# Integration and functionality of retinal organoid transplants

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2023 · $580,176

## Abstract

Retinal pigment epithelium (RPE) and photoreceptors depend on each other for normal function and survival.
Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) lead to irreversible loss of vision in
millions worldwide, due to RPE dysfunction and photoreceptor degeneration. Our long-term goal is to reverse
vision loss by a combined transplant of neural retina sheets containing photoreceptor progenitors, plus a
polarized functional RPE monolayer to support the photoreceptors.
 Human embryonic stem cells (hESCs) differentiated into RPE and retina organoids (RO) - which would
substitute for neural retina sheets - can provide an unlimited supply of clinically applicable retinal donor tissue.
Retinal sheet transplants - dissected from hESC-ROs – develop photoreceptors, improve visual acuity,
responses to light, and integrate with the host retina. However, RO’s are generally devoid of a polarized RPE
layer. Therefore, cografting of hESC–derived neural retina and a healthy RPE monolayer is needed for treatment
of advanced disease conditions; but have not been performed on a large scale. To advance cell replacement
therapy, the mechanism of action of the transplant should be well understood. Although synaptic connectivity of
retinal transplants has been ascribed a role for visual improvement, details regarding the circuitry between
transplant and host retina remain unknown. To obtain better insight, retinal degenerate (RD) rats that express a
specific label to identify defined host retinal neuron populations need to be used. Thus, the goal of this project is
to improve the efficiency of transplants and analyze the functional recovery in relationship to neural connectivity.
 The proposed studies are aimed (1): To determine the efficacy of cografting “complete transplants”.
We hypothesize that “complete” transplants consisting of hESC-neural retina together with RPE will improve
visual recovery - compared to transplanting hESC-neural retina or RPE alone. Royal College of Surgeons (RCS)
rats, a model of a hereditary (chronic) RPE defect, at an advanced stage of RD will receive either “cografts”, or
transplants of ROs or RPE alone, and analyzed long-term (6-8 months) after grafting. The successful outcome
of this Aim should allow us to quantitatively evaluate the improved outcome of cografting. (2): To determine
mechanisms of functional recovery by detailing transplant-host connectivity. We hypothesize that visual
improvement will correlate with integration and synaptic connectivity of neural retinal sheet transplants in the
host retina. This will be tested by labels for both the donor and specific retinal neurons of the host retina. In
collaboration with Envigo, we will produce immunodeficient rhodopsin mutant (Rho S334ter-3) RD recipients
expressing Td-Tomato either universally (cre/lox inducible) or in CaMKII retinal neurons (using CRISPR-Cas9
technology), which will allow us to examine in detail the connectivity of RO transplants with spec...

## Key facts

- **NIH application ID:** 10601017
- **Project number:** 5R01EY031834-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Magdalene J Seiler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $580,176
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10601017

## Citation

> US National Institutes of Health, RePORTER application 10601017, Integration and functionality of retinal organoid transplants (5R01EY031834-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10601017. Licensed CC0.

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