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Gene Therapy for SCID-X1 with Low Dose Busulfan and a SIN-lentiviral Vector

Award Number: U01AI125051
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/07/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2024

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Gene Therapy for SCID-X1 with Low Dose Busulfan and a SIN-lentiviral Vector - Gene therapy using autologous C034+ cells is a promising treatment for primary immunodeficiency, particularly for individuals without optimal allogeneic donors. SCIO-X1 is caused by mutations in IL2RG, which encodes the common gamma chain (ye) of multiple cytokine receptors. Boys with SCIO-X1 lack T and NK cells, and their B cells fail to produce antibodies due to the lack of IL-7, IL-15 and IL-21 function respectively. This project seeks to test the efficacy and safety of a new self-inactivating lentiviral (LV) vector to treat SCIO- X1. We hypothesize that this trial will improve immune reconstitution through the introduction of low dose busulfan conditioning (Aim 1) and improve safety through the change from a gammaretroviral (yRV) vector used in previous trials to the LV vector in this trial (Aim 2). Previous trials of gene therapy for SCIO-X1 have infused cells without chemotherapy conditioning, which resulted in robust T cell recovery and gene marking, but negligible gene marking in B cells and failure of humoral immune reconstitution. Initial development and marking in NK cells was not sustained. In Aim 1 we will examine the impact of low dose busulfan conditioning on 1) cell type specific engraftment and gene marking, 2) in vivo T cell reconstitution, T cell phenotype and TRB repertoire by deep sequencing, 3) in vivo humoral immune reconstitution, B cell number, phenotype, IL-21 dependent function and IGH repertoire by deep sequencing, 4) NK cell number, phenotype and function. Previous trials of gene therapy for SCIO-X1 have used a yRV vector with intact viral promoters/enhancers, which resulted in 5/20 patients developing T cell leukemia due to insertional oncogenesis. Gene therapy using a self-inactivating yRV vector in which viral enhancers have been deleted shows encouraging evidence of reduced insertion sites near lymphoid oncogenes, but an initial insertion site pattern that is still risky. The proposed trial in this application will further improve safety by using a self-inactivating LV vector. In Aim 2 we will investigate the initial insertion site pattern in the patients' C034+ transduced cells and compare samples from the proposed trial to historical trials using yRV, analyze insertion site profile in peripheral blood after gene therapy to perform lineage tracing and compare clustering with samples from previous trials.


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 = $1,305,361 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	1/24/2025	COMPETING CONTINUATION	$1,305,361
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	8	2/19/2025	COMPETING CONTINUATION	$894,481
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	7	2/19/2025	EXTENSION WITH OR WITHOUT FUNDS	-$894,481
														Subtotal = $1,305,361

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	7	1/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	7	12/14/2023	EXTENSION WITH OR WITHOUT FUNDS	$958,572
2024	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	6	12/14/2023	NON-COMPETING CONTINUATION	-$778,478
2024	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	12/14/2023	NON-COMPETING CONTINUATION	-$180,094
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $1,285,631 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	8/29/2023	EXTENSION WITH OR WITHOUT FUNDS	$1,285,631
														Subtotal = $1,285,631

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	4/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $778,478 )
2021	2021	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	6	6/22/2021	NON-COMPETING CONTINUATION	$778,478
2021	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	11/18/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $778,478

Issue Date FY: 2020 ( Subtotal = $982,311 )
2020	2020	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	7/1/2020	NON-COMPETING CONTINUATION	$982,311
														Subtotal = $982,311

Issue Date FY: 2019 ( Subtotal = $1,404,772 )
2019	2019	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	7/12/2019	NON-COMPETING CONTINUATION	$1,404,772
														Subtotal = $1,404,772

Issue Date FY: 2018 ( Subtotal = $1,418,589 )
2018	2018	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	7/3/2018	NON-COMPETING CONTINUATION	$1,418,589
														Subtotal = $1,418,589

Issue Date FY: 2017 ( Subtotal = $598,418 )
2017	2017	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/30/2017	NON-COMPETING CONTINUATION	$598,418
														Subtotal = $598,418

Issue Date FY: 2016 ( Subtotal = $1,132,346 )
2016	2016	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	7/7/2016	NEW	$1,132,346
														Subtotal = $1,132,346

Grand Total All Awards = $8,905,906

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Gene Therapy for SCID-X1 with Low Dose Busulfan and a SIN-lentiviral Vector

Award Number: U01AI125051

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/07/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2024

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