Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

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

Award Number: UG3TR004713
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/20/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2027

Group Awards By:

View Award Description

A non-viral CRISPR-mediated genome editing delivery platform as a potential therapy for neurogenetic diseases - Project summary 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 huma 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 and encouraging signals from initial clinical trial. This well-defined mechanism and exceptional effort by the Foundation of Angelman Therapeutics (FAST) has led the first ever phase 1/2 trial using an ASO in 2020. Currently, there are 3 current phase 1/2 trials using ASOs. However, the trial has illustrated a few major limitations associated with ASO-based treatment, which is that the effect is transient requiring re-dosing in short period of time. 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 both AS and H1-4 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $3,500,001 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	002	3	8/3/2026	SUPPLEMENT FOR EXPANSION	$3,500,001
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	3	3/9/2026	NON-COMPETING CONTINUATION	$0
2026	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	001	3	6/29/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $3,500,001

Issue Date FY: 2025 ( Subtotal = $10,672,633 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	001	3	7/29/2025	NON-COMPETING CONTINUATION	$10,672,633
2025	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	2	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $10,672,633

Issue Date FY: 2024 ( Subtotal = $10,834,632 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	001	2	9/20/2024	NON-COMPETING CONTINUATION	$10,834,632
2024	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	1	12/28/2023	NEW	$0
														Subtotal = $10,834,632

Issue Date FY: 2023 ( Subtotal = $5,019,038 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	1	9/20/2023	NEW	$5,019,038
														Subtotal = $5,019,038

Grand Total All Awards = $30,026,304

Top

All Categories

About

Search

Reports

Data Submission

Award Information

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

Award Number: UG3TR004713

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/20/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer