# Delivering genetic medicines to photoreceptors with lipid nanoparticles

> **NIH NIH R43** · ENTERX BIOSCIENCES, INC. · 2024 · $294,052

## Abstract

Project Summary
Inherited retinal diseases (IRDs) are a heterogeneous group of genetic diseases that lead to loss of vision and
often progress to blindness. As a group, IRDs are linked to over 280 genes and affect ~4.5 million people
worldwide. In all IRDs, the ultimate cause of vision loss is degeneration of light-sensing photoreceptor (PR) cells
and, in most cases, genetic correction is needed specifically in PRs. Genome editing using the CRISPR-Cas9
toolkit has the potential to correct mutations directly in the patient’s DNA. Unfortunately, lack of a safe, efficient
delivery vehicle to PRs is a major barrier to developing gene therapies for IRDs. Viral gene therapies for IRDs
are in clinical testing but they have limited cargo size and induce a strong immune response. Lipid nanoparticles
(LNPs) are the most clinically advanced, non-viral nucleic acid delivery vehicle. LNPs form a “bubble” composed
of different lipids (and other compounds) that envelop nucleic acids and provide robust and safe delivery in vivo.
To address this PR-specific delivery barrier, EnterX Biosciences is developing novel PR-specific LNPs to
deliver RNA-based gene editing components based on our best-in-class, proprietary lipid technology.
Recently, we demonstrated the first and only use of lipid-based delivery to transfect PRs with mRNA in vivo,
which was accomplished by attaching a small proprietary peptide targeting moiety to the LNP. Our novel,
proprietary ionizable lipid, NTRX-7, can also generate LNPs that deliver mRNA to PRs. Combining this novel
lipid chemistry and targeting peptide could enable gene editing in PRs. To improve PR-specific delivery of gene
editors, we have two major Aims: 1) investigate efficiency of gene editor delivery via LNPs using NTRX lipids
and a targeting peptide in PRs; and 2) deploy top LNP candidates to quantify gene editing efficiency and retinal
toxicity. These experiments will identify the top LNP candidate(s) capable of safe, efficient delivery of RNA gene
editing components for immediate follow up studies of gene editing in specific IRDs. In Aim 1, we will screen LNP
delivery of gene editors to PRs. First, in Aim 1A, we will use DNA barcoding to rapidly identify the most potent
derivatives of NTRX-7 LNPs and evaluate which LNPs have suitable delivery efficiency to PRs via subretinal
injection in mice. The most potent LNP formulations identified by barcoding will then be formulated with Cas9
mRNA and gRNA and injected subretinally. By sectioning and immunostaining Ai9 reporter mouse retinas, we
will assay the number of tdTomato+ PRs to determine the spatial extent of gene editing (successful editing will
“allow” tdTomato expression in Ai9 mice) and determine the most potent lipids. In Aim 1B, we will similarly test if
adding the peptide targeting moiety to the LNP surface can further improve gene editing efficacy and fine-tune
PR specificity. Finally, in Aim 2, the top LNP candidates from Aim 1 will be tested longitudinally for retin...

## Key facts

- **NIH application ID:** 10821043
- **Project number:** 1R43EY035865-01
- **Recipient organization:** ENTERX BIOSCIENCES, INC.
- **Principal Investigator:** Adam Tuttle
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $294,052
- **Award type:** 1
- **Project period:** 2024-03-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821043

## Citation

> US National Institutes of Health, RePORTER application 10821043, Delivering genetic medicines to photoreceptors with lipid nanoparticles (1R43EY035865-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10821043. Licensed CC0.

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