**4. Genetically modified models**

Genetically modified models allow for a careful examination of the influence of typically a single gene mutation on the onset of elevated IOP, RGC damage, and the progression of glaucoma. They allow for manipulation of loci that contribute to this multifactorial mechanism but require a longer timeframe of study than mechanically induced models [15]. An ideal model should be easily reproducible, economical, and closely emulate human pathology [15]. Of all the species, the mouse is a very common model due to its low cost, ease of breeding and the vast genetic resources that are available. Examples of rodent glaucoma models include but are not limited to the following: intraocular injection of RGC toxins; crush or transection of the ON; manual elevation of IOP using microneedle injection into the anterior chamber; laser photocoagulation of the trabecular meshwork or episcleral veins; transgenic mice with specific mutations (reviewed in [11, 61]); and bead injection into the anterior chamber. While all of these methods have merit, none of them completely mimics the array of human disease presentation, and therefore additional models of glaucoma are still an unmet need of the vision research community.

#### **4.1 POAG models**

Transgenic models have been developed such as the *bug eye* mutant, the *lrp2* (lipoprotein receptor-related protein 2) mutant, and the *wdr36* mutant in zebrafish. The *bug eye* shows RGC death and high IOP and was used to identify *lrp2* as the gene responsible for the endophenotypes of elevated IOP, large eyes, decreased retinal neurons, activation of RGC stress genes, and optic nerve pathology [62–64]. Kimura *et al*. also reports a *P2Y*6 (pyrimidinergic receptor) knockout (KO) mouse that presents with age-dependent optic nerve and RGC degeneration and impaired visual function due to excess production of aqueous humor [46].

#### **4.2 PACG models**

*Vav2/Vav3* (guanine nucleotide exchange factors) KO mice mimic human spontaneous development of glaucoma, but there is poor understanding of the pathophysiology. These models develop buphthalmia and the iridiocorneal angle changes before 6 months of age and ultimately chronic angle closure glaucoma occurs [65]. They have additionally been identified as candidate genes for a sub-group of openangle glaucoma in the Japanese [20]. Bouhenni *et al.* find three notable features of

### *An Overview of Glaucoma: Bidirectional Translation between Humans and Pre-Clinical… DOI: http://dx.doi.org/10.5772/intechopen.97145*

this model: first, elevated IOP occurs naturally in this model; second, the incidence of this phenotype is high and occurs at a reasonably young age; third, human hypotensive glaucoma treatments have shown IOP-lowering effects in this model [11]. This makes this model useful for targeting molecular mechanisms in developing understanding of the pathophysiology.
