Animal Utilization in Drug Development: Clinical, Legal,
7.7 LANDMARKS IN PRECLINICAL DEVELOPMENT
SPECIES SELECTION AND RATIONALE
Multiple models, species, and experimental strategies have been used to cre- ate a “signature” for a given mechanism so as to narrow the applicability of one model where its use is most effective [25].
7.7.1 Animal Models of Depressions: Minipig and Beagle Animal Models
Minipig and beagle animal model genomes are the ideal choice in phar- maceutical discovery and development. The beagle is a commonly used animal species in preclinical studies even though the genomes are distinct from other key model organisms [26]. The beagle dog has been very useful in cardiovascular safety pharmacology testing. Over time, the minipig has found a niche application in cardiovascular, skin, and renal studies.
7.7.2 Animal Models of Cancer
Cancer disease is a generic term as the word “cancer” covers a multiplic- ity of disparate biological characteristics and associated pathways. Animal models of cancer are essential in understanding the pathophysiology of the cancer disease for identifying new targets and therapeutic agents. Homoge- neity and rapid development are the principal characteristics of the mouse that makes it most suitable as an animal model of cancer. Even though not exactly a perfect fit for use, suitable experimental design and evaluation could enhance the predictive power as cancer models.
Carcinogen-induced models enable the evaluation of time-dependent progression of tumor pathogenesis due to external influences or carcino- gens [27]. These same types of models are expected to be useful in deter- mining dose–response relationships, which are needed to understand the tumor PK/PD effects and the potential effect of therapy on tumor progres- sion when exposed to the drug [28]. Genetically engineered mouse models have been limited by time of development of tumor – tumor development does follow the same timing as that of the transgenic host. In addition, they do not often express the clinical symptoms and irregularities in tumor fre- quency and growth properties [29].
7.7.3 Animal Models of Alzheimer’s Disease in Drug Development
The etiology of Alzheimer’s disease has not been well established and for this reason “amyloid hypothesis” only provides a working principle used as a premise for developing therapy and experimental modalities [30]. Animal models of Alzheimer’s disease are used to study the effect of therapeutic agents on the neuropathological indicators like b-amyloid plaques (Ab) and neuronal and synaptic loss in brain regions of the disease. Identification of activity is based on certain clinical signs like the cognitive function in animal model even though it lacks definitive information about the effect
Social Aspects of Drug Discovery, Development and Commercialization 160
in humans. Selection of animal is based on the phylogenic proximity to humans and its ability to recapitulate the Alzheimer’s neuropathology [31].
Several aging diseases develop in the same way in rhesus monkeys and hu- mans, and this has led to the choice of rhesus monkeys as the most widely accepted model because diagnosis has been possible and they are well suited for development of safe medicines for these disorders. The small prosimian primate is highly recommended due to age-related changes that simulate those of humans. This primate, with a lifespan of 8–10 years, is a prime as- set for studying age-related disease [32]. Dogs have been used because the amino acid sequence of the Ab is similar to that of humans. Mouse lemurs also show the disease patterns.
The transgenic species were created by transferring the amyloid pre- cursor protein to the animal model. The mouse transgenic models are able to reproduce the patterns of Ab-induced neuropathological manifestations leading to the observed the clinical symptoms like Ab-production, deposi- tion, and clearance [33] to rapid progression with respect to humans. Mouse lemurs are good models as they develop to full blown at 5 years and older.
Certain undesirable effects have been associated with the pattern of distri- bution of amyloid plaques in the mouse lemur. In humans, it is initiated at the hippocampus while that of the mouse lemur begins at the cortical regions. Since only about 20% of the adult mouse lemur will develop the associated symptoms, a diagnostic-based selection is needed. However, there are no such tools available [34]. There is biochemical composition mismatch between the mouse model and the Alzheimer’s disease brain, which has contributed to failure in developing an important pathological signature of Alzheimer’s – the neurofibrillary tangles [35]. Even though no single animal has been a true representative model for Alzheimer’s disease, certain aspects of the disease have been well represented in certain models, which has been a great utility in understanding and supporting the research objective. Thus, a major hurdle is to find the model that could be used to serve as an experi- mental model for the underrepresented aspects of the disease. Experimental parameters may need to be modified to create a condition that more closely mimics aspects of the disease.
7.7.4 Insect Models: The Fruit Fly
The fruit fly, even though it has only a portion of human brain cells due to its miniaturized scale, has similarities in the basic cell biology activities and it possesses an excellent brain organization. This is the principal reason why it is an extensively characterized insect model [36]. An interesting quality
of the fruit fly is its cuticle – a transparent cuticle facilitates the study of disease progression in unmodified models, which has not been achieved in animals [37,38].
7.8 ANIMAL MODELS IN THE DEVELOPMENT