Morphological and functional integration of stem cell derived retina organoid sheets into degenerating retina models

Retinitis pigmentosa (RP) comprises a multifaceted assembly of inherited disorders categorized by advanced deterioration and impairments of the retina, principally distressing photoreceptor, and pigment epithelial function. The clinical appearances of RP include night blindness, loss of peripheral vision from loss of PR, and inconsistently loss of central vision. It’s a rare disease that’s passed from parent to child. One out of every 4,000 people gets it. About half of all folks with RP have a relative who also has it. Treatment includes gene therapy, stem cell therapy, and visual implants, etc. Most with RP lose much of their sight by early adulthood. Then by age 40, they are often legally blind. The goal is to reverse vision loss in chronic disease stages of RD when PR cannot be rescued, initially targeting RP as this is an orphan disease with loss of PR. Fetal retinal sheets transplanted into both rodent models of RD and humans improved the vision of the transplant recipient (both rats and humans. Since 2007, Drs. Magdalene Seiler, Hans Keirstead and Gabriel Nistor have been working to perfect the methods of producing hESC-derived 3D retina structures (ROs), with similar functionality to human fetal retina tissue. This team has demonstrated that retinal organoids can be manufactured in clinically scalable quantities. ROs transplanted into two different models of immunodeficient RD rats improved light perception comparable to transplants of human fetal retinal tissue.

To date, there is no currently available cure for RP and the impact to patients is blindness. An effective therapy would allow RP patients to retain their ability to perform daily activities. Taken together with our preliminary preclinical efficacy studies, there is accumulating confirmation to support using stem cell-derived products to treat RP, and therefore, the team is developing ROs derived from CSC14 hESCs as a potential long-term cell based treatment for RP. There is a significant unmet medical need for a treatment for this devastating disease and the benefit to patients and their families would be profound.

Seiler MJ, Aramant RB, 2012. Cell replacement and visual restoration by retinal sheet transplants. Prog Retin Eye Res, 31:661-87. PMC3472113. PMID 22771454

Lin B, McLelland BT, Aramant RB, Thomas BB, Nistor G, Keirstead HS, Seiler MJ, 2020. Retina

Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction. Invest Ophthalmol Vis Sci, 61:34. PMC7509771. PMID 32945842

McLelland BT, Lin B, Mathur A, Aramant RB, Thomas BB, Nistor G, Keirstead HS, Seiler MJ, 2018. Transplanted hESC-Derived Retina Organoid Sheets Differentiate, Integrate, and Improve Visual Function in Retinal Degenerate Rats. Invest Ophthalmol Vis Sci, 59:2586-2603. PMC5968836. PMID 29847666

Nistor G, Seiler MJ, Yan F, Ferguson D, Keirstead HS, 2010. Three-dimensional early retinal progenitor 3D tissue constructs derived from human embryonic stem cells. J Neurosci Methods, 190:63-70. PMID 20447416

Grant Application Details

Application Title:

Morphological and functional integration of stem cell derived retina organoid sheets into degenerating retina models

Public Abstract:

Translational Candidate

Retina organoid sheets (ROs) derived from CSC14 human embryonic stem cells (NIH registry line #0284) manufactured under GMP conditions

Area of Impact

Retinitis PIgmentosa (RP) (irreversible loss of photoreceptors) due to mutation of photoreceptors and/or other retinal genes

Mechanism of Action

Proposed mechanism of action is cell replacement, combined with trophic effects. Transplanted hESC-derived retina organoid sheets will mature into photoreceptors and integrate with the degenerate recipient’s retina. Such transplants have improved visual acuity and responses to flashes of light in the midbrain (superior colliculus) of immunodeficient retinal degenerate rats (two different models).

Unmet Medical Need

There is currently no treatment for retinitis pigmentosa which is designated an Orphan disease by the FDA. Therapies in current clinical trials only target trophic effects which are only effective in early stages to delay degeneration.

Project Objective

Pre-IND meeting

Major Proposed Activities

Establishment of Working Cell Bank, GMP implementation of retina organoid (RO) production, establish product specification and release criteria
Identify and demonstrate markers correlated with function after maturation in vitro; functional in vitro imaging (FLIM and HSpec)
In vivo pharmacology: demonstrate efficacy in immunodeficient and -competent rat model and in immunocompetent rabbit model of RP,

Statement of Benefit to California:

Retinal diseases reduce the quality of life of patients, at significant cost to the health care system. The proposed replacement therapy is the only one that targets more mature disease stages of RP, for which no other therapy exists. An effective treatment will keep afflicted individuals productive, enhance State tax revenues and defray the healthcare cost burden to taxpayers. It will also lead to robust industry developments, effectively leading to job creation and tax benefits.

Publications

Front Neurosci (2021): Co-grafts of Human Embryonic Stem Cell Derived Retina Organoids and Retinal Pigment Epithelium for Retinal Reconstruction in Immunodeficient Retinal Degenerate Royal College of Surgeons Rats. (PubMed: 34764853)
Transl Vis Sci Technol (2021): Deep Learning-Assisted Multiphoton Microscopy to Reduce Light Exposure and Expedite Imaging in Tissues With High and Low Light Sensitivity. (PubMed: 34668935)
J Ocul Pharmacol Ther (2020): Pluripotent Stem Cell-Based Organoid Technologies for Developing Next-Generation Vision Restoration Therapies of Blindness. (PubMed: 33052761)
Asia Pac J Ophthalmol (Phila) (2022): The Prospects for Retinal Organoids in Treatment of Retinal Diseases. (PubMed: 36041146)
Invest Ophthalmol Vis Sci (2020): Retina Organoid Transplants Develop Photoreceptors and Improve Visual Function in RCS Rats With RPE Dysfunction. (PubMed: 32945842)
Lab Chip (2021): Retinal organoids on-a-chip: a micro-millifluidic bioreactor for long-term organoid maintenance. (PubMed: 34236056)
Front Cell Neurosci (2021): Retinal Organoids Long-Term Functional Characterization Using Two-Photon Fluorescence Lifetime and Hyperspectral Microscopy. (PubMed: 34955757)