**1.3 Classification of glaucoma and early diagnosis in humans**

POAG is the most common form of glaucoma and is associated with increased IOP [9]. In broad contrast, PACG has a functional trabecular meshwork with obstructed access, while the trabecular meshwork in POAG is pathological, but open and unobstructed. The initiatory event of PACG is thought to be a blockage between the pupillary portion of the iris and the anterior lens surface, which is correlated with mid-dilation of the pupil [10]. Primary congenital glaucoma, often associated with autosomal recessive disease heritability, results from an abnormal development of the anterior segment and angle of the anterior chamber [11]. NTG is a disease that is nearly identical to POAG but lacks the increased IOP. Pigmentary glaucoma is characterized by accumulation of pigment in the trabecular meshwork and corneal endothelium [12].

Because IOP is the only known modifiable risk factor, it is the target of the majority of current treatment modalities. Increased age has also demonstrated increased risk of ocular hypertension resulting in elevation of IOP and onset of POAG [9]. Damage can also ensue from non-IOP-related mechanisms such as reduced ocular perfusion pressure, excitotoxicity from excessive glutamate,

autoimmune-mediated nerve damage, loss of neurotrophic factors, failure of cellular repair mechanisms, and abnormal autoregulation of retinal and choroidal vasculature [4]. African-Caribbean descent, near-sightedness, decreased thickness of the central cornea, first-degree family history, low ocular perfusion pressure, and diabetes are other associated risk factors [13].

The clinical diagnosis of glaucoma relies on recognition of signs of optic nerve damage via slit lamp biomicroscopy and examination of the optic nerve head, followed by measurement of IOP, assessment of the angle via gonioscope and measurement of visual fields. The only directly observable pathology of the optic nerve is in the intrascleral portion which can be observed as an increased cup-to-disc ratio [14]. Glaucoma can progress over decades if it is not appropriately treated. Because it is not painful unless IOP becomes extremely elevated, the early stages of glaucoma often progress undetected. It manifests clinically in advanced stages, where it first affects the peripheral vision of the affected eye. Unfortunately, the other eye, if unaffected, often compensates for changes in the visual field, making most patients unaware of the development and slow loss of vision. Early characteristics might be identified as difficulty reading in dim light. Due to its asymptomatic and silent onset, assessment of family history and frequent clinical assessment is vital. Additionally, assessment of secondary causes of IOP elevation can be beneficial in devising a treatment strategy that can include medical, laser, and surgical modalities [5].

## **2. Pre-clinical models of glaucoma**

While progress has been made in understanding the genetic pathophysiology of glaucoma in humans using genome-wide association studies (GWAS), pre-clinical animal models provide an extremely valuable resource for identifying and understanding cellular mechanisms of action underlying specific mutations, genetic interactions, and ultimately, a knowledge of the disease pathogenesis to better treat the condition. They have been used to observe and modify the interplay of genetic and environmental factors in complex diseases such as glaucoma. They have also been used to develop and evaluate novel therapeutics. This cycle of observation of a disease phenotype and therapeutics response in humans, followed by replication and in-depth examination in pre-clinical models, with subsequent verification in humans, is a bidirectional translation model that is essential to continual forward progression of disease and treatment studies (**Figure 2**). Although there is great value to the models that have been created, there remain unmet needs.

There are many factors to consider when selecting an animal species population for modeling disease. One is the reproduction of the experimental procedure in both the pre-clinical models and humans [15]. For example, in performing an electroretinogram (ERG), a measurement of the electrical activity of the retina in response to light stimulus, employing the use of anesthetics can affect neurotransmission and affect test results [16]. This can become a confounding issue in smaller animals which must be anesthetized. Other factors to consider include the animal's body temperature and age. If body temperature decreases enough, metabolic processes that affect the chemical reactions necessary for an ERG will be decreased, suppressing the amplitude of the ERG, mainly in mice, rats, and rabbits due to their body weight to surface area ratio [17]. Age should also be considered as it influences amplitudes as well. This has been observed in rabbits with younger rabbits exhibiting smaller amplitudes and older rabbits displaying larger amplitudes [18]. Obtaining IOP values can also be difficult and the method *An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical… DOI: http://dx.doi.org/10.5772/intechopen.97145*

#### **Figure 2.**

*The progression of bi-directional translation. (A) A disease phenotype is observed in human patients. (B) The observed phenotype is then modeled in a preclinical animal model with as much fidelity to the human condition as possible. (C) After rigorous testing in animal models, the outcomes of those tests (pharmaceutical, or other therapeutic) are then taken back to the human patients and tested for safety and efficacy. If needed, the process repeats. This cycle gives a better comprehension of the disease and how to treat it most effectively.*

varies per animal model. In addition, different animal models are susceptible to variations from blood pressure, pulse, respiration, anxiety, as well as sedation and measurement complications [15].
