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Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy

Award Number: R01NS120485
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: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy - Summary/Abstract Many of the growing family of over 40 neuromuscular and neurodegenerative repeat expansion diseases, including myotonic dystrophy (DM), involve a strong RNA gain-of- function (GOF) mechanism with toxicity induced by expansion RNAs. In this mechanism, the expanded RNAs sequester RNA binding proteins (RBPs) leading to the disruption of multiple downstream RNA processing pathways. The reduction of the expanded RNAs to alleviate disease mechanism and downstream pathogenesis is therefore an attractive therapeutic approach. We have previously demonstrated promising small molecule efficacy including: (1) actinomycin D mediated selective reduction of transcription from expanded CTG repeats; (2) microtubule inhibitors mediated selective modulation of toxic CUG RNA levels; and (3) diamidines mediated reduction of toxic RNAs. While these results show promise, many of these compounds are toxic and display sub-optimal properties leading us to develop a new set of modified polycyclic compounds (MPCs). These compounds are based on three elements: a heterocyclic core; a benzimidazole side group; and functionalized end groups. Modifying each of these elements provides a large panel of potential compounds to aid in understanding mechanism of action and develop new drug candidates to address the urgent unmet therapeutic need in DM. Preliminary data for two of these MPCs shows robust rescue of splicing in both DM1 and DM2 cell lines in the nanomolar range with little associated toxicity or effects on cell viability as well as rescue of mis-splicing in 2 independent DM mouse models. In this proposal, we will use parallel in vitro and in vivo design-model-test cycles to systematically modify and evaluate compounds by focusing on replacement, testing and refinement of the three MPC elements (core, side and end groups). These data will provide a better understanding of their mechanism of action and be followed by testing of their therapeutic potential in DM patient-derived cell lines and animal models. The successful completion of this project will provide a new class of therapeutic small molecules, a better understanding of their mechanism of action and in vivo data from multiple animal models supporting their future therapeutic potential. Taken together this information will address the large unmet need for therapeutic approaches for DM and provide supporting data towards future clinical studies.


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 = $494,397 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/6/2025	SUPPLEMENT FOR EXPANSION	$69,192
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/24/2025	NON-COMPETING CONTINUATION	$425,205
														Subtotal = $494,397

Issue Date FY: 2024 ( Subtotal = $548,574 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	3/27/2024	SUPPLEMENT FOR EXPANSION	$69,192
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/21/2024	NON-COMPETING CONTINUATION	$432,082
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	4/8/2024	NON-COMPETING CONTINUATION	$33,606
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/26/2024	SUPPLEMENT FOR EXPANSION	$13,694
														Subtotal = $548,574

Issue Date FY: 2023 ( Subtotal = $590,149 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/7/2023	SUPPLEMENT FOR EXPANSION	$45,776
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/7/2023	NON-COMPETING CONTINUATION	$488,445
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/5/2023	SUPPLEMENT FOR EXPANSION	$55,928
														Subtotal = $590,149

Issue Date FY: 2022 ( Subtotal = $509,840 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/22/2022	NEW	$0
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/22/2022	NEW	$509,840
														Subtotal = $509,840

Grand Total All Awards = $2,142,960

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Design, Synthesis and Efficacy of New Small Molecule Therapeutics to Impede Myotonic Dystrophy

Award Number: R01NS120485

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: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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