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Repair of neurological disorders through RNA editing

Award Number: R01NS110868
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Repair of neurological disorders through RNA editing - Project Summary In this revised proposal, we continue to develop an approach to repair base mutations at the level of RNA, for attenuating symptoms in mouse models of human neurological disease. The experiments are an outgrowth of a pilot NIH Director’s Transformative Research Award that supported both recently published and preliminary results attesting to feasibility of this approach. Our work is currently focused on Rett syndrome, a devastating neurological disease due to mutations in the gene encoding the transcription factor, MECP2. We focused initially on a human patient guanosine (G) to adenosine (A) mutation in MECP2, MECP2317G>A, which interferes severely with its ability to bind to chromatin and results in Rett syndrome. We showed, for the first time, that endogenous Mecp2317G>A RNA can be recoded to the wild type amino acid efficiently in non-dividing neurons cultured from a Mecp2317G>A mouse line that exhibits severe Rett-like symptoms. The recoding occurred through site- directed deamination by a hijacked catalytic domain of Adenosine Acting on RNA 2 (ADAR2) (Editase), fused to a bacteriophage RNA binding peptide, which we targeted to the Mecp2 mutation by an RNA guide. In this revised application, we present new data indicating that recoding also occurs in vivo, in 3 different hippocampal neuronal populations, after direct hippocampal injection of AAV encoding the hybrid ADAR2 protein and Mecp2 RNA guides. Moreover, recoding resulted in amount of MeCP2 localization to chromatin consistent with amount of editing at the RNA level. We have developed the tools and reagents that now place us in an ideal position to address critical unanswered questions for reversing neurological phenotypes of Rett syndrome, and for testing hypotheses related to site-directed repair. In Aim 1, we test the hypotheses that brain-wide repair of Mecp2317G>A RNA, by site-directed editing, can be tuned to high efficiency and specificity in mice, and restores proper chromatin interaction. For this purpose, we perform whole transcriptomic RNA seq analysis across the brain after peripheral injections of an efficient brain AAV serotype virus encoding optimized editing or control components. In Aim 2, we test new guides for the ability to recruit endogenous ADAR2 to mutant Mecp2 RNA in vivo, circumventing potential immune responses to the bacteriophage moiety in the hybrid ADAR2 protein and potentially minimizing off-target editing. Our initial model is Mecp2311G>A that has the ideal nonsense codon for this approach. In Aim 3, we inject peripherally the virus encoding our current and optimized editing components, or controls, to test our hypothesis that site-directed RNA editing can stabilize/reverse Rett-like symptoms in both Mecp2G>A mouse lines. In addition to Rett syndrome, our approach has the potential to cure thousands of additional pathogenic G>A mutations.


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 = $0 )
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $326,770 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/5/2023	NON-COMPETING CONTINUATION	$303,188
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/23/2024	NON-COMPETING CONTINUATION	$23,582
														Subtotal = $326,770

Issue Date FY: 2023 ( Subtotal = $336,875 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/15/2022	NON-COMPETING CONTINUATION	$303,188
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/31/2023	NON-COMPETING CONTINUATION	$33,687
														Subtotal = $336,875

Issue Date FY: 2022 ( Subtotal = $336,875 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/24/2021	NON-COMPETING CONTINUATION	$303,187
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/10/2022	NON-COMPETING CONTINUATION	$33,688
														Subtotal = $336,875

Issue Date FY: 2021 ( Subtotal = $336,875 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/5/2021	NON-COMPETING CONTINUATION	$33,688
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/30/2020	NON-COMPETING CONTINUATION	$303,187
														Subtotal = $336,875

Issue Date FY: 2020 ( Subtotal = $336,875 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/13/2019	NEW	$336,875
														Subtotal = $336,875

Grand Total All Awards = $1,674,270

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Repair of neurological disorders through RNA editing

Award Number: R01NS110868

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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