# The contribution of plasticity to the recovery of retinal function following gene therapy

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $104,721

## Abstract

PROJECT SUMMARY/ABSTRACT
Gene replacement therapy for inherited retinal degenerations has improved visual function in animal models,
which has built momentum to curing blindness in humans. Optimal therapy is the return of normal visual function,
however, current clinical trials face challenges associated with variability and durability of recovery due to the
lack of rigorous mechanistic understanding of the retinal circuit's reaction to the therapies and any potential
hinderance to full recovery. To restore vision, it is essential to understand how surviving retinal neurons modify
synaptic connections upon vision restoration treatment and how retinal plasticity can be leveraged to improve
visual function. Our long-term goal is to elucidate fundamental mechanisms that enable the retina to establish
functional connections following gene therapy. The objectives of the proposed work are to determine underlying
mechanisms of functional recovery at cellular and circuit resolution using a mouse model of achromatopsia,
which restores selective loss of cone-mediated function after gene therapy. In Aim 1, we will determine the
recovery of spatial and temporal processing in ON and OFF pathways after gene therapy. We will measure
spatio-temporal receptive fields of specific ganglion cell types. In Aim 2, we will determine the contribution of
synaptic remodeling and transmitter release homeostasis to the structure and function of cone bipolar cells
following gene therapy. Achieving robust and sustained therapies require understanding of how gene therapy
restores rewiring and neurotransmitter release from first- and second-order synapses. Imaging and
electrophysiology will allow us to determine the wiring patterns of outer and inner retina, and how cones and
bipolar cell release rates potentially adapt to changes in inputs to reach homeostasis. The approach is innovative
for a new perspective on restoring vision in the context of the retinal plasticity investigating the effects of gene
therapy on connectivity patterns and functional properties at the single-cell level of the retinal circuit. The results
will be significant for (1) revealing whether retinal plasticity is constructive toward restoring visual function, (2)
determining mechanisms that allow the remaining retinal neurons to re-establish functional connections with
newly rescued cones, and (3) providing knowledge essential for maximizing function after photoreceptor
recovery.

## Key facts

- **NIH application ID:** 10761795
- **Project number:** 5K99EY033858-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Joo Yeun Lee
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $104,721
- **Award type:** 5
- **Project period:** 2023-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10761795

## Citation

> US National Institutes of Health, RePORTER application 10761795, The contribution of plasticity to the recovery of retinal function following gene therapy (5K99EY033858-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10761795. Licensed CC0.

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