**2.1 Naturally occurring models of primary open angle glaucoma (POAG)**

#### *2.1.1 Introduction to naturally occurring animal models of POAG*

Many genetic loci containing spontaneous polymorphisms have been identified in both human POAG patients and in animals. A few causative genes have been identified such as *MYOC*, *OPTN*, and *WDR36* [11]. Recent studies also postulate RGC number is a risk factor with lower numbers found with gene polymorphisms in *SIX6* (homeobox protein*)* and *ATOH7* (atonal basic helix–loop–helix transcription factor 7), both of which are associated with worse outcomes [19–22].

### *2.1.2 POAG in monkeys*

Low and high tension POAG was first described in monkeys in 1993. It was found to be maternally inherited, and greater than 40% of the models showed elevated IOP. They displayed loss of RGCs, degeneration of the optic nerve, and damage to the retinal peripheral field. Though while these models are a closer mimic to the human condition, they have strong drawbacks including excessive expense, care, and more complicated handling procedures [15, 23–25].

## *2.1.3 POAG in dogs*

An autosomal recessive POAG has been studied in beagles. Elevation of IOP was seen at 1–2 years of age due to a reduction in aqueous humor outflow. The disease was biphasic: early in the disease the iridiocorneal angle was open, followed by closure with lens subluxation and displacement from the anterior vitreous patellar fossa. The model was used in a genome wide single nucleotide polymorphism array study in which the metallopeptidase *Adamts10*, a candidate gene for POAG, was identified. One noteworthy anatomical difference between dogs and humans is that dogs have an intrascleral plexus rather than a Schlemm's canal, which may result in minor discrepancies between the two models [11, 15, 26, 27].

#### *2.1.4 POAG in mini-pigs*

Mini-pig models have also been used as their retina shows likeness to the human retina with holangiotic retinal vasculature, cone photoreceptors in the external retina, a similar scleral thickness, and three types of RGCs [28, 29]. This model can reproduce IOP elevation and can be used to study ocular regeneration with stem cells. Another benefit of this model is its suitability for OCT, corneal topography imaging, and ERG analyses [30].

#### *2.1.5 POAG in birds*

Avian models of POAG via light induction technique have been described. They have shown response to antiglaucoma drugs also, which could be beneficial in drug trials targeting IOP [11].

## *2.1.6 POAG in rodents*

Rodent models are valued for their ease of handling and lower management costs. They also have a relatively comparable genome to humans. Drawbacks of mouse models include the lack of a collagenous lamina cribrosa, although it is replaced by one composed of astrocytes. Because the lamina cribrosa is a major location of the pathology that causes optic nerve damage, species differences must be taken into account [11].

Presently, studies have shown that the mutated human myocilin gene, *MYOC Tyr437His* mutation, causes autosomal dominant severe glaucoma with juvenile onset. Mice with a mutation in this same gene develop elevated IOP and 20% RGC loss at 18 months, as well as axonal degeneration in the optic nerve and detachment of the endothelial cells of the trabecular meshwork [31]. A *Col1a1* (alpha-1 subunit of collagen type 1) mutation abrogates matrix metalloproteinase-related cleavage, necessary for turnover of trabecular meshwork, which leads to aggregation and thus increased IOP and RGC death at 24 weeks. This finding infers a correlation between IOP regulation and the turnover of fibrillar collagen in the trabecular meshwork [32]. *An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical… DOI: http://dx.doi.org/10.5772/intechopen.97145*

## **2.2 Naturally occurring models of PACG**

Spontaneous mutations in *B10*-*Sh3pxd2b*nee, a rare mutation seen in Frank-ter Haar Syndrome, results in glaucoma alongside skeletal and cardiovascular abnormalities. The formation of podosomes, which degrade the extracellular matrix, is impaired, causing the proliferation of the trabecular meshwork and development of iridiocorneal adhesions due to outflow blockage and high IOP resulting in RGC loss by 3–4 months in mice harboring the mutation [5]. Spontaneous mutations in another gene, the serine protease *Prss56*, mimic angle-closure glaucoma as the ocular axial length is reduced, the lens is large, and thus the angle is narrow [33].

#### **2.3 Primary congenital glaucoma**

Congenital glaucoma types include autosomal recessive mutations in *CYP1B1* (cytochrome P450 family 1 subfamily B polypeptide 1) and *LTBP2* (Latenttransforming growth factor beta-binding protein)*,* and autosomal dominant mutations in *MYOC* (myocilin), *OPTN* (optineurin), and *WDR36* (WD repeat-containing protein 36) [5]. Another study adds that the transcription factors FOXC1 (Forkhead box C1*),* FOXC2 (Forkhead box C2)*,* PITX2 (Paired Like Homeodomain 2)*,* LMX1B (LIM homeobox transcription factor 1 beta*),* and PAX6 (Paired box protein*)* contribute to congenital glaucoma [34].

## *2.3.1 Congenital PACG in rabbits, rats, and cats*

Naturally occurring congenital glaucoma was first observed in rabbits in 1886 [11]. It was also documented in albino New Zealand white rabbits in the 1960s that presented with anomalies in the anterior chamber [35–37]. In rats, spontaneous congenital glaucoma was seen in 1926 in an inbred family of Wistar-Albino-Glaxo rats [38]. This population presents with enlargement of the globe, elevated IOP, decreased number of RGCs, and degeneration of the optic nerve head. It has also been used in other studies [11]. Feline glaucoma has also been observed with buphthalmia and similar phenotypes to human primary congenital glaucoma, though its occurrence is rare [39].

#### *2.3.2 Congenital PACG in dogs*

Evangelho *et al*. document that the anatomy of dogs suits the development of angle closure because they have reduced ocular axial length, an enlarged lens, and a narrow angle [15]. Congenital PACG has been observed in dogs, but it is very rare, and has not been used widely for studies of this subtype of glaucoma [11, 40].

### *2.3.3 Congenital PACG in turkeys*

In turkeys, secondary angle closure glaucoma has been observed, presenting with buphthalmia, low-grade aqueous cells and flare associated with posterior synechiae formation, resulting in pupillary block and iris bombe [41]. It provides a functional model for angle closure glaucoma, but it is also rare.

#### **2.4 Pigmentary dispersion glaucoma**

Pigmentary dispersion glaucoma, first described in the DBA/2 J mouse in 1978 presents with a continual increase of IOP until approximately 9 months coupled with early onset iris depigmentation. It is caused by spontaneous mutations in

tyrosinase-related protein 1 (*Tyrp1*<sup>b</sup> ) and glycosylated protein nmb (*Gpnmb*R150X) [15, 42]. Co-existing mutations in these two genes, leads to pigment dispersion, iris atrophy, anterior synechiae, and increased IOP, as well as loss of RGCs and optic nerve atrophy that is progressive, even after the IOP returns to lower IOP levels in older DBA/2 J mice [43–45]. Similar to humans, it progresses in severity with increasing age. Although pigmentary dispersion glaucoma can affect humans, it is not linked to mutations in either *Tyrp1* or *Gpnmb*.
