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Expanding the Chemical Diversity of Therapeutic Oligonucleotides

Award Number: R01NS104022
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: 09/25/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Expanding the Chemical Diversity of Therapeutic Oligonucleotides - Project Summary/Abstract Therapeutic oligonucleotide compounds (e.g., siRNA, antisense) hold promise as transformative drugs for the treatment of many genetically-defined neurodegenerative disorders, including Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Therapeutic oligonucleotides silence disease genes by targeting and degrading mRNA, thus preventing the expression of toxic gene products. The sequence specificity and long- lasting effect of therapeutic oligonucleotides provide a powerful therapeutic paradigm, as long as they can be delivered to the relevant target tissue. Funded by NINDS, we have identified two classes of therapeutic siRNA that show robust distribution and efficacy in the central nervous system (CNS): di-valent siRNAs and lipophilic conjugates. This discovery has resulted in transformative therapeutic candidates advancing towards formal clinic investigation. Nevertheless, efficient, uniform, long-term, allele-selective, non-toxic delivery remains a significant hurdle in expanding oligonucleotide drugs to treat neurodegenerative disorders. This proposal aims to develop and characterize innovative chemistries that enable uniform distribution, multi-target silencing, and intra-nuclear gene modulation in the CNS in vivo. This proposal describes a class of multivalent siRNA compounds that exhibit complete metabolic stability, robust distribution in the spinal cord and brain (rodents, sheep, NHPs) when infused via cerebrospinal fluid (CSF), efficient uptake by neurons, and potent and durable silencing without toxicity for at least six months after a single injection. While developing CNS-active di-valent siRNAs, we developed stabilizing backbone chemistry called exNA. Here, we propose structure-function studies to investigate how valency (above two), linker, and exNA-based stabilization affect therapeutic activity. Remarkably, increased valency further reduces the rate of CSF clearance, while exNA- based stabilization enhances the duration of effect. In addition, modulating the chemical architecture can shift the intracellular distribution of siRNA from the cytoplasmic to the nucleus to target nuclear-localized mRNA. Finally, the use of orthogonal chemistry to synthesize multi-targeting compounds is essential for treating diseases with complex etiology. Completion of this proposal will: (i) optimize multivalent, ultra-stable configuration that supports uniform, potent, specific, and durable multi-target silencing (longer than six months) in the central nervous system; and (ii) establish a developmental path toward novel combinatorial treatments for HD and ALS. In addition, this proposal seeks to establish a technology platform to directly target any gene or combination of genes expressed in any region of the central nervous system. Successful completion of this work will therefore enable studies of gene function in the central nervous system and the development of novel oligonucleotide-based therapies for genetically defined neurodegenerative 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 = $688,196 )
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/20/2025	NON-COMPETING CONTINUATION	$619,376
2025	2025	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	8/11/2025	NON-COMPETING CONTINUATION	$68,820
														Subtotal = $688,196

Issue Date FY: 2024 ( Subtotal = $667,550 )
2024	2024	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/3/2024	NON-COMPETING CONTINUATION	$667,550
2024	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	9/24/2024	COMPETING CONTINUATION	$670
2024	2021	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	9/24/2024	NON-COMPETING CONTINUATION	-$670
														Subtotal = $667,550

Issue Date FY: 2023 ( Subtotal = $688,196 )
2023	2023	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/29/2023	COMPETING CONTINUATION	$688,196
2023	2021	UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/28/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $688,196

Issue Date FY: 2021 ( Subtotal = $659,650 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/29/2021	NON-COMPETING CONTINUATION	$659,650
														Subtotal = $659,650

Issue Date FY: 2020 ( Subtotal = $659,650 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/14/2020	NON-COMPETING CONTINUATION	$659,650
														Subtotal = $659,650

Issue Date FY: 2019 ( Subtotal = $664,751 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/3/2019	NON-COMPETING CONTINUATION	$664,751
														Subtotal = $664,751

Issue Date FY: 2018 ( Subtotal = $664,751 )
2018	2018	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/22/2018	NON-COMPETING CONTINUATION	$664,751
														Subtotal = $664,751

Issue Date FY: 2017 ( Subtotal = $664,751 )
2017	2017	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE N	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/21/2017	NEW	$664,751
														Subtotal = $664,751

Grand Total All Awards = $5,357,495

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Expanding the Chemical Diversity of Therapeutic Oligonucleotides

Award Number: R01NS104022

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: 09/25/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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