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Precision Medicine for Inherited Retinal Degenerations

Award Number: R01EY012910
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/08/1999
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Precision Medicine for Inherited Retinal Degenerations - Project Summary/Abstract The long-term goals of the proposed research are to identify the genetic causes of inherited retinal degenerations (IRDs), define the mechanisms by which mutations in IRD disease genes lead to retinal degeneration, and to use this information to develop effective therapies to prevent vision loss from these blinding disorders. IRDs are important causes of vision loss that affect people across the age spectrum. While great progress has been made identifying the genetic causes of IRDs, approximately 1/3rd of patients have genetic causality that remains elusive. Further, the mechanisms by which mutations in specific IRD disease genes cause retinal degeneration remain to be defined for the majority of IRD disease genes. Identifying the genetic causes of IRDs and the mechanisms of disease pathogenesis has become especially important as genetic therapies such as gene augmentation therapy and neuroprotective therapies show great promise for the treatment of IRDs. But several challenges remain to be addressed to succeed with broad application of genetically informed therapies for IRDs. These include the need to define genetic causality for the 1/3rd of patients with elusive genetic causes of disease, and the need to more completely define the cellular mechanisms that connect mutations in a given gene with photoreceptor and RPE degeneration. The goal of Aim 1 is to address the first of these challenges. Evidence suggests that the majority of IRD disease genes have been identified, leading to the hypothesis that much of the missing genetic causality in the 1/3rd of IRD patients resides in the non-coding portions of the currently known IRD disease genes. It is challenging, however, to determine which of the 100s of rare deep intronic variants identified by whole genome sequencing (WGS) in IRD genes in patients with IRDs are pathogenic. In Aim 1 a novel high throughput splicing assay (HTSA) will be used to empirically test the functional effects of rare deep intronic variants identified in patients with IRDs and to prospectively characterize rare deep intronic variants in actionable IRD genes. The goal of Aim 2 is to address the second challenge by studying the mechanisms by which mutations in NMNAT1 cause severe early onset IRD. Despite being required for nuclear NAD+ synthesis in all cells, reduced NMNAT1 function causes retina-specific disease in most patients. Data from studies using a mouse model of NMNAT1- associated disease suggest that photoreceptor cells have the greatest demand for DNA repair of any cells in the human body and thus are the most vulnerable to reduced NMNAT1 function. To identify the source(s) of the DNA damage that underlie this high demand for DNA repair in photoreceptor cells the DNA modifications that accumulate and the DNA damage response pathways that are activated in mouse and human models of NMNAT1-associated disease will be studied in Aim 2. The results of these studies could inform development of additional therapies for NMNAT1-associated IRD, and potentially other forms of IRD as well.


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 = $641,107 )
2025	2025	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	28	7/29/2025	NON-COMPETING CONTINUATION	$641,107
														Subtotal = $641,107

Issue Date FY: 2024 ( Subtotal = $640,774 )
2024	2024	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	27	7/19/2024	NON-COMPETING CONTINUATION	$640,774
2024	2023	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	26	7/9/2024	COMPETING CONTINUATION	$1,827
2024	2022	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	25	7/9/2024	NON-COMPETING CONTINUATION	-$1,827
														Subtotal = $640,774

Issue Date FY: 2023 ( Subtotal = $640,439 )
2023	2023	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	26	8/4/2023	COMPETING CONTINUATION	$640,439
														Subtotal = $640,439

Issue Date FY: 2022 ( Subtotal = $676,658 )
2022	2022	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	25	7/18/2022	NON-COMPETING CONTINUATION	$676,658
														Subtotal = $676,658

Issue Date FY: 2021 ( Subtotal = $686,713 )
2021	2021	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	24	7/20/2021	NON-COMPETING CONTINUATION	$643,375
2021	2021	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	24	7/26/2021	SUPPLEMENT FOR EXPANSION	$43,338
														Subtotal = $686,713

Issue Date FY: 2020 ( Subtotal = $663,274 )
2020	2020	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	23	7/20/2020	NON-COMPETING CONTINUATION	$663,274
														Subtotal = $663,274

Issue Date FY: 2019 ( Subtotal = $663,274 )
2019	2019	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	22	9/11/2019	NON-COMPETING CONTINUATION	$663,274
2019	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	20	2/10/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $663,274

Issue Date FY: 2018 ( Subtotal = $663,274 )
2018	2018	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	21	8/15/2018	COMPETING CONTINUATION	$663,274
														Subtotal = $663,274

Issue Date FY: 2017 ( Subtotal = $575,381 )
2017	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	20	7/27/2017	NON-COMPETING CONTINUATION	$575,381
2017	2015	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	18	2/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $575,381

Issue Date FY: 2016 ( Subtotal = $576,380 )
2016	2016	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	19	7/21/2016	EXTENSION WITH OR WITHOUT FUNDS	$576,380
														Subtotal = $576,380

Issue Date FY: 2015 ( Subtotal = $565,801 )
2015	2015	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	18	7/9/2015	NON-COMPETING CONTINUATION	$565,801
														Subtotal = $565,801

Issue Date FY: 2014 ( Subtotal = $778,725 )
2014	2014	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	17	8/6/2014	NON-COMPETING CONTINUATION	$566,725
2014	2014	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	17	9/16/2014	SUPPLEMENT FOR EXPANSION	$212,000
														Subtotal = $778,725

Issue Date FY: 2013 ( Subtotal = $585,000 )
2013	2013	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	16	7/25/2013	COMPETING CONTINUATION	$585,000
														Subtotal = $585,000

Issue Date FY: 2012 ( Subtotal = $514,795 )
2012	2012	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	15	7/23/2012	NON-COMPETING CONTINUATION	$514,795
2012	2011	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	14	1/12/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$45,079
2012	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	001	13	1/12/2012	NON-COMPETING CONTINUATION	$45,079
														Subtotal = $514,795

Issue Date FY: 2011 ( Subtotal = $514,347 )
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	001	13	8/31/2011	NON-COMPETING CONTINUATION	-$471,484
2011	2011	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	000	13	6/29/2011	NON-COMPETING CONTINUATION	$514,347
2011	2011	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	14	9/2/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$471,484
														Subtotal = $514,347

Issue Date FY: 2010 ( Subtotal = $524,862 )
2010	2010	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	000	12	6/30/2010	NON-COMPETING CONTINUATION	$524,862
														Subtotal = $524,862

Issue Date FY: 2009 ( Subtotal = $501,178 )
2009	2009	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	001	11	7/20/2009	COMPETING CONTINUATION	$501,178
2009	2008	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	000	10	7/20/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $501,178

Issue Date FY: 2008 ( Subtotal = $436,820 )
2008	2008	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	000	10	6/4/2008	NON-COMPETING CONTINUATION	$436,820
														Subtotal = $436,820

Issue Date FY: 2007 ( Subtotal = $1,200,973 )
2007	2007	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	001	9	9/17/2007	SUPPLEMENT FOR EXPANSION	$763,280
2007	2007	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Vision Research	000	9	6/21/2007	NON-COMPETING CONTINUATION	$437,693
														Subtotal = $1,200,973

Grand Total All Awards = $15,497,456

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Precision Medicine for Inherited Retinal Degenerations

Award Number: R01EY012910

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/08/1999

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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