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Multi-Targeting Oligonucleotide Therapeutics for Familial and Sporadic Amyotrophic Lateral Sclerosis

Award Number: R01NS111990
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: 05/15/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2029

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Multi-Targeting Oligonucleotide Therapeutics for Familial and Sporadic Amyotrophic Lateral Sclerosis - Project Summary Neurodegenerative diseases are devastating age-related disorders that represent a tremendous disease burden worldwide. The need for effective therapies is increasingly urgent as the population ages. Most familial adult-onset neurodegenerative disorders are caused by dominantly-transmitted gene defects (e.g. C9ORF72 and SOD1 in ALS, HTT in Huntington’s, α-synuclein in Parkinson’s). Thus, one approach toward primary therapy for such disorders is to suppress expression of the offending genes. RNA-targeted medicines, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are a promising class of therapeutics for dominantly-inherited neurodegenerative disorders. Two ASOs have been approved to treat spinal muscular atrophy and SOD1-dependent ALS, while dozens of others are in clinical trials for Huntington’s, Alzheimer’s disease, ALS, Parkinson’s disease, genetic epilepsies, and more. Nevertheless, there are two key unmet needs in the field of RNA-targeted medicines which require urgent and focused investment. The first is that the phosphorothioate backbone used in most oligonucleotide drugs often causes some toxicity when administered into the central nervous system, giving these drugs a narrow therapeutic index. The second key unmet need is that for many neurodegenerative diseases, silencing one gene may not be sufficient to provide a meaningful change in disease course. Given the complexity of many of these diseases, target combinations are likely to have a broader effect on the outcomes than single targets. We have developed a platform technology that addresses both of these limitations: during the first term of our R01 we found that a conjugated molecule containing an siRNA domain and an ASO domain shows very high safety and efficacy throughout the CNS. We will further develop this ‘platform technology’, seek to understand the mechanism for its high safety and efficacy relative to previous technologies, and test its ability to modulate the expression and processing of targets relevant to ALS. Applying these insights, we will advance six drug candidates for ALS into extensive testing in iPSC-derived neurons and animal models of ALS. We will examine the safety, efficacy and duration of effect of our advanced molecules both at the molecular level and at the level of change in disease phenotype. In this proposal, our laboratories will combine innovative chemistry with deep expertise in neurology and disease-relevant mouse models. We aim to develop broadly applicable platform technology with a substantial improvement in therapeutic index relative to the ASOs and siRNAs currently in clinical development. Moreover, we will develop three drugs that silence pairs of targets, and another three drugs that silence one target in combination with splice modulation of a second target. Successful completion of our work would allow these candidates to reach the point of readiness for IND-enabling studies and clinical development for the treatment of familial and sporadic ALS.


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 = $665,737 )
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	002	7	5/13/2025	NON-COMPETING CONTINUATION	$665,737
2025	2024	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	2/27/2025	COMPETING CONTINUATION	$24,778
2025	2023	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	2/27/2025	NON-COMPETING CONTINUATION	-$24,778
														Subtotal = $665,737

Issue Date FY: 2024 ( Subtotal = $665,737 )
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	001	6	5/20/2024	COMPETING CONTINUATION	$665,737
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	000	5	5/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $665,737

Issue Date FY: 2023 ( Subtotal = $635,090 )
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	000	5	3/22/2023	NON-COMPETING CONTINUATION	$635,090
														Subtotal = $635,090

Issue Date FY: 2022 ( Subtotal = $635,090 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/1/2022	NON-COMPETING CONTINUATION	$635,090
														Subtotal = $635,090

Issue Date FY: 2021 ( Subtotal = $635,090 )
2021	2021	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/18/2021	NON-COMPETING CONTINUATION	$635,090
														Subtotal = $635,090

Issue Date FY: 2020 ( Subtotal = $635,090 )
2020	2020	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/3/2020	NON-COMPETING CONTINUATION	$635,090
														Subtotal = $635,090

Issue Date FY: 2019 ( Subtotal = $660,421 )
2019	2019	UNIVERSITY OF MASSACHUSETTS	55 LAKE AVE NORTH	WORCESTER	MA	01655	WORCESTER	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/1/2019	NEW	$660,421
														Subtotal = $660,421

Grand Total All Awards = $4,532,255

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Multi-Targeting Oligonucleotide Therapeutics for Familial and Sporadic Amyotrophic Lateral Sclerosis

Award Number: R01NS111990

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: 05/15/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2029

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