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In vivo gene therapy for hemoglobinopathies with multiplexed virus-like particles

Award Number: R01HL136135
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/17/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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In vivo gene therapy for hemoglobinopathies with multiplexed virus-like particles - PROJECT SUMMARY/ABSTRACT Patients with genetic blood diseases and disorders are commonly treated with blood (hematopoietic) stem cell (HSC) transplants from healthy, human leukocyte antigen (HLA)-matched sibling donors. Unfortunately, for most patients, there is no HLA-identical sibling donor available, and transplantation of HSCs from alternative donors can lead to life-threatening complications such as graft-vs-host disease (GVHD). To avoid severe side effects, especially from GVHD, correcting the patient’s own HSCs—a process called gene therapy—has become a promising alternative treatment approach for genetic diseases and disorders affecting the blood. Despite significant progress in the field of HSC gene therapy, currently available treatment strategies are greatly limited by the requirement of highly sophisticated infrastructure in specialized facilities similar to HSC transplantations limiting the application of this treatment to very few patients. The main bottleneck is the current inability to safely and efficiently perform HSC gene therapy directly in the patient (in vivo). The ability to genetically modify HSCs in vivo would improve the feasibility of HSC gene therapy, enable portable gene therapy, and avoid expensive infrastructure. With the aim to refine the target for HSC gene therapy, we performed comprehensive studies in our nonhuman primate (NHP) stem cell transplantation and gene therapy model. This study identified CD90- positive cells as a highly HSC-enriched cell subset that contained all required cells for rapid short-term recovery and robust long-term multilineage engraftment of gene-modified cells providing the ideal target for in vivo gene therapy. More recently, we engineered multiplexed virus-like particles (MVPs) to deliver multiple gene editing base editors (BEs). In synergy, we have recently reported the successful design of CD90-targeting molecules for targeting viral envelopes specifically to HSCs. Finally, we developed novel selection/enrichment/protection strategies to ablate or edit the surface marker CD90 to protect and increase the frequency of successfully edited HSCs in vivo using either anti-CD90 CAR T cells or antibody-drug conjugates (ADCs). Here, we propose to equip nuclease-loaded MVPs with anti-CD90 targeting moieties to specifically deliver gene therapy agents into the HSC-enriched CD90+ subset in vivo. We hypothesize that the delivery of gene-modifying agents using HSC- targeted MVPs will be: 1) highly HSC-specific; 2) portable; 3) cost effective; and 4) versatile for many hematological diseases and disorders. In Aim 1, we will evolve our existing HSC-targeted viral particles to allow multiplex gene editing of a therapeutic transgene simultaneously with CD90 for selection. In Aim 2, we will establish protocols and optimize the application of in vivo selection agents, here specifically the CD90 ADC. In Aim 3, we will employ MVPs directly in vivo followed by selection with CD90 ADCs to stepwise boost the editing efficiency of successfully targeted and protected HSCs.


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: 2026 ( Subtotal = $904,885 )
2026	2026	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	10	8/5/2026	COMPETING CONTINUATION	$905,029
2026	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	9	6/2/2026	NON-COMPETING CONTINUATION	-$144
														Subtotal = $904,885

Issue Date FY: 2024 ( Subtotal = $728,713 )
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	9	6/12/2024	NON-COMPETING CONTINUATION	$59,488
2024	2024	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	9	1/15/2024	NON-COMPETING CONTINUATION	$669,225
														Subtotal = $728,713

Issue Date FY: 2023 ( Subtotal = $767,986 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	8	1/5/2023	NON-COMPETING CONTINUATION	$691,187
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	8	3/3/2023	NON-COMPETING CONTINUATION	$76,799
														Subtotal = $767,986

Issue Date FY: 2022 ( Subtotal = $785,067 )
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	7	6/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$643,127
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	6	6/28/2022	NON-COMPETING CONTINUATION	-$643,127
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	003	7	7/5/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$78,508
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	6	12/31/2021	NON-COMPETING CONTINUATION	$706,559
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	006	7	8/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$117,819
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	005	6	8/31/2022	NON-COMPETING CONTINUATION	-$63,432
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	004	5	8/31/2022	COMPETING CONTINUATION	-$54,387
														Subtotal = $785,067

Issue Date FY: 2021 ( Subtotal = $747,027 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	003	5	7/1/2021	COMPETING CONTINUATION	$76,453
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	004	5	7/3/2021	COMPETING CONTINUATION	$0
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	5	12/30/2020	COMPETING CONTINUATION	$747,027
2021	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	002	4	7/1/2021	NON-COMPETING CONTINUATION	-$76,453
2021	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	4	12/31/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $747,027

Issue Date FY: 2020 ( Subtotal = $921,786 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	4	3/7/2020	NON-COMPETING CONTINUATION	$46,089
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	4	1/17/2020	NON-COMPETING CONTINUATION	$875,697
														Subtotal = $921,786

Issue Date FY: 2019 ( Subtotal = $921,786 )
2019	2019	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	3	1/15/2019	NON-COMPETING CONTINUATION	$921,786
														Subtotal = $921,786

Issue Date FY: 2018 ( Subtotal = $921,786 )
2018	2018	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	001	2	6/9/2018	NON-COMPETING CONTINUATION	$18,436
2018	2018	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	2	1/15/2018	NON-COMPETING CONTINUATION	$903,350
														Subtotal = $921,786

Issue Date FY: 2017 ( Subtotal = $959,786 )
2017	2017	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Blood Diseases and Resources Research	000	1	1/17/2017	NEW	$959,786
														Subtotal = $959,786

Grand Total All Awards = $7,658,822

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In vivo gene therapy for hemoglobinopathies with multiplexed virus-like particles

Award Number: R01HL136135

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/17/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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