An Overview of Age-Related Macular Degeneration: Clinical, Pre-Clinical Animal Models and Bidirectional Translation

Abstract

Age-related macular degeneration (AMD) is a multifactorial disease that results from a complex and unknown interplay among environmental, genetic, and epidemiologic factors. Risk factors include aging, family history, obesity, hypercholesterolemia, and hypertension, along with cigarette smoking, which is the most influential modifiable risk factor. Single nucleotide polymorphisms (SNPs) in numerous genes such as complement factor H (CFH) pose some of the known genetic risks. The pathophysiology in AMD is incompletely understood, but is known to involve oxidative stress, inflammation, dysregulated antioxidants, lipid metabolism, and angiogenesis. Animal models have been integral in expanding our knowledge of AMD pathology. AMD is classified as non-exudative or exudative. Because there is no perfect animal model that recapitulates all aspects of the human disease, rodents, rabbits, and non-human primates offer different advantages and disadvantages to serve as models for various aspects of the disease. Scientific advances have also allowed for the creation of polygenic pre-clinical models that may better represent the complexity of AMD, which will likely expand our knowledge of disease mechanisms and serve as platforms for testing new therapeutics. There have been, and there continues to be, many drugs in the pipeline to treat both exudative and non-exudative AMD. However, Food and Drug Administration (FDA)-approved therapies for exudative AMD that mainly target angiogenic growth factors are the only therapeutics currently being used in the clinics. There remains no FDA-approved therapy for the non-exudative form of this disease. This chapter contains a basic overview and classification of AMD and multiple animal models of AMD are highlighted. We include an overview of 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 this highly prevalent disease.

Mitochondrial damage and clearance in retinal pigment epithelial cells

“…Researchers have developed various animal and cell‐based models to investigate AMD pathways, enhancing our understanding of its pathophysiology (Pennesi et al., 2012; Rho et al., 2022). However, the evidence consistently points to ageing and related oxidative stress as major contributing factors (Abokyi et al., 2020; Kushwah et al., 2023; Maurya et al., 2023; Ruan et al., 2021).…”

Chronic Proinflammatory Signaling Accelerates the Rate of Degeneration in a Spontaneous Polygenic Model of Inherited Retinal Dystrophy

“…Progressive RDs affect a myriad of diverse populations. For instance, AMD preferentially afflicts elderly white females from western cultures while RP and LCA primarily affect young and middle-aged adults and children/teenagers, respectively, from regions with more consanguineous families ( den Hollander et al, 2008 ; Jordan et al, 2021 ; Rho et al, 2021 ). The heterogeneity of RDs has, to date, been one of the most in surmountable factors in producing therapeutics capable of tackling multiple types of RDs.…”

“…In the case of AMD, patients may not even know they have an RD until the degeneration has already set in. By this point, the lost vision cannot be restored as the photoreceptors and/or RPE in that region have already degenerated and the disease progression cannot, as of yet, be halted or even hindered in many cases, especially in the dry form ( Chintalapudi et al, 2019 ; Rho et al, 2021 ).…”

“…One of these, and currently one of the most promising targets, is retinal inflammation. All RDs present with some form of inflammatory phenotype, be it association with the complement system in AMD, upregulation of cytokine release and their downstream pathways in RP and LCA, or overactive aberrantly functioning monocytes, RDs are now seemingly always associated with a proinflammatory retinal uptick ( Iannaccone et al, 2015 ; Iannaccone et al, 2017 ; Hollingsworth and Gross, 2020 ; Hollingsworth et al, 2021 ; Jordan et al, 2021 ; Rho et al, 2021 ). Targeting these molecules, cells and pathways could likely allow for the ability to slow the progression of the degenerative phenotypes associated with progressive RDs.…”

“…Progressive retinal dystrophies (RDs) result in the loss of the rod and cone photoreceptors, though, depending on the disease itself, the degeneration observed will occur at varying rates with specific cell types affected more so than others ( Cremers et al, 2004 ; Hunt et al, 2004 ; Hollingsworth and Gross, 2012 ; Iannaccone et al, 2015 ; Rho et al, 2021 ). For example, diseases like age-related macular degeneration (AMD) and Stargardt’s disease primarily or initially affect cone photoreceptors, the retinal pigment epithelium (RPE), or both, with the rates and onsets of degeneration varying dramatically between the two ( Cremers et al, 2004 ; Hunt et al, 2004 ; Al-Zamil and Yassin, 2017 ; Fleckenstein et al, 2021 ; Rho et al, 2021 ). Contrarily, retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) both affect rod photoreceptors first, and ultimately the cones as well, while advancing at rates varying from gene to gene and person to person ( Rivolta et al, 2002 ; den Hollander et al, 2008 ; Ferrari et al, 2011 ; Hollingsworth and Gross, 2012 ; O'Neal and Luther, 2021 ).…”