# Engineering Chemically Modified RNPs for Effective Treatment of Angelman Syndrome

> **NIH NIH R41** · COURAGENE, INC. · 2024 · $339,999

## Abstract

Angelman syndrome (AS) is a neurogenetic disorder caused by the deficiency of the maternal
UBE3A and characterized by severe developmental delay. Current treatment only helps manage
symptoms and cannot meet clinical need to effectively treat AS. The expression of Ube3a in
neurons can be activated through inhibition of non-coding antisense RNA of UBE3A (UBE3A-
ATS). Genome editing strategy targeting UBE3A-ATS is a promising therapeutic approach for AS.
AAV is the most widely used vector for genome editing. However, AAV presents potential safety
concerns of immunogenicity and off-target effects. Thus, there is a clear unmet need for novel
nonviral delivery technologies for safe and efficient delivery of the CRISPR machinery to neurons
for AS treatment. In this application, Couragene proposes to develop a novel, chemically modified
ribonucleoprotein (cRNP) complexed with Cas9 protein and gRNA for delivery of CRISPR
mediated gene editing to the brain for treatment of AS. cRNPs have been previously shown to
enable brain-wide genome editing and achieve long-term persistent therapeutic benefits in AS
mice through single intrathecal (IT) administration. The proposed project will focus on formulation
optimization of the cRNP for delivery of genome editing to neuronal cells in vitro in Aim 1, seeking
to achieve over 70% editing efficiency in primary AS neuronal cells. The leading cRNP formulation
will then be characterized in Aim 2 to determine cRNP-based genome editing delivery efficiency
and safety in Ube3a-YFP AS reporter mice. We aim to achieve brain-wide genome editing with
over 50% neuronal editing efficiency without significant toxicity through single intrathecal injection
in AS mouse. The successful completion of the proposed work will build a solid foundation for
Phase II projects where further biodistribution and phenotypic rescue evaluation in Ube3a
maternal deficiency mice, off-target study and IND-enabling studies with potential partners will
take place. The projects will eventually result in a nonviral genome editing therapy with
Couragene’s innovative chemically modified ribonucleoprotein cRNP technology, greatly
enhancing the clinical treatment for patients with AS.

## Key facts

- **NIH application ID:** 10918729
- **Project number:** 1R41NS134480-01A1
- **Recipient organization:** COURAGENE, INC.
- **Principal Investigator:** Ying Xie
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $339,999
- **Award type:** 1
- **Project period:** 2024-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918729

## Citation

> US National Institutes of Health, RePORTER application 10918729, Engineering Chemically Modified RNPs for Effective Treatment of Angelman Syndrome (1R41NS134480-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10918729. Licensed CC0.

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