# Defining Barriers to Gene Therapy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $95,661

## Abstract

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.
We will 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 (Pde6b) mouse as a model for rod dystrophy.
The Gnat2floxSTOP/Gnat2floxSTOP::Arr3CreERT2/WT and Pde6cfloxSTOP/Pde6cfloxSTOP::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: i) determine whether metabolic reprogramming can serve as an
efficacious, non-gene-specific strategy for treating retinal degeneration, ii) define the factors limiting interventional
therapy, and iii) validate a new, inducible models of cone-mediated retinal degeneration.

## Key facts

- **NIH application ID:** 11081362
- **Project number:** 3R01EY018213-16S1
- **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:** $95,661
- **Award type:** 3
- **Project period:** 2008-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11081362

## Citation

> US National Institutes of Health, RePORTER application 11081362, Defining Barriers to Gene Therapy (3R01EY018213-16S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11081362. Licensed CC0.

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