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Gene therapy for long QT syndrome type 2

Award Number: R01HL166165
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Gene therapy for long QT syndrome type 2 - Abstract There are >500 pathologic variants within 17 genes causing congenital long QT syndrome, which leads to polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD). About 30% of the mutations are concentrated in the KCNH2 gene resulting in loss-of-function of the rapidly activating delayed rectifier potassium current IKr causing prolongation of the action potential duration and QT interval (LQT2). We developed a transgenic rabbit model for LQT2 that recapitulate the human phenotype. This application is aimed at developing gene therapy for LQT2 using our rabbit model and an AAV9-mediated mosaic gene expression of hERG. Aim 1 to rescue the phenotype of LQT2G by delivering AAV9-encoded shRNA that will abolish expression of both the human pore mutant transgene and endogenous rERG with an shRNA-resistant hERG (hERG*) under the control of the CMV promoter at doses of 6E13vg/kg and 2E14vg/kg as compared to vehicle control. The Aim also proposes to study the cellular phenotype of the treated rabbits as compared to vehicle control. Aim 2 proposes to monitor ant test the two groups for spontaneous and inducible arrhythmias. This application outlines the roadmap for gene therapy of all variants causing human LQT2 syndrome and has the potential to revolutionize the therapy of this syndrome.


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 = $808,179 )
2025	2025	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	001	2	6/26/2025	NON-COMPETING CONTINUATION	$80,818
2025	2025	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	2	4/18/2025	NON-COMPETING CONTINUATION	$727,361
														Subtotal = $808,179

Issue Date FY: 2024 ( Subtotal = $814,039 )
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	3/12/2024	NEW	$732,634
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	001	1	6/21/2024	NEW	$81,405
														Subtotal = $814,039

Grand Total All Awards = $1,622,218

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Gene therapy for long QT syndrome type 2

Award Number: R01HL166165

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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