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Models of Pathologies Associated with Age-Related Macular Degeneration and Their Utilities in Drug Discovery

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Drug Delivery Challenges and Novel Therapeutic Approaches for Retinal Diseases

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 35))

Abstract

Age-related macular degeneration is the leading cause of vision loss in the elderly in the developed world, with an ever-increasing prevalence in the developing world. The complexity of the disease and lack of effective therapies speak to the necessity of further understanding the pathobiology and mechanisms underlying initiation and progression of this retinal neurodegenerative disease, as well as identifying new therapeutic targets. Designing and characterizing cell culture and animal models that promulgate the human AMD condition provide preclinical avenues to address these two unmet needs. Herein we discuss strengths and weaknesses associated with current in vitro and in vivo models available that facilitate testing of potential AMD-targeting drugs and discovery of new pathways involved in disease development.

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Abbreviations

A2E:

Diretinoid-pyridinium-ethanolamine

ABCA1:

ATP-binding cassette transporter A1

AhR:

Aryl hydrocarbon receptor

AMD:

Age-related macular degeneration

APOE:

Apolipoprotein E

BrM:

Bruch’s membrane

CDH5:

Cadherin 5

CEP:

Carboxyethylpyrrole

CETP:

Cholesterol ester transfer protein

CFH:

Complement factor H

ChEC:

Choroidal endothelial cells

CNV:

Choroidal neovascularization

CRALBP:

Cellular retinaldehyde-binding protein

CSE:

Cigarette smoke extract

CX3CR1:

C-X3-C motif chemokine receptor 1

DHA:

Docosahexaenoic acid

ECM:

Extracellular matrix

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinases

ESC-RPE:

Embryonic stem cell-derived RPE cells

FAK:

Focal adhesion kinase

FBS:

Fetal bovine serum

GWAS:

Genome-wide association study

H2O2:

Hydrogen peroxide

HDL:

High-density lipoprotein

HFD:

High-fat diet

hfRPE:

Human fetal RPE cells

HMGCS2:

3-Hydroxy-3-methylglutaryl-coA synthase 2

HPV:

Human papilloma virus

INSIG1:

Insulin-induced gene-1

iPSC-RPE:

Induced pluripotent stem cell-derived RPE

KEAP1:

Kelch-like ECH-associated protein 1

LDL:

Low-density lipoproteins

LIPC:

Hepatic lipase

NRF2:

Nuclear factor 2

OCT:

Optical coherence tomography

OCT3/4:

Octamer-binding transcription factor ¾

PAX6:

Paired box 6

PECAM1:

Platelet and endothelial cell adhesion molecule 1

PLVAP:

Plasmalemma vesicle-associated protein

PPARβ/δ:

Proliferator-activated receptor beta/delta

RAL:

Retinaldehyde

RDH:

All-trans-retinol dehydrogenases

ROS:

Reactive oxygen species

RPE:

Retinal pigment epithelium

RPESC:

Retinal pigment epithelial stem cells

SOD:

Superoxide dismutase

SRC:

Src proto-oncogene, non-receptor tyrosine kinase

SYK:

Spleen associated tyrosine kinase

TGFBR1:

TGFβ type I receptor

TGFβ:

Transforming growth factor beta

TSPO:

Translocator protein

VEGFA:

Vascular endothelial growth factor A

Vldlr:

Very low-density lipoprotein receptor

ZO1:

Zonula occludens 1

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Acknowledgments

We thank our funding agencies [National Eye Institute grants R01 EY027802 and R01 EY028160 (to GM), P30 EY005722 (to the Duke Eye Center), and the Research to Prevent Blindness, Inc. (RPB) Core grant (to the Duke Eye Center)] for their continued support of our ongoing research and quest to understand complex retinal diseases and identify new therapeutic targets. We also express our gratitude to the donors and their families for their generosity.

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Authors and Affiliations

  1. Departments of Ophthalmology and Pathology, Albert Eye Research Institute, Duke University, Durham, NC, USA

    Goldis Malek

  2. Department of Ophthalmology, Duke University, Durham, NC, USA

    Pei-Li Yao & Mayur Choudhary

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  1. Goldis Malek
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  2. Pei-Li Yao
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  3. Mayur Choudhary
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Correspondence to Goldis Malek .

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  1. Departments of Basic and Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, NY, USA

    Christopher L. Cioffi

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Funding: This study was funded by National Eye Institutes grants R01 EY028702 and R01 EY028160 (to GM), P30 EY005722 (to the Duke Eye Center), and the Research to Prevent Blindness, Inc. (RPB) Core grant (to the Duke Eye Center).

Ethical Approval: Donor tissues obtained are used following approval from the Duke Institutional Review Board (IRB) committee. Similarly, animal studies are performed following protocol approval from the Duke Institutional Animal Care and Use Committee (IACUC).

Informed Consent: Not applicable.

Conflict of Interest: The authors have no conflicts of interest to disclose.

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Malek, G., Yao, PL., Choudhary, M. (2020). Models of Pathologies Associated with Age-Related Macular Degeneration and Their Utilities in Drug Discovery. In: Cioffi, C.L. (eds) Drug Delivery Challenges and Novel Therapeutic Approaches for Retinal Diseases. Topics in Medicinal Chemistry, vol 35. Springer, Cham. https://doi.org/10.1007/7355_2020_93

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