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Precision Base Editing for the Treatment of Motor Neuron Diseases

Award Number: R00NS119743
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: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Precision Base Editing for the Treatment of Motor Neuron Diseases - Motor neuron diseases (MNDs) such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are a class of progressive neurodegeneration disorders, often caused by minor genetic abnormalities to which motor neurons are particularly vulnerable. Because each of these diseases is rare and the molecular pathologies so diverse and unresolved, it is hard to envision a therapeutic intervention tailored to each individually, or a single treatment to effectively treat them all. Current genome editing tools are easily programmable to target discrete genomic loci and affected tissues of MNDs are largely similar. Thus, a general genome editing therapeutic strategy for MNDs fitted to each mutation could meet this urgent need. Base editing tools can theoretically correct any C:G>T:A and A:T>G:C transition, yet the factors that determine efficiency and precision of base editing are not fully understood, and editing outcomes at a given locus are frequently unpredictable. For the development of base editing correction strategies at a great number of loci, screening through a multitude of base editor variants – currently any permutation of >10 deaminase enzymes and >15 Cas proteins, and counting – and sgRNA combinations for every target is prohibitive. A clear understanding of Cas protein, deaminase, and sequence determinants of editing outcomes is needed to facilitate the design of base editing strategies. We intend to develop a general workflow to design effective base editing strategies for causal MND SNPs and deliver these tools to MND affected tissues. SMA is a monogenic MND with a well-defined genetic cause, and animal models harboring the human causal gene that faithfully recapitulate disease phenotypes of SMA patients. Successful development of an effective and safe SMA genome editing treatment will assist the development of similar genome editing therapeutics for other genetic MNDs, including some forms of familial ALS. In this project we will (1) create a computational predictive model of base editing to facilitate the design of effective base editing strategies; (2) develop protocols to efficiently deliver base editing therapeutics to disease relevant tissues in mice to enable genome editing; and (3) use this pipeline to optimize a base editing therapeutic to rescue SMA in mice, and develop genome editing therapeutics for other causal MND mutations, focusing first on the most common single point mutation causal to ALS in North America, SOD1A4V. I will take advantage of the world-class genomics environment of the Broad Institute and the expertise in AAV-delivery at the Stanley Center for Psychiatric Research to realize these goals and develop skills that will help me to continue this work as an independent investigator. Through mentorship meetings and courses on grant-writing and data visualization I will improve my science-communication skills so that I may compete successfully for additional NIH R01 and R21 funding as a faculty member. By attending conferences and publishing my work I intend to establish myself as leader in the field of therapeutic genome editing for MND.


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 = $249,000 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	2/24/2026	NON-COMPETING CONTINUATION	$24,899
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/15/2026	NON-COMPETING CONTINUATION	$224,101
														Subtotal = $249,000

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $314,756 )
2024	2024	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	7/1/2024	NON-COMPETING CONTINUATION	$241,531
2024	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/20/2024	EXTENSION WITH OR WITHOUT FUNDS	$73,225
														Subtotal = $314,756

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/13/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $812,756

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Precision Base Editing for the Treatment of Motor Neuron Diseases

Award Number: R00NS119743

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: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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