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Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia

Award Number: R01HL147324
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/20/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia - ABSTRACT Fanconi anemia (FA) is an inherited bone marrow (BM) failure disorder resulting from an intrinsic defect in DNA repair leading to an increased risk of cancers such as acute myeloid leukemia and squamous cell carcinoma. Approximately 130,000 children born worldwide each year are affected by FA. Currently, the only cure for the hematologic complications of FA is an allogeneic BM or hematopoietic stem cell transplant (HSCT) from a suitable HLA donor. A key component is preparing the recipient BM using some form of conditioning to both eliminate diseased cells and promote engraftment of donor product. All of the currently used conditioning regimens for FA rely on the use of alkylating chemotherapy drugs and/or irradiation, both of which are associated with an increased risk of developing secondary malignancies, especially in DNA repair disorders like FA. As an alternative strategy, antibody drug conjugates (ADCs) targeting hematopoietic stem cells (HSCs) are a promising nongenotoxic method of facilitating engraftment of gene-modified autologous or allogeneic grafts. Recent studies have shown the effective use of ADCs with either CD45 or CD117 (c-Kit) antibodies conjugated to the immunotoxin saporin (SAP). Since the general consensus is that genotoxic conditioning should be avoided in FA and other diseases with DNA repair defects, we propose to develop novel approaches to overcome these critical limitations for current gene therapy and HSCT protocols. Thus, in Aim 1, we will develop nongenotoxic conditioning regimens for FA using a FANCA knockout mouse model to optimally deplete residual HSCs and facilitate engraftment of gene-modified or allogeneic cells. Despite eliminating as many host HSCs as safely possible, there will be a risk of remaining host HSCs, which can result in residual disease-related hematopoiesis after transplantation of gene-modified cells and also in the setting of nonmyeloablative, T-cell depleted allogeneic HSCT. Aim 2 will pursue a novel approach to eliminate residual FA cells after gene therapy or allogeneic HSCT. While Aim 1 seeks to avoid allo-HSCT complications, not all FA patients will be good candidates for gene therapy. Thus, in Aim 3, we will determine whether our novel nongenotoxic conditioning approach can deplete host HSCs and prevent host immune-mediated BM graft rejection and thus permit allogeneic HSC engraftment in Fanca-/- mice. The proposed studies will develop an entirely novel approach of nongenotoxic conditioning for autologous HSC gene therapy and as a key component of a novel regimen for allogeneic HSC transplantation. In addition, we describe an innovative strategy, applicable to both gene therapy and allogeneic transplantation, to eliminate residual and uncorrected FA hematopoietic cells that may develop into leukemic cells post-transplant.


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 = $0 )
2025	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	5	1/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $811,794 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	5	3/4/2023	NON-COMPETING CONTINUATION	$81,178
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	5	12/8/2022	NON-COMPETING CONTINUATION	$730,616
2023	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	3	5/16/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $811,794

Issue Date FY: 2022 ( Subtotal = $818,850 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	006	4	9/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$81,885
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	4	6/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$669,485
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	3	11/30/2021	NON-COMPETING CONTINUATION	$736,965
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	005	4	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$227,094
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	004	3	8/31/2022	NON-COMPETING CONTINUATION	-$67,480
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	3	6/28/2022	NON-COMPETING CONTINUATION	-$669,485
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	003	2	8/31/2022	NON-COMPETING CONTINUATION	-$159,614
														Subtotal = $818,850

Issue Date FY: 2021 ( Subtotal = $823,789 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	11/19/2020	NON-COMPETING CONTINUATION	$741,410
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	2	5/24/2021	NON-COMPETING CONTINUATION	$82,379
														Subtotal = $823,789

Issue Date FY: 2020 ( Subtotal = $849,490 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	1	12/18/2019	NEW	$849,490
														Subtotal = $849,490

Grand Total All Awards = $3,303,923

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Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia

Award Number: R01HL147324

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/20/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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