# Defining Barriers to Gene Therapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $405,911

## Abstract

PROJECT SUMMARY
Of the retinal degenerative diseases that affect 9 million Americans, rod and cone photoreceptor dystrophies
are arguably the most devastating. Gene therapy is a potential means to strengthen photoreceptor viability.
However, the first human gene therapy trial for retinal degeneration found improved visual function but did not
slow degeneration of photoreceptors. The goal of this gene therapy-oriented proposal is to determine whether
therapy is achievable in the context of an already diseased retina and at what timepoints gene therapy should be
administered in order to improve functional vision in rod and cone dystrophies.
During the previous funding period, we succeeded in restoring retinal function in mouse model of rod
degeneration, demonstrating that only 12% of resilient photoreceptors are needed for rescue. We now intend to
determine if this threshold may be shifted to an even lower number of resilient photoreceptors (6%) for functional
vision. We will also determine whether cone-specific rescue is possible at late stages of disease. Finally, we will
determine the latest timepoint at which gene therapy can be administered for rod monochromatism. To do this, we
will use a novel, inducible genetic rescue system in the cone-specific G-protein, guanine nucleotide binding α-
transducin 2 (Gnat2), which will allow us to conditionally reverse GNAT2-deficiency while controlling the temporal
and spatial aspects of phenotypic reversal. We will also use a phosphodiesterase 6 (Pde6) mouse as a model for
rod dystrophy.
The Gnat2floxSTOP/ Gnat2floxSTOP::Arr3CreERT2/WT and Pde6floxSTOP/PdefloxSTOP::Arr3CreERT2/WT programmable models will
provide a platform for contributing to ongoing efforts aimed at increasing restoration of visual function following
gene therapy for rod- and cone-mediated dystrophies. They will also allow us to address several compelling,
clinically relevant questions: Is the brain’s circuitry sufficiently plastic to recover from the pathological changes
caused by the Gnat2 mutation? Is there a point of no return after which, despite reversion of the genotype to
wild type, cones cannot be salvaged? Can temporal barriers to gene therapy be relieved by metabolic
reprogramming?
Taken together, this proposal is certain to 1) define the factors limiting interventional therapy; 2) validate a new,
inducible models of rod- and cone-mediated retinal degeneration; and 3) determine whether metabolic
reprogramming can serve as an efficacious, non-gene-specific strategy for treating retinal degeneration.

## Key facts

- **NIH application ID:** 10909992
- **Project number:** 5R01EY018213-16
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Stephen H Tsang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $405,911
- **Award type:** 5
- **Project period:** 2008-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909992

## Citation

> US National Institutes of Health, RePORTER application 10909992, Defining Barriers to Gene Therapy (5R01EY018213-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909992. Licensed CC0.

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