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Overcoming Barriers to retinal ganglion cell replacement in experimental glaucoma

Award Number: U24EY033269
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 05/08/2026

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Overcoming Barriers to retinal ganglion cell replacement in experimental glaucoma - Project Summary / Abstract Retinal ganglion cells (RGCs) are the output neurons of the retina responsible for transmitting information about the visual world from the eye to the brain. Thus, RGC damage and loss, a characteristic of many disorders of the visual system, has the direct consequence of vision impairment, or blindness when RGC loss is more severe. Our translation-enabling approach builds on a very well-established, thoroughly characterized and validated experimental glaucoma (EG) model. This affords our study the distinct advantage of conducting each of the proposed hypothesis-driven experiments within the framework of a reliable model of RGC degeneration that closely recapitulates the anatomical changes and pathophysiological processes observed in human glaucoma. Moreover, our preliminary results establish the feasibility of our approach, demonstrating that we have already achieved successful transplantation of human induced pluripotent stem cell (iPSC)-derived RGCs into the EG retina, while also characterizing major barriers that require targeted solutions. Hence, we propose to employ a series of manipulations to both donor RGCs and the recipient EG retina in order to overcome the existing barriers to RGC replacement and thus make a giant leap forward toward realization of the audacious goal to restore vision in persons blinded by glaucoma or other optic neuropathies. Each of our Aims is soundly based on existing knowledge of the relevant biology and will lead to meaningful enhancement of donor RGC survival, integration, and function in the glaucomatous EG retina. We will utilize rigorous quantitative electrophysiological and anatomical assessments for testing the hypothesis at the core of each Aim. Aim 1 will target neuroinflammation to improve the long-term survival of transplanted RGCs. We will create hypoimmunogenic iPSCs and manipulate the host retinal environment using systemic immunosuppressive agents or inhibition of microglial activation. Aim 2 will augment donor cell survival and integration through modulation of cellular age, with host retinal glia experimentally induced to an immature state through cellular rejuvenation. Aim 3 will enhance the connectivity and axon outgrowth of donor RGCs in the retina. Donor RGCs will be edited to express hM3Dq DREADD receptors for chemogenetic stimulation and mTOR activators. Thrombospondin will be overexpressed in host retinal astrocytes and donor RGCs, leveraging astrocyte-derived factors that promote axonal outgrowth and synaptogenesis. Together, these Aims will generate a wealth of knowledge and resources for the scientific community and bring us significantly closer to the reality of vision restoration through RGC replacement.


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 = $0 )
2026	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	4	11/18/2025	OTHER REVISION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,283,906 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	002	5	8/4/2025	NON-COMPETING CONTINUATION	$1,283,906
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	004	5	9/27/2025	NON-COMPETING CONTINUATION	$0
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	001	4	5/29/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	4	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	003	4	8/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,283,906

Issue Date FY: 2024 ( Subtotal = $1,473,917 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	002	4	8/12/2024	SUPPLEMENT FOR EXPANSION	$145,254
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	001	4	7/30/2024	NON-COMPETING CONTINUATION	$1,328,663
2024	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	3	7/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,473,917

Issue Date FY: 2023 ( Subtotal = $1,526,179 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	004	3	9/11/2023	SUPPLEMENT FOR EXPANSION	$93,412
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	001	2	2/6/2023	SUPPLEMENT FOR EXPANSION	$93,412
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	003	3	9/8/2023	NON-COMPETING CONTINUATION	$1,339,355
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	002	2	6/16/2023	NON-COMPETING CONTINUATION	$0
2023	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	2	12/14/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,526,179

Issue Date FY: 2022 ( Subtotal = $1,353,535 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	001	2	8/29/2022	NON-COMPETING CONTINUATION	$1,353,535
2022	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	1	3/14/2022	NEW	$0
														Subtotal = $1,353,535

Issue Date FY: 2021 ( Subtotal = $1,393,605 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	1	9/15/2021	NEW	$1,393,605
														Subtotal = $1,393,605

Grand Total All Awards = $7,031,142

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Overcoming Barriers to retinal ganglion cell replacement in experimental glaucoma

Award Number: U24EY033269

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 05/08/2026

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