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Targeted Systemic Delivery of SDF-1 DNA for the Treatment of Chronic Heart Disease

Award Number: R01HL138242
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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Targeted Systemic Delivery of SDF-1 DNA for the Treatment of Chronic Heart Disease - PROJECT SUMMARY / ABSTRACT Stromal-derived factor-1 (SDF-1)-based gene therapy that can improve mesenchymal stem cell (MSC) homing to the region of myocardial infarct for the treatment of acute myocardial infarction (MI) or chronic heart failure (CHF) has shown considerable promise in preclinical and clinical trials. However, the most established technology requires trans-endocardial injection using a specific device, which can only be handled by an expert. For convenience administration and cost-effective treatment, a targeted systemic delivery strategy has to be developed. In this application, a plasmid DNA encoding SDF-1 will be systemically and specifically delivered to the infarct site by the formation of the SDF-1/ischemic myocardium targeting peptide (IMTP) complex. To generate the SDF-1/IMTP complex, for the first time, we utilize the ligand-to-metal charge transfer transition allowing for direct incorporation of the targeting peptide to the plasmid SDF-1 DNA without the need for any gene carriers. We hypothesized that the LMCT transition between Zn2+ ions and the sulfhydryl group in cysteine of the targeting peptide could spontaneously drive the integration of the peptide to the plasmid SDF-1 that has already been modified to contain Zn2+ ions. It has been known that divalent metal ions, such as Zn2+, lead to the conversion of normal B-DNA to metal-bound DNA (M-DNA) through intercalation into the DNA base pairs in the pH range of 7.0-8.5. In the preliminary studies, we generated M-DNA using Zn2+ ions, confirmed the formation of the M-DNA/targeting peptide complex through the LMCT transition, and demonstrated that the M-DNA/targeting peptide complex led to the enhancement in the gene transfection in the target cells. In this project, in an animal model of CHF, we intend to demonstrate therapeutic efficacy of the targeted systemic delivery of a plasmid SDF-1 DNA by the formation of the SDF-1/IMTP complex generated through the LMCT transition. To achieve the final goal, we intend to demonstrate the followings: 1) direct integration of IMTP into the SDF-1 plasmid through the LMCT transition; 2) targeted transfection of the SDF-1 gene into hypoxic primary cardiomyocytes and the infarct site in the animal model; and 3) facilitated migration of MSCs towards the SDF-1 gradient in the animal model.


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 = -$391 )
2024	2021	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	6	3/8/2024	NON-COMPETING CONTINUATION	$0
2024	2021	UNIVERSITY OF NORTH TEXAS	1112 DALLAS DR STE 4000	DENTON	TX	76205	DENTON	USA	Cardiovascular Diseases Research	001	7	3/8/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$391
														Subtotal = -$391

Issue Date FY: 2023 ( Subtotal = -$14,598 )
2023	2021	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	000	6	5/27/2023	NON-COMPETING CONTINUATION	-$40,468
2023	2021	UNIVERSITY OF NORTH TEXAS	1155 UNION CIR #305250	DENTON	TX	76203	DENTON	USA	Cardiovascular Diseases Research	001	7	5/29/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$40,468
2023	2021	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Cardiovascular Diseases Research	002	6	6/20/2023	NON-COMPETING CONTINUATION	-$14,598
														Subtotal = -$14,598

Issue Date FY: 2021 ( Subtotal = $511,932 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	6	7/12/2021	NON-COMPETING CONTINUATION	$511,932
														Subtotal = $511,932

Issue Date FY: 2020 ( Subtotal = $507,037 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	5	7/20/2020	NON-COMPETING CONTINUATION	$507,037
														Subtotal = $507,037

Issue Date FY: 2019 ( Subtotal = $472,656 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	4	7/22/2019	NON-COMPETING CONTINUATION	$472,656
														Subtotal = $472,656

Issue Date FY: 2018 ( Subtotal = $430,962 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	000	3	7/23/2018	NON-COMPETING CONTINUATION	$430,962
														Subtotal = $430,962

Issue Date FY: 2017 ( Subtotal = $405,275 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Cardiovascular Diseases Research	002	2	8/15/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$405,275
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	000	1	6/21/2017	NEW	$405,275
2017	2017	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cardiovascular Diseases Research	001	1	8/14/2017	NEW	-$405,275
														Subtotal = $405,275

Grand Total All Awards = $2,312,873

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Targeted Systemic Delivery of SDF-1 DNA for the Treatment of Chronic Heart Disease

Award Number: R01HL138242

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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