Sunday, May 11, 2025 5/11/2025

Novel grafted terpolymers for targeted delivery of CRISPR/Cas9- mediated precise genome editing to the brain

Award Number: UH3NS115597
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Description

Novel grafted terpolymers for targeted delivery of CRISPR/Cas9- mediated precise genome editing to the brain - CRISPR/Cas9- mediated precise genome editing represents one of the most promising approaches to clinical management of a variety of human genetic diseases in the central nervous system (CNS). However, translation of this technology for clinical applications has been limited by several major hurdles, including the lack of safe approaches for efficient, specific delivery of Cas9, sgRNA, and donor DNA simultaneously to the disease location, the limited homology-directed repair (HDR) frequency due to the predominant role of non- homologous end-joining (NHEJ) in DNA repair, and the inability to cross the blood-brain barrier (BBB). To overcome those challenges, we propose to develop novel, simple polymeric NPs that are optimized for delivery of precise genome editing to the brain through both locoregional and systemic administration. As preliminary work, we developed novel chemistry and synthesized a group of terpolymers for gene delivery. We established an array of techniques for locoregional delivery of nanoparticles (NPs) to the brain via convection-enhanced delivery (CED), as well as an effective approach for systemic delivery of NPs to the brain via autocatalytic brain- targeting (ABT). We synthesized grafted terpolymeric NPs that can mediate efficient delivery of genetic materials, including CRISPR/Cas9, to the brain. We discovered leucine-rich repeat-containing protein 31 (LRRC31) that preferentially inhibits NHEJ and significantly enhances the efficiency of CRISPR/Cas9- mediated precise genome editing. Building on those progress, we propose to synthesize grafted polymeric NPs that are optimized for CRISPR/Cas9 delivery, identify LRRC31 motifs responsible for NHEJ inhibition, and evaluate them for direct, locoregional delivery and systemic delivery of precise genome editing to the mouse brain in the UG3 Development Phase, and to develop approaches to scaling up the synthesis of polymers and NPs, and evaluate them in experimental pigs in the UH3 Demonstration Phase. Successful completion of the study will establish a versatile platform for efficient delivery of CRISPR/Cas9- mediated precise genome editing to the brain, which could be potentially translated 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: 2025 ( Subtotal = -$55,032 )
2025	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	4	10/25/2024	EXTENSION WITH OR WITHOUT FUNDS	-$55,032
														Subtotal = -$55,032

Issue Date FY: 2024 ( Subtotal = $206,495 )
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	002	4	8/15/2024	EXTENSION WITH OR WITHOUT FUNDS	-$27
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	001	4	2/23/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	4	11/17/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	004	4	9/24/2024	EXTENSION WITH OR WITHOUT FUNDS	$27
2024	2022	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	003	4	9/24/2024	EXTENSION WITH OR WITHOUT FUNDS	$206,495
														Subtotal = $206,495

Issue Date FY: 2022 ( Subtotal = $416,135 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Trans-NIH Research Support	000	4	8/23/2022	EXTENSION WITH OR WITHOUT FUNDS	$416,135
														Subtotal = $416,135

Grand Total All Awards = $567,598

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Novel grafted terpolymers for targeted delivery of CRISPR/Cas9- mediated precise genome editing to the brain

Award Number: UH3NS115597

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer