Wednesday, February 5, 2025 2/5/2025

Hepatic gene transfer for the treatment of hemophilia B and other genetic diseases

Award Number: R01HL064274
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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View Award Abstract

The major objective of our work is to advance the scientific principles governing vector biology that will result in improved gene transfer/genome editing approaches. All of the studies described in this proposal have the potential to enhance gene therapeutics for the treatment of Hemophilias A and B. However, the work outlined in the proposal is a platform technology that will advance gene therapeutics/genome editing. The ultimate goal will be to provide a curative treatment after a single vector dose at the time of diagnosis. This will be important not only for treating hemophilia but other inherited metabolic diseases. Specifically, we propose studies that will further enhance nuclease-free AAV mediated homologous recombination (AAV-HR) strategies. We will determine how factors that include host gene selection, composition of chimeric mRNA transcripts, tissue regeneration, transcription, chromatin, R-loop, and direction and timing of DNA replication affect the efficiency of AAV-HR and AAV-mediated HR transgene expression. We will also pursue preclinical strategies for temporarily knocking down genes encoding proteins in the FANCM protein complex. Furthermore, we study FDA approved drugs, which inhibit the ribonucleotide reductase complex and may enhance AAV-HR in the liver. We will test a novel rAAV capsid variant we previously discovered, which has the capacity to package larger genomes for its ability to package more robust classical AAV-human factor VIII expression cassettes and allow for AAV-HR of the hFVIII coding sequence. The work outlined will not only address mechanistic aspects related to AAV-HR but it will expand the utility of this approach and define potential limits to the current technology.


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 = $631,179 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	23	1/8/2025	NON-COMPETING CONTINUATION	$631,179
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	002	22	1/15/2025	COMPETING CONTINUATION	$4,735
2025	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	21	1/15/2025	NON-COMPETING CONTINUATION	-$4,735
														Subtotal = $631,179

Issue Date FY: 2024 ( Subtotal = $701,277 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	003	22	6/28/2024	COMPETING CONTINUATION	$70,127
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	22	1/25/2024	COMPETING CONTINUATION	$631,150
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	002	21	3/7/2024	NON-COMPETING CONTINUATION	$0
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	21	1/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $701,277

Issue Date FY: 2022 ( Subtotal = $697,224 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	21	7/29/2022	NON-COMPETING CONTINUATION	$697,224
														Subtotal = $697,224

Issue Date FY: 2021 ( Subtotal = $697,224 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	20	6/30/2021	NON-COMPETING CONTINUATION	$697,224
														Subtotal = $697,224

Issue Date FY: 2020 ( Subtotal = $697,224 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	19	6/9/2020	NON-COMPETING CONTINUATION	$697,224
														Subtotal = $697,224

Issue Date FY: 2019 ( Subtotal = $697,224 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	18	8/5/2019	COMPETING CONTINUATION	$697,224
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	002	18	8/15/2019	COMPETING CONTINUATION	$12
2019	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	17	8/15/2019	NON-COMPETING CONTINUATION	-$12
														Subtotal = $697,224

Issue Date FY: 2018 ( Subtotal = $555,896 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	17	5/24/2018	NON-COMPETING CONTINUATION	$555,896
														Subtotal = $555,896

Issue Date FY: 2017 ( Subtotal = $553,368 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	16	5/23/2017	NON-COMPETING CONTINUATION	$553,368
														Subtotal = $553,368

Issue Date FY: 2016 ( Subtotal = $551,004 )
2016	2016	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	15	5/19/2016	NON-COMPETING CONTINUATION	$551,004
														Subtotal = $551,004

Issue Date FY: 2015 ( Subtotal = $549,017 )
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	14	8/3/2015	COMPETING CONTINUATION	-$7,054
2015	2015	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	14	7/22/2015	COMPETING CONTINUATION	$556,071
														Subtotal = $549,017

Issue Date FY: 2014 ( Subtotal = $536,089 )
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	13	2/28/2014	NON-COMPETING CONTINUATION	$43,765
2014	2014	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	13	11/18/2013	NON-COMPETING CONTINUATION	$492,324
														Subtotal = $536,089

Issue Date FY: 2013 ( Subtotal = $520,771 )
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	12	6/27/2013	NON-COMPETING CONTINUATION	$28,445
2013	2013	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	12	12/4/2012	NON-COMPETING CONTINUATION	$492,326
														Subtotal = $520,771

Issue Date FY: 2012 ( Subtotal = $547,029 )
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	11	4/23/2012	NON-COMPETING CONTINUATION	$16,352
2012	2012	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	11	11/25/2011	NON-COMPETING CONTINUATION	$530,677
														Subtotal = $547,029

Issue Date FY: 2011 ( Subtotal = $579,815 )
2011	2011	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	10	11/22/2010	NON-COMPETING CONTINUATION	$542,918
2011	2011	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	10	7/1/2011	NON-COMPETING CONTINUATION	$36,897
														Subtotal = $579,815

Issue Date FY: 2010 ( Subtotal = $587,482 )
2010	2010	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	9	12/18/2009	COMPETING CONTINUATION	$587,482
														Subtotal = $587,482

Issue Date FY: 2008 ( Subtotal = $513,056 )
2008	2008	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	8	3/20/2008	NON-COMPETING CONTINUATION	$513,056
														Subtotal = $513,056

Issue Date FY: 2007 ( Subtotal = $508,011 )
2007	2007	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	7	3/12/2007	NON-COMPETING CONTINUATION	$508,011
														Subtotal = $508,011

Issue Date FY: 2006 ( Subtotal = $507,684 )
2006	2006	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	6	3/15/2006	NON-COMPETING CONTINUATION	$507,684
														Subtotal = $507,684

Issue Date FY: 2005 ( Subtotal = $504,498 )
2005	2005	STANFORD UNIVERSITY	651 SERRA STREET, ROOM 110	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	5	3/22/2005	COMPETING CONTINUATION	$504,498
														Subtotal = $504,498

Grand Total All Awards = $12,867,542

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Hepatic gene transfer for the treatment of hemophilia B and other genetic diseases

Award Number: R01HL064274

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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