# A Ribozyme Rescue Strategy for Dry Age-Related Macular Degeneration

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2020 · —

## Abstract

In common dry age-related macular degeneration (dAMD) and orphan juvenile macular degeneration (JMD)
(e.g., Stargardt) cellular and biochemical debris accumulates within and beneath the retinal pigment epithelium
(RPE). These diseases reflect naturally occurring circadian shedding of rod and cone photoreceptor (PR) outer
segment tips, and phagocytosis and lysosomal digestion by RPE cells. In the human parafovea, where dAMD
and JMD starts, a single RPE cell underlies and supports about 30-35 rods and fewer cones. RPE enzymatic
limitations cause age-related lipofuscin to accumulate in phagolysosomes. Lipofuscin has protein, lipid and
carbohydrate components and contributes to intra- and sub-RPE deposits (flecks, drusen) seen in JMD/dAMD.
Lipofuscin has a brilliant autofluorescence and photoreactivity under blue light excitation due to the dominant
presence of toxic bis-retinoids (TBR) such as pyridinium salts (A2E) and retinaldehyde dimers (RetDi). These
derive from covalent reaction, in PR outer segments, of two molecules of retinaldehydes, resulting from visual
pigment bleaching and regeneration, with lipids and proteins. TBR pigments accumulate in RPE cells normally
with age (> 30 years) integrated over many years. Any stressors (e.g., macular degenerative processes) that
promote accelerated TBRs buildup will exert toxic apoptotic effects on RPE cells, loss of support of overlying
PRs and cell death (e.g., dAMD/JMD). TBRs are validated molecular targets for therapy. Daily turnover of
massive amounts of rod visual pigment in the parafovea is a huge burden for the RPE (most metabolically
active cells in human body) and contributes to accumulation of intracellular and subretinal debris; 50%
reduction of normal human rod rhodopsin (RHO) has no degenerative effect and people still see stars. 90% of
rod photoreceptor mass is RHO. RHO is a validatable target. Our hypothesis is that dAMD/JMD can be
treated by reducing RHO and related time-dependent accumulation of debris and TBRs in PR and RPE
cells. The rationale or strategy is that steady-state reductions in RHO and related TBRs would slow age-
related toxic buildup of byproducts, decrease metabolic burden, and maintain viable RPE cells longer into life.
This would preserve overlying rods and cones, maintain central cone vision, and slow or halt emergence of
geographic atrophy. The long term objective is to develop a safe and effective gene therapy for dAMD/JMD.
The objective of the proposed experiments is to use hammerhead ribozymes (hhRz) or RNA interference
(shRNA) as genetic tools to knockdown (KD) RHO expression to relieve daily outer retinal stresses (TBRs,
metabolic stresses). This novel strategy is tested in multiple mouse models of dAMD/JMD (ABCR-/-//RDH8-/-;
ELOVL4mut, SOD2ko), which all have outer retinal PR/RPE degenerations. The expected outcome is that
RHO reduction will rescue outer retinal degenerations, with preserved photopic sensitivity (cones use a Müller
cell retinoid visual cycle...

## Key facts

- **NIH application ID:** 9892813
- **Project number:** 2I01BX000669-09A1
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** JOHN M. SULLIVAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892813

## Citation

> US National Institutes of Health, RePORTER application 9892813, A Ribozyme Rescue Strategy for Dry Age-Related Macular Degeneration (2I01BX000669-09A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892813. Licensed CC0.

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