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SCGE Disease Models Studies Supplement: Cardioediting Ttntvs in a humanized mouse model

Award Number: U01HL156349
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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SCGE Disease Models Studies Supplement: Cardioediting Ttntvs in a humanized mouse model - ABSTRACT Somatic cell genome editing (SCGE) has remarkable promise to transform our therapeutic toolbox for heart failure due to Titin truncation variants (TTNtvs). However, despite having the knowledge of the pathogenic TTNtvs, their molecular consequences, and SCGE technologies including CRISPR genome editing and transcriptional activation to target TTNtvs, the lack of in vivo studies using humanized TTNtv animal models has hindered clinical development. There remain key knowledge gaps limiting SCGE development for TTNtvs including the lack of a systematic examination of the proportion of TTNtv alleles and cardiomyocytes that need to be corrected for clinical benefit, and the toxicology profile of SCGE enzymes and delivery systems including genotoxicity and immunogenicity. Our long-term goal is to develop SCGE for heart failure patients. While in vitro studies to evaluate the efficacy and safety of SCGE editors and delivery systems such as by utilizing human engineered heart tissues (EHTs) are important, they do not replace the need for animal model studies that recapitulate the complex pathophysiology of heart failure. Guided by our comprehensive preliminary data and unique reagents including SCGE components functionally validated in TTNtv EHTs, humanized Ttntv mice and cardiotropic adeno-associated viruses; our 1-year study will include two Specific Aims to determine efficacy and safety of 1) TTNtv reading frame repair and 2) TTN transcriptional activation in a humanized Ttntv mouse. Execution of these Aims will provide editing thresholds, safety, and toxicity for two SCGE approaches to treat TTNtvs that we expect will serve as a resource for the broader scientific community.


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: 2024 ( Subtotal = -$39,077 )
2024	2022	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	6/17/2024	NON-COMPETING CONTINUATION	-$29,710
2024	2022	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON AVE	FARMINGTON	CT	06030	CAPITOL	USA	Trans-NIH Research Support	001	4	6/17/2024	SUPPLEMENT FOR EXPANSION	-$9,367
														Subtotal = -$39,077

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Trans-NIH Research Support	000	4	11/2/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $969,408 )
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Trans-NIH Research Support	001	4	9/9/2022	SUPPLEMENT FOR EXPANSION	$232,382
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Trans-NIH Research Support	002	4	9/13/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	7/22/2022	NON-COMPETING CONTINUATION	$737,026
														Subtotal = $969,408

Issue Date FY: 2021 ( Subtotal = $737,975 )
2021	2021	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	3	8/6/2021	NON-COMPETING CONTINUATION	$737,975
2021	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	3/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $737,975

Issue Date FY: 2020 ( Subtotal = $738,903 )
2020	2020	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	8/21/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$738,903
														Subtotal = $738,903

Grand Total All Awards = $2,407,209

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SCGE Disease Models Studies Supplement: Cardioediting Ttntvs in a humanized mouse model

Award Number: U01HL156349

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/09/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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