Models of retinal diseases and their applicability in drug discovery

ABSTRACT

Introduction: The impact of vision debilitating diseases is a global public health concern, which will continue until effective preventative and management protocols are developed. Two retinal diseases responsible for the majority of vision loss in the working age adults and elderly populations are diabetic retinopathy (DR) and age-related macular degeneration (AMD), respectively. Model systems, which recapitulate aspects of human pathology, are valid experimental modalities that have contributed to the identification of signaling pathways involved in disease development and consequently potential therapies.

Areas covered: The pathology of DR and AMD, which serve as the basis for designing appropriate models of disease, is discussed. The authors also review in vitro and in vivo models of DR and AMD and evaluate the utility of these models in exploratory and pre-clinical studies.

Expert opinion: The complex nature of non-Mendelian diseases such as DR and AMD has made identification of effective therapeutic treatments challenging. However, the authors believe that while in vivo models are often criticized for not being a ‘perfect’ recapitulation of disease, they have been valuable experimentally when used with consideration of the strengths and limitations of the experimental model selected and have a place in the drug discovery process.

KEYWORDS:

• Age-related macular degeneration
• animal models
• cell culture models
• diabetic retinopathy

Article highlights

• Current treatments for complex retinal diseases including diabetic retinopathy (DR) and age-related macular degeneration (AMD), major causes of vision loss in the young and elderly populations, are limited.

• In vitro and in vivo models are valuable tools to not only study the pathogenesis of disease, but also identify new therapeutic targets.

• The complexity of retinal diseases such as DR and AMD, may preclude development of the ‘perfect’ model, which features all the phenotypic and genotypic characteristics of the human disease.

• Rational design should be employed when using models currently available in pre-clinical studies to validate the efficacy of drugs; cognizant of the strengths and weaknesses of the model, as well as the phenotype or pathogenic pathway being targeted.

• New avenues for drug discovery may arise from breakthroughs in identifying potential therapies for other complex diseases, with which DR and AMD share common pathways and/or cell-types affected.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The authors acknowledge the following funding agencies for their support of our ongoing research projects: the National Eye Institute grants: EY02868 (to G Malek), EY016077 (to JV Busik), EY025383 (to MB Grant and JV Busik), and P30 EY005722 (to the Duke Eye Center); the Edward N. & Della L. Thome Memorial Foundation Award (to G Malek); BrightFocus Macular Degeneration Grant (to G Malek) and the Research to Prevent Blindness, Inc (RPB) Core grant (to the Duke Eye Center).