rulicke 2007). Additional ethical considerations are the violation of
species boundaries and the recognition that animal life should not be seen as a
chemical commodity that can be genetically modied and patented for commercial
gain. Genetic engineering of animals also disrupts the animal’s integrity or telos.
Telos refers to the collection of genetically determined wants and interests that are
manifested in the environment and together shape the style of life shown by an animal. The fulllment or obstruction of these needs and interests is signicant to the
animal (Van Eenennaam 2006).
In India, the treatment of animals is inuenced by religious and ethical beliefs,
making it important to address religious sensitivities and public awareness
(Giridharan etal. 2000). The 3R principles (Reduction, Renement, Replacement)
are designed to decrease pain and suffering endured by animals involved in experimental procedures (Ormandy etal. 2011). Despite the aforementioned issues, transgenic animals may be considered an “improvement” compared to many conventional
experimental illness models in which animals endure signicant pain. A genotype
serves as a very effective representation of disease, specically focusing on certain
bodily processes at the cellular or molecular level. In contrast, the corresponding
phenotype exhibits total health. Therefore, it is imperative to contemplate the ethical ramications of creating such a species, as well as implementing strategies to
mitigate animal distress (Mertens and Rulicke 2007).
10.10 Transgenic Animal Patents
The patenting of animal models is crucial at present as it serves as an essential tool for
evaluating the effectiveness of new molecules in treating different illnesses. The assessment of the therapeutic effectiveness of a new molecule is mostly reliant on identifying
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a signicant pathological state in animals. Eliminating inert ingredients makes it simpler for pharmacologists to evaluate the therapeutic potential and examine the toxicological aspects of new chemical or biological molecules (Gupta and Maurya 2018).
The two primary considerations for awarding patents to animal models are ethicality
and replicability. Additional issues such as the imposition of restricted licensing on
patents might impede the dissemination of information (Hunter etal. 2005).
Preclinical animal models play an important role in drug discoveries since they
provide the foundation for human trials. Patents continue to be a crucial method for
pharmaceutical corporations to recoup their research expenses. According to Sects.
3i and 3j of the Indian Patent Law, it is specied that surgical methods and animals
are not eligible for patents. Therefore, animal models cannot be patented in India. If
appropriate modications are implemented, animal models might become eligible
for patent protection in India, hence creating new opportunities for research in the
country (Gupta and Maurya 2018).
S. Banerjee et al.
10.11 Regulating Transgenic Animals
Animals are used in pharmaceutical research in India, with support from the
National Institute of Immunology, the Department of Biotechnology, and the
Environmental Protection Act. The Animal Welfare Board is an administrative
board with a Committee for the Protection and Care of Experimental Animals
(CPCSEA). The CPCSEA is in charge of ensuring that all aspects of animal research
adhere to the law and are conducted ethically. Research animal care standards are in
accordance with those established by the International Committee for Laboratory
Animal Science (ICLAS). However, cloned and transgenic animals are not governed by any hard and fast laws or principles. Providing it is focused on important
scientic goals, the Indian Council of Medical Research’s 2000 study supports
transgenic animal research (Fenwick etal. 2009; Tait etal. 2007).
The modications in the drug discovery process have led to the creation of animal models that closely resemble human diseases. As a result, US patents on these
animal models serve as an incentive for scientists in America and Europe to develop
such models, which greatly aid in the drug development process (Gupta and Maurya
2018). The Indian regulatory authorities must anticipate and be ready to address the
ethical, regulatory, and patent-related difculties associated with transgenic animals.
10.12 Future Prospects
The potential exists for successful cell-based therapy in human patients using cells
generated from xenogeneic sources, namely pigs. There has been some long-term
success in transplanting pig islet cells into diabetic patients. Patients with neurological disorders including Huntington’s disease, Parkinson’s disease, focal epilepsy,
and stroke have had neural cells from pig embryos transplanted into their brains.
10 Drug Design Models forHuman Diseases by Transgenic Animals
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One signicant benet of pig brain cells over human brain cells is their widespread
availability (Niemann and Kues 2003). Diseases including hypochondroplasia,
Turner syndrome, and intrauterine growth retardation have been linked to decits in
growth hormone-releasing hormone, and the pig provides a useful model for studying these conditions (Niemann and Kues 2007). Eggs provide a noninvasive alternative to traditional harvesting methods. Interferon β-1a and -a humanized monoclonal
antibody (miR24) were generated in signicant concentrations in the egg whites of
genetically engineered chickens. miR24 is now being developed as a treatment for
malignant melanoma (Begley and Ellis 2012).
Transgenic animals have been created to produce specialized biological materials, such as polymers derived from spider silks. These materials have potential use
in face and orthopedic reconstructive surgery, serving as sutures or plastic materials
(Van Eenennaam 2006; Goldman etal. 2004). It is very improbable that enough
plasma butyrylcholinesterase (BChE) will be available to cure those who have been
confronted with organophosphorus substances utilized in agricultural and chemical
warfare operations. Milk from transgenic animals is being studied for its potential
to produce recombinant BChE (Huang etal. 2007). If 90,000 human blood samples
were used instead of transgenic goats, the yearly supply of human antithrombin III
would be equivalent to 1. Several human outputs may be replaced by the products
of transgenic animals due to their high productivity and usefulness. Advancements
in transgenic technology include inducible gene expression, articial chromosomes,
and progress in nuclear transfer (Niemann and Kues 2003; Cooper 2003; Park 2007).
203
10.12.1 Emerging Transgenic Technologies (Niemann
andKues 2007; Hunter etal. 2005; Park 2007)
• Lentiviral transfection is used to introduce genetic material into oocytes and
zygotes.
• Ribonucleic acid interference.
• Chimera formation is achieved by injecting pluripotent cells into blastocysts.
• Culturing spermatogonia and transferring them to male recipients.
Scientists are utilizing transgenic animals to create treatments for the ailments
mentioned before, as well as additional conditions such as emphysema, anemia,
malaria, hemophilia, and rheumatoid arthritis (Bagle etal. 2012).
10.13 Conclusion
The ongoing improvement of reproductive biotechnologies provides better predictive models for the success and safety of transgenic animals. Genetically engineered
animals will have far-reaching consequences for the future of biomedicine, notably
in the elds of animal disease modeling, drug development, xenotransplantation,
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S. Banerjee et al.
gene pharming, antibody production, and blood replacements (Niemann and Kues
2007). It is important to carefully analyze the regulatory concerns and ethical impli-
cations while using transgenic animals. Research suggests that goods obtained from
pigs and transgenic animals, like as milk and eggs, have promise in the development
of medicinal techniques. Drugs derived from transgenic mice may improve the efciency of target and chemical combinations, reducing the dropout rate in clinical
trials and facilitating a more rapid move from the discovery to the development
stages. The usage of transgenic technology has the capability to impact several
phases of the discovery process, including identifying and validating targets.
Additionally, it offers models specically created to promptly notify researchers
about possible issues related to medication metabolism and toxicity. This will aid in
the development of improved models for human disorders (Snaith and Törnell 2002).
The area of transgenics is fast progressing to generate better disease models and
has successfully developed the rst medicine for transgenic animals along with the
recognition of the US FDA.Hence, the utilization of transgenic animals has the
capability to surmount the present and forthcoming requirements in the eld of
medicine and is now an imperative rather than a discretionary concern.
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Chapter 11
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Role ofGenomics andProteomics inDrug
Discovery
JeevandranSundarasekar andGeethaaSahgal
Abstract Genomics and proteomics are two powerful technologies that are revo-
lutionizing the drug discovery process. Genomics is the study of the entire genome
of an organism, including the DNA sequence and gene expression patterns.
Proteomics is the study of all the proteins in an organism, including their structure,
function, and interactions. Both genomics and proteomics can be used to identify
new drug targets. A drug target is a molecule that is involved in the disease process.
By understanding the molecular basis of disease, scientists can identify potential
drug targets that can be modulated to treat the disease. This chapter provides an
overview of the role of genomics and proteomics in drug discovery. The chapter
begins by discussing the basics of genomics and proteomics. It then goes on to
discuss how these technologies can be used to identify new drug targets, develop
new drugs, and improve the safety and efcacy of existing drugs. The chapter also
discusses the challenges and future directions of genomics and proteomics in drug
discovery.
Keywords Genomics · Proteomics · Drug discovery · Biotechnology
J. Sundarasekar
Faculty of Applied Science, AIMST University, Bedong, Kedah, Malaysia
e-mail: jeevan@aimst.edu.my
G. Sahgal (*)
Faculty of Pharmacy, AIMST University, Bedong, Kedah, Malaysia
Ltd. 2024
S. Bose et al. (eds.), Concepts in Pharmaceutical Biotechnology and Drug
Development, Interdisciplinary Biotechnological Advances,
https://doi.org/10.1007/978-981-97-1148-2_11
207© The Author(s), under exclusive license to Springer Nature Singapore Pte
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J. Sundarasekar and G. Sahgal
11.1 Introduction
Drug discovery is a multi-stage, complex process with the goal of nding, creating,
and commercializing new therapeutic medications. It entails the methodical identication and improvement of substances with the potential to treat particular illnesses or medical situations. There are usually numerous important steps to the drug
development process, which will be covered in more detail below. Genomics and
proteomics are two potent technologies that have transformed biology and are now
having a signicant inuence on drug discovery. The study of an organism’s entire
genome, including its DNA sequence and patterns of gene expression, is known as
genomics. The study of all the proteins in an organism, together with their structure,
use, and connections, is known as proteomics.
Proteomics and genomics are complementary elds of study. Proteomics gives
information on the proteins that are really made and expressed by the organism,
whereas genomics provides information about the genetic code of an organism.
These data can be utilized to nd novel pharmacological targets, create new medications, and enhance the potency and security of currently available medications
(Baloch etal. 2023).
11.1.1 Importance ofGenomics andProteomics
inDrug Discovery
Scientists screen millions of molecules to locate a select handful that have the
required therapeutic effect in the traditional drug discovery process. This method is
time-consuming and expensive, and it frequently results in the creation of medications with unanticipated side effects. By giving researchers a greater understanding
of the molecular causes of disease, genomics and proteomics can aid in overcoming
these difculties. With the help of these data, new medication targets that are more
likely to be both successful and safe can be found.
There are many approaches to using genomics and proteomics to nd new therapeutic targets. Finding genes that have been altered or are overexpressed in sick
tissues is one approach. More likely to be implicated in the illness process are genes
that have undergone mutations or are overexpressed in sick tissues, which makes
them attractive therapeutic targets.
Studying protein-protein interactions is another method for leveraging genetics
and proteomics to nd new therapeutic targets. For proteins to function, they must
interact with one another. Scientists can pinpoint proteins that are crucial to the
development of disease by researching protein-protein interactions. The potential as
therapeutic targets for these proteins can subsequently be explored.
The discovery of novel medication targets for a number of diseases, such as cancer, Alzheimer’s disease, and HIV/AIDS, has been facilitated by the use of genomics and proteomics (Wang etal. 2019). For instance, by using genomics, researchers
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