Wednesday, July 2, 2025 7/2/2025

Making Oligonucleotides Better Biopharmaceuticals by Steric Protection

Award Number: R01GM121612
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Making Oligonucleotides Better Biopharmaceuticals by Steric Protection - Project Summary/Abstract Oligonucleotides face several biopharmaceutical difficulties, including stability and delivery issues as well as non-hybridization activities such as coagulopathy and unwanted activation of the immune system. We have developed a unique oligonucleotide delivery system, termed pacDNA, which uses a high-density bottlebrush polymer to provide oligonucleotides with binding selectivity. The polymer amounts to an entropic barrier, reducing access to the oligonucleotide by various proteins (and thus side effects) but still allows for unhindered hybridization. This novel strategy not only improves nuclease stability, preserves target-binding capability, and minimizes off-target side effects, but also massively enhances plasma pharmacokinetics, tissue retention, and antisense potency in vivo. Our current studies also reveal that the pacDNA’s pharmacological properties are intimately related to the bottlebrush backbone. In addition, the pacDNA appears to be uniquely capable of evading anti-carrier adaptive immunity, which is useful for therapies that requires long-term/frequent dosing. Finally, the pacDNA deposits into tissues and organs that lack mature delivery technologies for, such as the skin, the skeletal muscle, and the heart. These surprising and enabling discoveries will be the basis for investigations in the next funding period, in which we will 1) explore the property space of the pacDNA structure using a combinatorial polymer library with specific backbone compositions and monomer sequences; 2) probe in vivo properties of the pacDNA in mouse and non-human primate models and how it is able to evade adaptive immunity; and 3) explore the potential of pacDNA to create first/best-in-class therapies that take advantage of its unique strengths using a relevant preclinical disease model (progeria). We anticipate that accomplishment of these objectives will yield significant fundamental understanding of this class of materials and bring us much closer to clinical evaluation of pacDNA.


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 = $426,546 )
2025	2025	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	8	3/25/2025	NON-COMPETING CONTINUATION	$426,546
														Subtotal = $426,546

Issue Date FY: 2024 ( Subtotal = $561,744 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	7	4/30/2024	SUPPLEMENT FOR EXPANSION	$88,145
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	7	6/11/2024	NON-COMPETING CONTINUATION	$47,359
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	7	3/22/2024	NON-COMPETING CONTINUATION	$426,240
														Subtotal = $561,744

Issue Date FY: 2023 ( Subtotal = $485,984 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	6	3/30/2023	COMPETING CONTINUATION	$485,984
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	6	6/13/2023	COMPETING CONTINUATION	$4,011
2023	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	5	6/13/2023	NON-COMPETING CONTINUATION	-$4,011
														Subtotal = $485,984

Issue Date FY: 2021 ( Subtotal = $311,457 )
2021	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	5	8/25/2021	NON-COMPETING CONTINUATION	$311,457
														Subtotal = $311,457

Issue Date FY: 2020 ( Subtotal = $436,225 )
2020	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	7/1/2020	SUPPLEMENT FOR EXPANSION	$127,559
2020	2020	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	4	9/9/2020	NON-COMPETING CONTINUATION	$308,666
														Subtotal = $436,225

Issue Date FY: 2019 ( Subtotal = $312,400 )
2019	2019	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	8/16/2019	NON-COMPETING CONTINUATION	$312,400
														Subtotal = $312,400

Issue Date FY: 2018 ( Subtotal = $309,768 )
2018	2018	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	9/18/2018	NON-COMPETING CONTINUATION	$309,768
														Subtotal = $309,768

Issue Date FY: 2017 ( Subtotal = $318,402 )
2017	2017	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	9/1/2017	NEW	$318,402
														Subtotal = $318,402

Grand Total All Awards = $3,162,526

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Making Oligonucleotides Better Biopharmaceuticals by Steric Protection

Award Number: R01GM121612

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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