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Controllable base editing therapy for DMD

Award Number: R01HL170260
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Controllable base editing therapy for DMD - PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a lethal muscle degenerative disease with cardiomyopathy in over 90% of patients, and heart failure is a leading cause of mortality. DMD patients commonly harbor out-of-frame mutations which result in complete loss of dystrophin protein. While CRISPR-gene editing has been employed to delete the mutant exon for restoration of the dystrophin reading frame, this strategy raises potential safety concerns as it relies on repair of the double strand DNA breaks created by CRISPR/Cas9, which may cause unwanted large deletion, DNA rearrangement and viral vector integration. Developing novel approaches to precisely and safely correct the disease-causing mutations in striated muscles is in urgent need to combat DMD. Recent advances in base editors allow us to explore the feasibility of precise correction of genetic mutations in animal models of DMD without creating double strand DNA breaks. Our recent studies demonstrate it is highly efficient to correct a disease-causing point mutation in the striated muscles of a mouse model of DMD using systemic delivery of adeno-associated virus 9 (AAV9). This paves the way for clinical translation of in vivo base editing for DMD. However, novel strategies are in urgent need to solve several safety-related issues (e.g. the accumulation of off-target activities with persistent expression of base editing agents following AAV delivery; high dose of AAV utilized; host immune responses). Here we propose to develop a novel controllable base editing system (to reduce accumulation of off-target editing events and exposure of base editor to the host immune system) delivered in recently engineered myotropic AAV capsids (to increase muscle transduction efficiency with 10-fold less of AAV as compared to AAV9). The therapeutic efficacy and safety will be extensively investigated using a newly established DMD rabbit model, which faithfully recapitulates the clinical signs of muscular dystrophy and cardiomyopathy in human DMD. We will further engineer immune-friendly vectors and develop a novel immune-modulating strategy to mitigate the host immune responses to the in vivo AAV-delivered base editing therapy. Completion of the proposed studies will significantly advance our translational efforts to develop safer precision medicine for DMD.


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 = $599,523 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	3	8/18/2025	NON-COMPETING CONTINUATION	$599,523
														Subtotal = $599,523

Issue Date FY: 2024 ( Subtotal = $587,533 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	2	7/26/2024	NON-COMPETING CONTINUATION	$587,533
														Subtotal = $587,533

Issue Date FY: 2023 ( Subtotal = $599,523 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cardiovascular Diseases Research	000	1	8/17/2023	NEW	$599,523
														Subtotal = $599,523

Grand Total All Awards = $1,786,579

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Controllable base editing therapy for DMD

Award Number: R01HL170260

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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