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CRISPR Based Rescue of Glaucoma in Lowe Syndrome

Award Number: R01EY025295
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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CRISPR Based Rescue of Glaucoma in Lowe Syndrome - ABSTRACT Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by bilateral congenital cataracts and glaucoma, renal tubular dysfunction, and mental retardation. Mutations in OCRL1, an inositol polyphosphate 5-phosphatase, cause Lowe syndrome. Despite the identification of OCRL1 as the causal gene underlying this rare disease, there is currently no therapy for Lowe syndrome. Children with Lowe syndrome often go blind due to glaucomatous optic neuropathy. We have developed a novel CRISPR-based approach to transcriptionally regulate the inositol enzymes that control the substrate of OCRL. We have developed a nuclease-deficient Cas protein that allows activation or inactivation of endogenous genes. Our preliminary data shows a novel hypercompact CasMINI for gene editing in a single viral package that allows “Plug-and-Play” delivery. We also established a nuclease-deficient CRISPR-CasMINI (dCasMINI) for gene transcriptional activation of protein expression, with functional rescue in vivo. We also established human Lowe syndrome-based human iPS stem cells, mouse and zebrafish models, and viral delivery approaches for in vivo therapies. We hypothesize that CRISPR-Cas based rescue strategies for inositol 5-phosphatases will restore the imbalance due to the loss of OCRL in Lowe syndrome. Our aims are to (1) transcriptionally activate a compensatory 5-phosphatase that degrades PI(4,5)P2, (2) generate exon-skipping transcripts to reduce OCRL loss phenotypes in human iPS models of Lowe syndrome, (3) use CRISPR-Pass strategy with both adenosine base editors and prime editors to correct OCRL gene mutations in Lowe patient derived cells. We anticipate this work will provide critical insights into how CRISPR-Cas can be used to rescue the loss of OCRL and provide important translation approaches for Lowe syndrome and then expanded to treat other forms of inherited genetic eye diseases.


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 = $613,140 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	7	6/10/2025	NON-COMPETING CONTINUATION	$613,140
														Subtotal = $613,140

Issue Date FY: 2024 ( Subtotal = $613,140 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	6	4/30/2024	COMPETING CONTINUATION	$613,140
														Subtotal = $613,140

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	5	8/30/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $295,813 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	5	2/25/2020	NON-COMPETING CONTINUATION	$295,813
														Subtotal = $295,813

Issue Date FY: 2019 ( Subtotal = $323,810 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	4	6/14/2019	NON-COMPETING CONTINUATION	$323,810
														Subtotal = $323,810

Issue Date FY: 2018 ( Subtotal = $376,593 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	3	5/4/2018	NON-COMPETING CONTINUATION	$37,661
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	3	3/16/2018	NON-COMPETING CONTINUATION	$338,932
														Subtotal = $376,593

Issue Date FY: 2017 ( Subtotal = $369,233 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	003	2	9/18/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$208,820
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	2	7/17/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$310,148
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	004	2	9/19/2017	SUPPLEMENT FOR EXPANSION	$59,085
2017	2016	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	000	1	7/17/2017	NEW	$0
2017	2016	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Vision Research	002	1	9/18/2017	NEW	-$208,820
														Subtotal = $369,233

Issue Date FY: 2016 ( Subtotal = $312,000 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	509 EAST 3RD STREET	BLOOMINGTON	IN	47405	MONROE	USA	Vision Research	000	1	2/18/2016	NEW	$312,000
														Subtotal = $312,000

Grand Total All Awards = $2,903,729

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CRISPR Based Rescue of Glaucoma in Lowe Syndrome

Award Number: R01EY025295

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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