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Deciphering unintended large gene modifications in gene editing for sickle cell disease

Award Number: R01HL169761
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Deciphering unintended large gene modifications in gene editing for sickle cell disease - Summary: Sickle cell disease (SCD) is a genetic disease that affects millions of people worldwide, with significant morbidity and a median life expectancy in the mid-forties. Although SCD can be cured by allogeneic hematopoietic stem cell transplantation (alloHSCT), this treatment strategy has substantial limitations and is only available to ~15% of patients. CRISPR/Cas9 based genome-editing strategies for treating SCD have been developed by either correcting the sickle mutation in β-globin (HBB) gene or disrupting the BCL11A erythroid enhancer in patients’ hematopoietic stem and progenitor cells (HSPCs). Multiple clinical trials using gene editing strategies have received FDA approval, and the Phase 1 clinical trial (NCT03745287) by Vertex Pharmaceuticals and CRISPR Therapeutics has shown promise. We have discovered recently that CRISPR/Cas9 genome editing can induce unintended large gene modifications, such as large deletions, insertions and complex local rearrangements, at the Cas9 on-target cut-site. Our results show that large deletions of up to several thousand bases occurred with high frequencies at/near the Cas9 on-target cut-sites on the HBB (11.7-35.4%), HBG (14.3%), and BCL11A (13.2%) genes respectively in HSPCs from patients with SCD. However, the persistence and biological consequences of these large gene modifications are largely unknown, the mechanisms of generating large deletions and insertions remain elusive, and no method is available to reduce the unwanted large gene modifications. There is an unmet need to determine the clinical implications of the unintended large gene modifications in gene-edited SCD HSPCs. The central hypothesis of the proposed research is that a good understanding of the persistence and functional consequences of unintended large gene modifications and the ability to control them will increase the efficacy and safety of gene-editing based treatment of SCD. In Aim 1 studies we will determine the ineffective maturation and HbF induction due to large gene modification in gene edited SCD HSPCs by performing SMRT-seq and single-cell RNA analysis. In Aim 2 we will determine the persistence of large gene modifications in HBB and BCL11A alleles after engraftment of gene-edited SCD HSPCs into mice and patients undergoing CRISPR/Cas9 gene- editing based SCD clinical trials. In Aim 3 we will develop strategies to minimize the detrimental large deletions by establishing a better understanding of the competition between different DNA damage repair pathways and designing and optimizing ssODN templates and short gRNAs as blockers. These studies will address an unmet need in the therapeutic genome editing field and facilitate the translation of genome editing based SCD treatment into clinical practice.


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 = $642,458 )
2025	2025	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Blood Diseases and Resources Research	001	3	8/6/2025	NON-COMPETING CONTINUATION	$642,458
2025	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Cardiovascular Diseases Research	000	2	6/4/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $642,458

Issue Date FY: 2024 ( Subtotal = $753,065 )
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Blood Diseases and Resources Research	000	1	2/29/2024	SUPPLEMENT FOR EXPANSION	$42,336
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Blood Diseases and Resources Research	001	2	6/25/2024	NON-COMPETING CONTINUATION	$632,319
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Cardiovascular Diseases Research	002	2	7/19/2024	SUPPLEMENT FOR EXPANSION	$78,410
2024	2024	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Blood Diseases and Resources Research	003	1	9/25/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $753,065

Issue Date FY: 2023 ( Subtotal = $662,035 )
2023	2023	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Blood Diseases and Resources Research	001	1	7/21/2023	NEW	$0
2023	2023	WILLIAM MARSH RICE UNIVERSITY	6100 MAIN ST	HOUSTON	TX	77005	HARRIS	USA	Blood Diseases and Resources Research	000	1	6/27/2023	NEW	$662,035
														Subtotal = $662,035

Grand Total All Awards = $2,057,558

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Deciphering unintended large gene modifications in gene editing for sickle cell disease

Award Number: R01HL169761

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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