Pluripotent stem cell‐derived retinal organoids for disease modeling and development of therapies

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Abstract

Retinal diseases constitute a genetically and phenotypically diverse group of clinical conditions leading to vision impairment or blindness with limited treatment options. Advances in reprogramming of somatic cells to induced pluripotent stem cells and generation of three‐dimensional organoids resembling the native retina offer promising tools to interrogate disease mechanisms and evaluate potential therapies for currently incurable retinal neurodegeneration. Next‐generation sequencing, single‐cell analysis, advanced electrophysiology, and high‐throughput screening approaches are expected to greatly expand the utility of stem cell‐derived retinal cells and organoids for developing personalized treatments. In this review, we discuss the current status and future potential of combining retinal organoids as human models with recent technologies to advance the development of gene, cell, and drug therapies for retinopathies.

Abstract

Retinal organoids offer a unique human model system to study mechanisms of disease pathogenesis and for developing therapies.

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Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis.

Seth R Flaxman, Rupert Bourne, Serge Resnikoff … (2017)

Contemporary data for causes of vision impairment and blindness form an important basis of recommendations in public health policies. Refreshment of the Global Vision Database with recently published data sources permitted modelling of cause of vision loss data from 1990 to 2015, further disaggregation by cause, and forecasts to 2020.

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Embryonic stem cell trials for macular degeneration: a preliminary report.

Steven D Schwartz, Jean-Pierre Hubschman, Gad Heilwell … (2012)

It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients. We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration--the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993. Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28). The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue. Advanced Cell Technology. Copyright Â© 2012 Elsevier Ltd. All rights reserved.

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A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Lars G. Fritsche, Wilmar Igl, Jessica N. Cooke Bailey … (2016)

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of >12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency < 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

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Author and article information

Contributors

Anand Swaroop:

ORCID: https://orcid.org/0000-0002-1975-1141

swaroopa@nei.nih.gov

Journal

Journal ID (nlm-ta): Stem Cells

Journal ID (iso-abbrev): Stem Cells

Journal ID (doi): 10.1002/(ISSN)1549-4918

Journal ID (publisher-id): STEM

Title: Stem Cells (Dayton, Ohio)

Publisher: John Wiley & Sons, Inc. (Hoboken, USA )

ISSN (Print): 1066-5099

ISSN (Electronic): 1549-4918

Publication date (Electronic): 07 June 2020

Publication date (Print): 01 October 2020

Volume: 38

Issue: 10 ( doiID: 10.1002/stem.v38.10 )

Pages: 1206-1215

Affiliations

[ ¹ ] Neurobiology, Neurodegeneration and Repair Laboratory National Eye Institute, National Institutes of Health Bethesda Maryland USA

Author notes

[*] [* ] Correspondence

Anand Swaroop, PhD, Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, 6 Center Drive, MSC0610, Bethesda, MD 20892.

Email: swaroopa@ 123456nei.nih.gov

Author information

Anand Swaroop https://orcid.org/0000-0002-1975-1141

Article

Publisher ID: STEM3239

DOI: 10.1002/stem.3239

PMC ID: 7586922

PubMed ID: 32506758

SO-VID: 4e01e38a-fc37-4634-a42f-8cdd5153d45c

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date received : 17 April 2020

Date revision received : 16 May 2020

Date accepted : 17 May 2020

Page count

Figures: 4, Tables: 0, Pages: 10, Words: 7536

Funding

Funded by: National Eye Institute , open-funder-registry 10.13039/100000053;

Award ID: ZIAEY000546

Award ID: ZIAEY000474

Award ID: ZIAEY000450

Custom metadata

source-schema-version-number 2.0

cover-date 1 October 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:26.10.2020

ScienceOpen disciplines: Molecular medicine

Keywords: neural differentiation,retina,retinal photoreceptors,somatic stem cells

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: neural differentiation, retina, retinal photoreceptors, somatic stem cells

Pluripotent stem cell‐derived retinal organoids for disease modeling and development of therapies

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Most cited references 91

Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis.

Embryonic stem cell trials for macular degeneration: a preliminary report.

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

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Funding

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