# Silica Nanocapsule-Mediated Nonviral Delivery of CRISPR Base Editor mRNA and Allele Specific sgRNA for Gene Correction in Leber Congenital Amaurosis

> **NIH NIH U19** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $3,069,959

## Abstract

PROJECT SUMMARY/ABSTRACT - LEAD TRAILBLAZER PROJECT 1
Leber Congenital Amaurosis (LCA) is a rare but severe form of pediatric blindness. One subtype, LCA16, is
caused by several single-point mutations in the KCNJ13 gene, which encodes the inwardly-rectifying potassium
channel Kir7.1 in the retina. There is no FDA-approved treatment for ultra-rare conditions such as LCA16. The
objective of Lead Project 1 is to develop a new LCA16 gene therapy utilizing a CRISPR base editor (BE)
delivered to the retinal pigment epithelium (RPE) via a nonviral silica nanocapsule (SNC). The SNCs possess
many desirable properties, including high delivery efficiency, versatile surface chemistry for ligand conjugation,
small particle sizes, good biocompatibility, and scalable production. In preliminary studies, we show that the SNC
can transiently deliver a wide range of biologics, including a BE to RPE cells in mice and LCA16 patient-derived
induced pluripotent stem cell (iPSC)-RPE. Within five years, we seek to optimize and validate a lead candidate,
SNC-101, progress to scaled-up and CGMP production of the product to enable non-human primate (NHP)
studies and file an Investigational New Drug (IND) application to the FDA for base editing therapy of LCA16. In
Aim 1, we will generate a preclinical validation package with a lead SNC formulation for W53* KCNJ13 correction.
We will first optimize the amount of ATRA targeting ligand (RPE cell-specific) and the modified KCNJ13 sgRNA
in vitro via the Human Cell Assays Core and in vivo in a W53* LCA16 mouse model. We will then develop a
scale-up production process for the optimized SNC (i.e., SNC101) for preclinical studies. We plan to complete
one INTERACT meeting at the end of this aim. In Aim 2, we will determine the gene correction efficiency, dosing,
and toxicity in mouse models and NHPs. We will comprehensively evaluate the immune, structural, and
functional consequences of subretinal delivery of SNC-101 through our W53* LCA16 mouse model. Using our
Large Animal Core, we will also perform dose-escalation safety studies in NHPs. Alongside the species
comparison, the study will ascertain storage stability, dosing, and toxicity profiles in detail, an important milestone
to support an IND with the FDA. In Aim 3, we will conduct IND enabling studies of SNC-101 for W53* KCNJ13
correction. A pre-IND meeting package will be submitted to FDA CBER with the help of our Regulatory Core.
Waisman Biomanufacturing will develop a full-scale engineering run to be used in GLP toxicology study in rats
and NHPs. Concurrent with the toxicology study, one entire CGMP batch will be manufactured. We will submit
an IND application to the FDA in the final year. To date, no nonviral genome editing therapeutic has reached an
IND in the eye. Success here with SNC-101 would pave the way for this new therapeutic modality. Finally, the
knowledge gained along this development path will accelerate the translation of other nonviral genome editing
leads, i...

## Key facts

- **NIH application ID:** 10842306
- **Project number:** 5U19NS132296-02
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHAOQIN - GONG
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,069,959
- **Award type:** 5
- **Project period:** 2023-05-16 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842306

## Citation

> US National Institutes of Health, RePORTER application 10842306, Silica Nanocapsule-Mediated Nonviral Delivery of CRISPR Base Editor mRNA and Allele Specific sgRNA for Gene Correction in Leber Congenital Amaurosis (5U19NS132296-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10842306. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*