# A non-viral CRISPR-mediated genome editing delivery platform as a potential therapy for neurogenetic diseases

> **NIH NIH UG3** · YALE UNIVERSITY · 2024 · $10,834,632

## Abstract

Genome editing holds great promise for the treatment of many genetic diseases; however its application in the
clinic has been slow due to the lack of the safe delivery tools and significant cost and time investment required
to custom-develop individual therapies. In our SCGE program phase 1 study, we developed a chemically
modified ribonucleoprotein (cRNP)-based gene delivery system that specifically targets neuronal cells
throughout the brain after intrathecal (IT) administration. The overarching goal of this application is to apply this
novel gene editing technology towards the treatment of two severe neurodevelopmental disorders (NDD):
Angelman syndrome (AS) and H1-4 syndrome (HIST1H1E syndrome). AS is a devastating neurodevelopmental
disease caused by the deficiency of the maternal and brain specific imprinting UBE3A gene in human
chromosome 15q11-q13 region. The structure of UBE3A is intact in the paternal chromosome in all AS cases
but transcriptionally repressed by a non-coding and antisense RNA of UBE3A (UBE3A-ATS) mediated
mechanism. It has been shown convincingly that reduction of UBE3A-ATS by antisense oligo (ASO),
topoisomerase inhibitors, and virus delivered Cas9 gene editing can de-repress the expression of UBE3A and
correct the abnormal neurological phenotypes in AS mouse models. H1-4 syndrome is caused by a gain of
function mechanism due to a mutated protein with aberrant C-terminal frameshift tail (CFT). H1-4 syndrome has
similar but milder clinical features than AS. There is no effective intervention for H1-4 syndrome. Thus, a long-
term molecular therapy for AS and H1-4, as well as other NDDs is urgently needed. In our preclinical study using
a well validated AS mouse model, we demonstrated that a single IT delivery of Ube3a antisense-targeting
RNP/Cas9efficiently de-represses the expression of Ube3a from the paternal chromosome, leading to correction
of neurobehavioral phenotypes. Similarly, the knockdown of H1-4 CFT rescue the abnormal phenotypes in H1-
4 humanized mice. We propose our cRNP-based platform for the treatment of AS and H1-4 syndrome utilizing
the same genome editor (CRISPR), delivery system (cRNPs), route (IT), target cell type (neurons), therapeutic
mechanism (genetic inactivation) and overall trial design. We have assembled an outstanding team from Yale
and Rush University with strong and complementary expertise in the areas of preclinical, IND enabling studies,
and clinical trials. The success of this study will lead to the first ever gene editing based therapy for AS and H1-
4. More importantly, it will support a paradigm shift for genome editing; rapidly expanding the number of
neurogenetic diseases treated by in vivo gene editing and accelerating the transition of genome editing
technology into clinical applications.

## Key facts

- **NIH application ID:** 10932377
- **Project number:** 5UG3TR004713-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Elizabeth Mara Berry-Kravis
- **Activity code:** UG3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $10,834,632
- **Award type:** 5
- **Project period:** 2023-09-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932377

## Citation

> US National Institutes of Health, RePORTER application 10932377, A non-viral CRISPR-mediated genome editing delivery platform as a potential therapy for neurogenetic diseases (5UG3TR004713-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10932377. Licensed CC0.

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