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Identification of novel safe harbors to be used in a gene editing strategy for the treatment of hemophilia A

Award Number: SC2GM136551
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/04/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Identification of novel safe harbors to be used in a gene editing strategy for the treatment of hemophilia A - TITLE Identification of novel safe harbors to be used in a gene editing strategy for the treatment of hemophilia A Project Summary Hemophilia A is a hereditary blood disorder caused by the loss of the functional coagulation factor, factor VIII (fVIII). Prophylactic administration of recombinant fVIII can alleviate blood loss with relatively small amounts of circulating fVIII protein in the bloodstream. However, the current treatment is invasive and expensive, costing upwards of $300,000 per year. In addition, up to 30% of severe hemophilia A patients develop inactivating antibodies to fVIII rendering the current therapy ineffective. As a monogenic disorder, hemophilia A is a promising candidate for gene therapy with a relatively large therapeutic window. Yet, a major barrier to developing gene therapy protocols for hemophilia A has been achieving sufficient expression from fVIII transgenes in a safe controllable manner. In addition, gene therapy protocols for hemophilia A overlook the immunosensitive patient population. In order to combat these shortcomings, we intend to utilize a non-viral genome editing method that will safely control integration and target a high- expression fVIII transgene (HPFVIII) to a specific location in the genome. By exploiting the repair mechanism of homologous recombination, the CRISPR-Cas9 system will be utilized to edit the genome of hematopoietic stem and progenitor cells. Two active loci, the 1) RhD locus and the 2) von Willebrand Factor (vWF) locus, will be evaluated, one for each hemophilia A subpopulation (those without neutralizing antibodies and those containing neutralizing antibodies). Since the RhD locus is disrupted in a substantial portion of the general population and found to be phenotypically asymptomatic, this location in the genome is optimal for addition of an exogenous gene. These studies will confirm the utilization of the RhD locus as a safe harbor extending the application of this study beyond treating individuals with hemophilia A without neutralizing antibodies. The vWF locus, on the other hand, is an attractive locus for the integration of HPFVIII for the correction of hemophilia A in immunosensitive patients. This is due to the confinement of vWF to the α granules of platelets. Thus HPFVIII, if regulated by the same regulatory elements as vWF, would be safely sequestered from the immune system in the granules of platelets until physiologically necessary. These studies will confirm that the sequestration of HPFVIII in platelets is feasible for the treatment of hemophilia A patients that produce inhibitors. In this manner, two novel gene editing protocols for the treatment of the entire hemophilia A population will be evaluated.


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 = -$99,496 )
2025	2022	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	1 WASHINGTON SQ	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	3/12/2025	NON-COMPETING CONTINUATION	-$99,496
														Subtotal = -$99,496

Issue Date FY: 2022 ( Subtotal = $146,500 )
2022	2022	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	3	7/13/2022	NON-COMPETING CONTINUATION	$146,500
														Subtotal = $146,500

Issue Date FY: 2021 ( Subtotal = $146,500 )
2021	2021	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 4TH ST 3RD FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	2	7/30/2021	NON-COMPETING CONTINUATION	$146,500
														Subtotal = $146,500

Issue Date FY: 2020 ( Subtotal = $139,586 )
2020	2020	SAN JOSE STATE UNIVERSITY RESEARCH FOUNDATION	210 FOURTH ST 4TH FL	SAN JOSE	CA	95112	SANTA CLARA	USA	Biomedical Research and Research Training	000	1	8/4/2020	NEW	$139,586
														Subtotal = $139,586

Grand Total All Awards = $333,090

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Identification of novel safe harbors to be used in a gene editing strategy for the treatment of hemophilia A

Award Number: SC2GM136551

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/04/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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