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Immunology of factor IX gene transfer to liver

Award Number: R01AI051390
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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ABSTRACT Adeno-associated viral (AAV) vectors are in advanced clinical development for treatment of multiple genetic diseases. Nevertheless, unexpected immune responses have substantially slowed down clinical advances, as for instance in the case of the X-linked bleeding disorder hemophilia, where activation of CD8+ T cells continues to cause complications for patients. For example, CD8+ T cells directed against AAV capsid target transduced human hepatocytes thus causing liver toxicity and loss of expression. Similarly, upon gene transfer into skeletal muscle aimed at treating a variety of genetic diseases, CD8+ T cell responses directed against capsid, and in some patients against the transgene product, were observed. These were often associated with prolonged inflammation and resulted in cytotoxicity and/or cytokine production and partial loss of expression. Another major concern for many replacement therapies is antibody formation against the transgene product, which we have extensively addressed in previous funding cycles. Our key discovery that hepatic AAV gene transfer can induce immune tolerance to the transgene product (partly through induction of regulatory T cell, Treg) facilitated the establishment of effective clinical gene therapies for hemophilia, as well as the pre-clinical development of immune modulatory gene therapies for multiple diseases. We have since established several alternative methods to prevent or reverse antibody formation against therapeutic proteins. Because of the clinical observations summarized above, we are now performing in-depth studies on the mechanism of CD8+ T cell activation in AAV gene transfer. We have also identified novel approaches to prevent such responses by blocking require innate immune signals. To address major gaps in knowledge on CD8+ T cell activation in response to AAV and to reduce immunogenicity of AAV gene transfer, we propose to define the mechanism of dendritic cell licensing in AAV gene transfer; to define the mechanisms that lead to transgene product-specific CD8+ T cell responses; and to develop innate immune blockade to prevent CD8+ T cell activation upon AAV- FIX gene transfer.


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: 2024 ( Subtotal = $0 )
2024	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	22	11/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $393,750 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	22	11/9/2021	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2021 ( Subtotal = $393,750 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	21	12/1/2020	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2020 ( Subtotal = $393,750 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	20	11/22/2019	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2019 ( Subtotal = $393,750 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	19	11/21/2018	NON-COMPETING CONTINUATION	$393,750
2019	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	17	2/22/2019	COMPETING CONTINUATION	-$159,160
2019	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	002	18	2/22/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$159,160
														Subtotal = $393,750

Issue Date FY: 2018 ( Subtotal = $388,532 )
2018	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	004	18	7/26/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$229,372
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	17	3/13/2018	COMPETING CONTINUATION	$78,201
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	17	11/16/2017	COMPETING CONTINUATION	$381,250
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	003	17	7/26/2018	COMPETING CONTINUATION	-$222,090
2018	2017	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	16	3/13/2018	NON-COMPETING CONTINUATION	-$78,201
														Subtotal = $388,532

Issue Date FY: 2017 ( Subtotal = $337,500 )
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	16	11/23/2016	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $337,500

Issue Date FY: 2016 ( Subtotal = $337,500 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	15	11/17/2015	EXTENSION WITH OR WITHOUT FUNDS	$337,500
														Subtotal = $337,500

Issue Date FY: 2015 ( Subtotal = $337,500 )
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	14	11/13/2014	NON-COMPETING CONTINUATION	$337,500
														Subtotal = $337,500

Issue Date FY: 2014 ( Subtotal = $336,188 )
2014	2014	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	13	6/9/2014	NON-COMPETING CONTINUATION	$33,619
2014	2014	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	13	11/15/2013	NON-COMPETING CONTINUATION	$302,569
														Subtotal = $336,188

Issue Date FY: 2013 ( Subtotal = $315,135 )
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	12	6/3/2013	COMPETING CONTINUATION	$13,410
2013	2013	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	12	11/27/2012	COMPETING CONTINUATION	$301,725
														Subtotal = $315,135

Issue Date FY: 2012 ( Subtotal = $326,329 )
2012	2012	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	11	5/29/2012	NON-COMPETING CONTINUATION	$32,633
2012	2012	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	11	11/15/2011	NON-COMPETING CONTINUATION	$293,696
														Subtotal = $326,329

Issue Date FY: 2011 ( Subtotal = $323,609 )
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	10	11/26/2010	NON-COMPETING CONTINUATION	$294,190
2011	2011	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	10	6/6/2011	NON-COMPETING CONTINUATION	$29,419
														Subtotal = $323,609

Issue Date FY: 2010 ( Subtotal = $294,512 )
2010	2010	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	9	11/16/2009	NON-COMPETING CONTINUATION	$294,512
														Subtotal = $294,512

Issue Date FY: 2009 ( Subtotal = $355,568 )
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	002	8	9/21/2009	NON-COMPETING CONTINUATION	$28,021
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	001	8	6/23/2009	NON-COMPETING CONTINUATION	$32,754
2009	2009	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	8	10/29/2008	NON-COMPETING CONTINUATION	$294,793
														Subtotal = $355,568

Issue Date FY: 2008 ( Subtotal = $325,028 )
2008	2008	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	7	12/24/2007	COMPETING CONTINUATION	$325,028
														Subtotal = $325,028

Issue Date FY: 2006 ( Subtotal = $248,642 )
2006	2006	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	6	6/30/2006	NON-COMPETING CONTINUATION	$248,642
														Subtotal = $248,642

Issue Date FY: 2005 ( Subtotal = $263,200 )
2005	2005	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Allergy and Infectious Diseases Research	000	5	9/15/2005	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$203,700
2005	2005	CHILDREN'S HOSPITAL OF PHILADELPHIA	34TH ST & CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	3/11/2005	NON-COMPETING CONTINUATION	$59,500
														Subtotal = $263,200

Issue Date FY: 2004 ( Subtotal = $297,500 ) (Continued on the next page)
Grand Total All Awards = $6,650,443

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Immunology of factor IX gene transfer to liver

Award Number: R01AI051390

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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