# Pluripotent Stem Cell Derived 3D Retinas for Studies of Early Onset Retinal Degeneration

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $395,000

## Abstract

SUMMARY
Retinal degenerative (RD) diseases, such as Retinitis pigmentosa (RP) and Leber congenital amaurosis
(LCA), cause dysfunction and cell death of photoreceptor (PR) cells, ultimately leading to blindness. LCA
is the leading cause of inherited childhood blindness resulting in a loss of vision at or soon after birth. Though
this is considered to be quite rare, these blinding diseases are devastating for those affected. Current efforts are
being made to develop gene-therapies aimed at correcting some of the genes affected in RD and this approach
has shown some promise in animals and humans for restoring RPE65 gene expression, but there are many
other causes of RD for which there is no cure. In addition, due to the many mutations involved in RD, there are
significant gaps in our understanding of how PR loss occurs. To address this, we will use human pluripotent
stem cell (PSC) based retinal cell-reporter lines with RD-associated alleles to help explore the mechanisms of
PR cell death. Given the typically long period of time required to generate human retinas in the laboratory, the
severity and rapid onset of degeneration in LCA makes it an attractive experimental model to study human RD
and to develop potential therapies. We will study the aryl hydrocarbon receptor interacting protein-like1 (AIPL1)
gene to explore three functional domains that harbor naturally occurring mutations in patients with LCA and
cone-rod dystrophy (CORD). A comparative analysis of different mutations might lead to a better understanding
of how rods and cones die and greater insight into other more common forms of PR degeneration, such as age-
related macular degeneration (AMD). A central hypothesis is that human PSC derived 3D retina organoids
with AIPL1 mutations will recapitulate human retinal dystrophy resulting in PR loss. This hypothesis is
supported by our recent work, and others, showing that human PSCs can be coaxed into becoming retinal
eyecup-like structures with PRs, a laminar morphology and outer segment structures that are similar to an actual
retina. This proposal will bridge two innovative technologies; (1) genome-editing to generate genetically
matched retinal reporter PSC derived retinas with disease-associated mutations and (2) gene-correction to
repair genetic defects and promote PR cell survival. Given the very early onset of LCA it is important to define
the appropriate windows of time for such treatment options. Not only will these studies lead to new insights
into the biology of RD disease, but could also provide an innovative resource to develop therapies for
the treatment of RD.

## Key facts

- **NIH application ID:** 10600997
- **Project number:** 5R01EY031318-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** KARL J WAHLIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $395,000
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10600997

## Citation

> US National Institutes of Health, RePORTER application 10600997, Pluripotent Stem Cell Derived 3D Retinas for Studies of Early Onset Retinal Degeneration (5R01EY031318-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10600997. Licensed CC0.

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