**5. Bidirectional translation from humans to pre-clinical models and back again**

In summary, the "virtuous cycle" of bidirectional translation allows the examination of the outcome of experimental modulation in normal and pathological phenotypic animal models to discover novel regulators with the potential to evade, delay, or overturn human disease [82]. This cycle demonstrates that breakthroughs in human and experimental models facilitate a recurring sequence of human observation, pre-clinical model experimentation, followed by verification in humans (**Figure 1**). Animal models are fundamental to this discipline, as they advance the progression of understanding of the genetic framework that produces the pathological condition of interest and is a potentially vital target for novel therapeutics. It is proven that this series of bidirectional translation efficiently drives the investigation of diagnosis, treatment, and prevention of congenital, progressive, and adult conditions alike [82].

At baseline, this methodology is possible due to advanced genetic and molecular technologies, as well as the Human Genome Project, which propelled the identification of complex traits and pathways causing disease. Those resources alone, however, do not account for the complex interplay between inherited and environmental factors. Animal models provide a degree of experimental control, not possible in humans, to explore just that [82]. Both phenotype-based (forward

#### **Figure 1.**

*Model of the "virtuous cycle" of bidirectional translation. (A) Bidirectional translation begins with the discovery of a human disease phenotype. (B) After observing a phenotype, animal models are generated to mimic the human condition as accurately as possible. This allows for a deeper understanding of the pathophysiology as well as a model on which to test therapeutics. (C) With the knowledge gained from animal models, treatments are carried back into human patients to test clinically the efficacy and tolerability of the therapeutics. The cycle then repeats allowing for a better understanding of both the disease itself and how to treat it more efficaciously.*

#### *An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models… DOI: http://dx.doi.org/10.5772/intechopen.96601*

genetics) and gene-based (reverse genetics) approaches permit linkage of genes and phenotypes in experimental animal models. Traditionally, genetic variants are accepted to relate in an additive fashion with functions that are stationary. Yet, there are many complexities in understanding these relationships, specifically in multigenic traits, with factors such as modifier genes, gene–gene interactions, gene–environment and gene-age interactions, and unconventional genetic complexities [82]. This is precisely where the beauty of animal models shines. They are the solution, the medium capable of exploring these intricacies. Puzzle pieces necessary to address gene–gene interactions, modifier genes, gene–environment interactions, and gene-age interactions can be tried and tested in preclinical models.

Although animal models cannot entirely replicate the human biological environment, they can reveal information that has been used to formulate hypotheses about the human manifestation of disease. This step has led to the discovery of genetic regulators and therapeutic modulators of disease, as part of the virtuous cycle of bidirectional translation. For example, the studies performed in mice undergoing oxidative stress (*Sod1*−/− and *Nrf2*−/− models) and the discovery that waste material from drusen contribute to RPE atrophy led to the development of treatments for lowering ROS and oxidative damage. Other studies demonstrated that loss of RPE cells and their functionality leads to an AMD-like phenotype, which then inspired the idea of RPE cell therapy [76]. Similarly, animal models (*Cfh*−/− mice) revealed the role of complement in AMD pathophysiology, which inspired the development of novel non-exudative AMD therapies that target complement such as Zimura and APL-2 [66, 67]. Finally, studies in which VEGF inhibition in animals led to the successful therapeutics (bevacizumab, ranibizumab, aflibercept, and brolucizumab) that are currently used to treat exudative AMD in humans [44]. In summary, observed phenotypes can be linked to specific genotypes (and vice versa) that can be corroborated between humans and pre-clinical models. This bidirectional translation and the virtual cycle using a cross-species approach has accelerated the discovery of novel disease-associated genes and the development of targeted therapies.

Nadeau and Auwerx recapitulate that the virtuous cycle pairs the trajectory of observations in humans with the potential of experimental animal models and confirmation in human cases. Human limitations are apparent, while animal models house the biological tools to foster disease onset and progression. They expose pathophysiology that illuminates related disease mechanisms in humans and are deemed vital for the prosperity of molecular, cellular, developmental, and physiological experimentation.
