# Optimizing Enhanced Hammerhead Ribozymes for Retinal Nucleic Acid Therapeutics

> **NIH EY R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2026 · $544,353

## Abstract

Many mutations in the human rod opsin (hRHO) and peripherin genes cause autosomal dominant retinitis
pigmentosa (adRP) and macular degenerations. The folded mRNAs are targets for mutation-independent
hammerhead ribozyme (hhRz) gene therapy. Our long-range goal is to translate effective hhRz therapeutics
for hRHO adRP and other genes into human clinical trials. We have discovered a potent form of hhRz, which
we call Enhanced-hhRz (EhhRz) therapeutics. All or most known mutations in a given dominant disease gene
could be treated with a mutation-independent EhhRz strategy that pairs knockdown (KD) of mutant (and WT)
mRNA with reconstitution (RECON) of WT protein with expression of a cleavage-resistant mRNA. The current
stage of development of EhhRzs (against hRHO) lead to kinetic turnover rates greater than 2-log orders
improved over historical minimal hhRzs (mhhRz); one mhhRz partially rescued mutant RHO retinal
degeneration in rodent models. EhhRzs function under substrate (target) excess conditions and physiological
levels of cofactor Mg2+, which are optimum for intracellular KD therapeutics. If this exciting kinetic potential can
be harnessed for the photoreceptor, retinal, or ocular cells then there is potential for nucleic acid drugs
(injectable EhhRzs) as therapeutics without vector-based gene therapy, for diverse ocular diseases and
inherited retinal degenerations. Recent clinical success with intravitreal injection of antisense agents
incentivizes this development. The objective is to optimize EhhRzs for intracellular performance in cultured
human cells and mouse photoreceptor cells that are “humanized” for RHO mRNAs (same targets as in clinical
trials). The central hypothesis is that optimization of EhhRz kinetic performance and delivery will maximize
target mRNA/protein KD; optimization requires quantitation of biophysical variables that underlie target: EhhRz
interaction, rational and/or evolutionary engineering of RNA structure-related function, and identi

## Key facts

- **NIH application ID:** 11332629
- **Project number:** 5R01EY035007-04
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** JOHN M. SULLIVAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** EY
- **Fiscal year:** 2026
- **Award amount:** $544,353
- **Award type:** 5
- **Project period:** 2023-08-01T00:00:00 → 2027-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11332629

## Citation

> US National Institutes of Health, RePORTER application 11332629, Optimizing Enhanced Hammerhead Ribozymes for Retinal Nucleic Acid Therapeutics (5R01EY035007-04). Retrieved via AI Analytics 2026-05-20 from https://api.ai-analytics.org/grant/nih/11332629. Licensed CC0.

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