The identification of small molecules that stimulate retinal pigment epithelial cells: potential novel therapeutic options for treating retinopathies

ABSTRACT

Introduction: Combinatory strategies using pharmacology and stem cell therapy have emerged due to their potential in the treatment of retinal pigment epithelium (RPE) cell related diseases, and a variety of different stem cell sources have been evaluated both in animal models and in humans. RPE cells derived from human embryonic stem cells (hESCs) and human induced pluripotent cells (hiPSCs) are already in clinical trials, holding great promise for the treatment of age-related macular disease (AMD) and hereditary RPE-related retinal dystrophies. Highly efficient protocol for RPE generations have been developed, but they are still time-consuming and laborious.

Areas covered: The authors review RPE related diseases, as well as the known functions of RPE cells in retinal homeostasis. The authors also discuss small molecules that target RPE in vivo as well as in vitro to aid RPE differentiation from pluripotent stem cells clinically. The authors base this review on literature searches performed through PubMed.

Expert opinion: Using high-throughput systems, technology will provide the possibility of identifying and optimizing molecules/drugs that could lead to faster and simpler protocols for RPE differentiation. This could be crucial in moving forward to create safer and more efficient RPE-based personalized therapies.

KEYWORDS:

• Hipscs
• retinal pigment epithelial cells
• retinal dystrophies
• cell therapy
• AMD
• RPE differentiation
• small molecules

Article highlights

• hiPSCs and their progeny hold great potential for regenerative medicine, as direct therapeutics for cell therapy and disease modeling as well as a platform for drug screening.

• RPE cells derived from hESC of hiPSC are already in the clinical trial to treat AMD and hold great promise for other eye diseases, especially hereditary dystrophies in which gene correction needs to be performed.

• A major requirement to perform an efficient cell therapy in RPE-related disorders is simple and fast differentiation protocols for the generation of pure and functional RPE cells. Nevertheless, most of the RPE protocols actually employ growth factors being time-consuming and laborious.

• RPE-based platforms are starting to be exploited for high-throughput compound screening to identify small molecules with suitable biological properties to speed up the differentiation toward RPE cells in vitro.

• The recent advances in the high-throughput screening biopharmaceutical field are expected to boost research in the discovery of new small molecules in hiPSC differentiation in the future.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors declare research funding from: a ‘Miguel Servet’ contract from the Institute of Health Carlos III (ISCIII) of the Spanish Ministry of Science and Innovation via salary contract CPII16/00037 and grant PI14-02209 (both to S Erceg) as well as resources from the Platform for Proteomics, Genotyping and Cell Lines, PRB3 of the ISCIII (PT17/0019/0024). They are also supported by the French Muscular Dystrophy Association (AFM-Téléthon grant no. 21180 to S Erceg), the Czech Science Foundation (via grant 18-04393S) and the National Sustainability Programme under project number LO1609 (via the Czech Ministry of Education, Youth and Sports), with project ‘Centre of Reconstructive Neuroscience’ (NEUROCON), under registration number CZ.02.1.01/0.0./0.0/15_003/0000419.