**1. Introduction**

Age-related macular degeneration (AMD) is a multifactorial disease that results from interplay among genetic, environmental, and epidemiologic factors. It is the leading cause of irreversible blindness in people over 60 years of age, with numbers projected to increase over time. Animal models have been integral for understanding pathophysiology of and to develop treatments for AMD. This chapter reviews the basics of AMD including pathophysiology and classification. We then highlight specific examples of animal models and the insight they provide. We discuss both current FDA-approved treatments and those in development. Lastly, we conclude with a summary of the important role of pre-clinical studies in the development of therapeutics for AMD.

### **1.1 Basics of AMD**

The retina plays an integral role in vision by converting light to an electrical stimulus, which is ultimately processed as an image in the occipital lobe of the visual cortex. The macula, located in the posterior pole of the retina, contains the highest concentration of cone photoreceptors across the retina and is responsible for central, high-resolution, and color vision [1]. AMD is a multifactorial disease of the elderly that progressively affects vision through pathological changes to the retinal pigment epithelium (RPE) and loss of photoreceptors in the macula [2]. AMD is classified as non-exudative or exudative. Non-exudative AMD is defined by the presence of drusen — aggregates of lipid, protein, and immune complexes — underneath the RPE with subsequent thickening of Bruch's membrane [3, 4]. AMD is responsible for about 8.7% of blindness and remains as a leading cause of blindness in people over 60 years of age in the developed world [5, 6]. The disease burden will increase as the population ages with longer life expectancies. The global estimate of AMD cases was 196 million in 2020 and is expected to be 288 million by 2040 [6].

Although age is the most impactful risk factor, others include obesity, hypercholesterolemia, hypertension, lighter iris colors, lack of exercise, cigarette smoking, Western diet, elevated C-reactive protein, and family history [7–10]. Cigarette smoking is the most influential modifiable risk factor [11].

In addition to the above risk factors, genetics plays an important role in this multifactorial disease. The International Age-Related Macular Degeneration Genomics Consortium conducted a genome-wide association study of 43,566 subjects that revealed 52 genetic variants of AMD shared between 34 loci. Some of these include genes encoding for collagen type IV (*COL4A3*), matrix metalloproteinases (*MMP9, MMP19*), ATP binding cassette (*ABCA1*) involved in cholesterol transport, paired immunoglobin like type 2 receptor beta (*PILRB*) involved in immune regulation, vascular endothelial growth factor A (*VEGFA*) involved in angiogenesis, and various components of the complement cascade including complement factor H (*CFH*), complement factor I (*CFI*), and complement factors 3 and 9 (*C3*, *C9*) [12]. Among the 34 AMD loci, burden testing of rare (frequency < 0.1%) variants identified 4 protein-altering genes — *CFH, CFI*, tissue inhibitor of metalloproteinases 3 (*TIMP3*), and solute carrier family 16 member 8 (*SLC16A8*) — that contribute to AMD pathology [12]. For example, a knockout mutation in *SLC16A8* resulted in defective lactate transport with consequent acidification along with dysfunction of the retina and photoreceptors [12]. Discovering susceptible AMD loci helps expand knowledge of factors underlying the pathophysiology of this multifactorial disease, along with plausible therapeutic targets.

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