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Engineering AAV for safe and efficient gene delivery to the human retina

Award Number: R01EY024280
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Engineering AAV for safe and efficient gene delivery to the human retina - ABSTRACT This is a competitive renewal of R01EY024280, “Engineering AAV for safe and efficient gene delivery to the human retina”. FDA approval of an Adeno associated virus (AAV)- based gene therapy for RPE65-Leber congenital amaurosis (LCA2) solidified gene therapy’s place in current medical practice. However, in the 6 years since, there have been no additional approvals, and multiple hurdles associated with retinal gene therapy have come to light. The development of therapies that safely and efficiently target the human retina remains a significant, unmet need. In previous funding cycles, we asked questions grounded in both basic and translational science. We have i) elaborated upon biological determinants of retinal transduction by AAV via different routes of administration, ii) identified novel variants with increased potency and neutralizing antibody evasion relative to benchmark vectors and iii) identified a novel variant with the ability to spread laterally beyond the margins of the subretinal injection bleb. Notably, we have also translated our findings- our laterally spreading capsid is being used in an ongoing Phase I/II clinical trial to treat X-linked retinoschisis (NCT05878860). The scope of our proposed studies is broadened based on the advances we’ve made, and our evolving understanding of challenges in the field. A significant portion of the proposed work will be performed in macaques as these challenges are most effectively modeled in intact eyes of animals with ocular characteristics and immune systems most similar to humans. In Aim 1, we explore the biological determinants of retinal transduction by AAV. We will use a novel in-situ visualization approach to analyze retinal glycans and their interactions with the AAV capsid across species, evaluate the role of Müller glia in retinal transduction following intravitreal injection, and determine the retinal distribution of ‘universal AAV’ host cell factors, AAVR and GPR108 and their roles in retinal transduction via multiple routes of administration. In Aim 2, we will enhance transduction and safety of AAV capsids delivered by intravitreal injection. Capitalizing on strong preliminary data, this Aim expands capsid library screening to non-AAV2- based capsids. In Aim 3, we will enhance the biodistribution and safety of AAV capsids delivered by subretinal injection. We propose to block capsid interactions with host cellular factors to limit transduction of peripheral tissues and/or endogenous antigen presenting cells, while simultaneously enhancing PR and/RPE transduction. Vectors and methods investigated in this proposal will have an immediate impact on planned clinical trials to address inherited retinal diseases as well as non-orphan indications such as AMD. Development of these tools by academia (rather than industry) will ensure the availability of shared resources with the broader scientific community.


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 = $637,990 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	002	12	8/4/2025	NON-COMPETING CONTINUATION	$637,990
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	001	11	2/24/2025	COMPETING CONTINUATION	$60,134
2025	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	10	2/24/2025	NON-COMPETING CONTINUATION	-$60,134
														Subtotal = $637,990

Issue Date FY: 2024 ( Subtotal = $651,115 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	11	9/5/2024	COMPETING CONTINUATION	$651,115
														Subtotal = $651,115

Issue Date FY: 2023 ( Subtotal = $673,592 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	10	5/15/2023	NON-COMPETING CONTINUATION	$673,592
														Subtotal = $673,592

Issue Date FY: 2022 ( Subtotal = $653,385 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	9	5/27/2022	NON-COMPETING CONTINUATION	$653,385
														Subtotal = $653,385

Issue Date FY: 2021 ( Subtotal = $687,914 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	8	5/27/2021	NON-COMPETING CONTINUATION	$687,914
														Subtotal = $687,914

Issue Date FY: 2020 ( Subtotal = $694,739 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	7	7/23/2020	NON-COMPETING CONTINUATION	$694,739
														Subtotal = $694,739

Issue Date FY: 2019 ( Subtotal = $703,593 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	001	6	8/29/2019	COMPETING CONTINUATION	$704,894
2019	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	5	8/26/2019	NON-COMPETING CONTINUATION	-$1,301
														Subtotal = $703,593

Issue Date FY: 2018 ( Subtotal = $240,782 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	5	6/19/2018	NON-COMPETING CONTINUATION	$240,782
														Subtotal = $240,782

Issue Date FY: 2017 ( Subtotal = $472,914 )
2017	2017	UNIVERSITY OF FLORIDA	207 GRINTER HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	4	6/19/2017	NON-COMPETING CONTINUATION	$472,914
														Subtotal = $472,914

Issue Date FY: 2016 ( Subtotal = $485,794 )
2016	2016	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	3	5/19/2016	NON-COMPETING CONTINUATION	$485,794
														Subtotal = $485,794

Issue Date FY: 2015 ( Subtotal = $542,844 )
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	2	6/8/2015	NON-COMPETING CONTINUATION	$486,143
2015	2015	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	001	2	9/21/2015	SUPPLEMENT FOR EXPANSION	$56,701
														Subtotal = $542,844

Issue Date FY: 2014 ( Subtotal = $374,584 )
2014	2014	UNIVERSITY OF FLORIDA	PO BOX 113001, 302 TIGERT HALL	GAINESVILLE	FL	32611	ALACHUA	USA	Vision Research	000	1	5/19/2014	NEW	$374,584
														Subtotal = $374,584

Grand Total All Awards = $6,819,246

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Engineering AAV for safe and efficient gene delivery to the human retina

Award Number: R01EY024280

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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