# Toward enhancing organization and defining synaptic connectivity of transplanted human pluripotent stem cell-derived photoreceptor grafts

> **NIH NIH F30** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $38,323

## Abstract

PROJECT SUMMARY
Outer retinal degenerative diseases (RDDs) resulting in photoreceptor (PR) cell death are a leading cause of
visual impairment worldwide, but options for rescuing or restoring vision in many of these patients are limited.
Human pluripotent stem cell (hPSC)-derived PR transplantation is increasingly being studied as a therapeutic
strategy for these patients, and neural regeneration within the retina has recently been identified as an area of
strategic focus by the National Eye Institute (NEI). Several preclinical studies have shown some degree of
visual restoration with bolus-delivered PR transplants in animal models, and clinical trials studying the safety
and efficacy of bolus-delivered fetal-derived retinal precursors in patients with severe retinal degeneration are
currently underway. Despite these recent successes, the field still faces several critical roadblocks before
clinical PR replacement therapy can be realized for most RDD patients. Current strategies for bolus subretinal
delivery of dissociated PRs fail to accurately reconstitute the complex organization of the outer retina, and they
are often accompanied by disorganization, unpredictable dosing, and overall low cell counts immediately after
injection due to reflux into the vitreous cavity. Further, it remains unclear whether visual responses commonly
attributed to transplanted donor PRs are actually due to anatomic integration and functional synapse formation
within the host degenerate retina. Indeed, the efficiency of synapse formation following PR transplantation, and
the relationship between de novo synaptogenesis and measurements of visual function has not been tested to
date.
Here, we seek to use state-of-the-art biomaterials and PR scaffolds along with rigorous synaptic tracing
methodologies to address these challenges in a rat model of severe photoreceptor degeneration. In Aim 1, we
will use a novel micro-patterned, biodegradable scaffold for targeted hPSC-PR transplantation to assess the
retention, survival, and maturation of bolus-delivered and scaffold-delivered PRs in vivo. In Aim 2, we will
define the synaptic connectivity of hPSC-PRs in degenerate retinal explants and live host degenerate retinal
tissue with an innovative monosynaptic retrograde tracing assay. The University of Wisconsin-Madison fosters
the ideal scientific and intellectual environment for successful completion of these aims with strong,
collaborative research communities spanning the fields of ophthalmology, biomedical engineering, and
regenerative medicine. The research proposal and fellowship training plans detailed here seek to address
current roadblocks within the field of PR replacement while also providing the necessary skillset to address the
next generation of challenges facing the burgeoning field of retinal regeneration.

## Key facts

- **NIH application ID:** 10324545
- **Project number:** 5F30EY031230-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Allison Lyn Ludwig
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,323
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10324545

## Citation

> US National Institutes of Health, RePORTER application 10324545, Toward enhancing organization and defining synaptic connectivity of transplanted human pluripotent stem cell-derived photoreceptor grafts (5F30EY031230-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10324545. Licensed CC0.

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