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Enhancing miRNA Therapeutics through Vehicle Free Delivery

Award Number: R01CA205420
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Enhancing miRNA Therapeutics through Vehicle Free Delivery - PROJECT SUMMARY Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of two mRNA vaccines to prevent against SARS-CoV-2 and the first three FDA approved RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to cancer cells is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success in this space is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and cost. Through hard work and dedication in this space, we have come up with an inclusive, easily synthesized, intramolecular molecule that will achieve all of these essential features. Moreover, the ligand used to achieve successful delivery is also being evaluated for imaging tumors localized in the central nervous system. The premise for this work is based on conjugating the tumor suppressive microRNA, miR-34a to 5- methyltetrahydrofolate (5-MTHF), a ligand that is superior for the intended needs, in this case, release from the receptor when an endosomal escape agent is present. Our preliminary data and strong scientific premise supports our objective to i) advance 5-MTHF as a specific and non-toxic therapeutic ligand for delivery of therapeutic miRNAs to triple negative breast cancer (TNBC) and ii) to characterize and prepare 5-MTHF-nigericin conjugated to a fully modified version of miR-34a for clinical trial. To support these objectives, the following Aims will be conducted: 1) To test the hypothesis that both in vivo and intracellular biodistribution of 5-MTHF conjugates are superior to folate conjugates, and 2) To evaluate activity, efficacy, toxicity, pharmacokinetics, dynamics, and combinatorial effects of 5-MTHF-nigericin conjugated to fully modified miR-34a in vivo. At the completion of this work we will have the first an all-encompassing RNAi delivery vehicle that can deliver a stabilized RNA to the intended cells, into the correct subcellular location, with limited toxicity for the treatment of TNBC.


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 = $386,127 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	7	2/28/2025	NON-COMPETING CONTINUATION	$347,515
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	7	5/22/2025	NON-COMPETING CONTINUATION	$38,612
														Subtotal = $386,127

Issue Date FY: 2024 ( Subtotal = $383,350 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	001	6	2/8/2024	COMPETING CONTINUATION	$386,127
2024	2021	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Treatment Research	000	5	2/7/2024	NON-COMPETING CONTINUATION	-$2,777
														Subtotal = $383,350

Issue Date FY: 2021 ( Subtotal = $354,563 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	5	8/10/2021	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2020 ( Subtotal = $354,563 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	4	8/13/2020	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2019 ( Subtotal = $338,785 )
2019	2019	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	3	8/20/2019	NON-COMPETING CONTINUATION	$338,785
														Subtotal = $338,785

Issue Date FY: 2018 ( Subtotal = $349,332 )
2018	2018	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	2	8/29/2018	NON-COMPETING CONTINUATION	$349,332
														Subtotal = $349,332

Issue Date FY: 2017 ( Subtotal = $349,399 )
2017	2017	PURDUE UNIVERSITY	401 SOUTH GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Treatment Research	000	1	9/25/2017	NEW	$349,399
														Subtotal = $349,399

Grand Total All Awards = $2,516,119

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Enhancing miRNA Therapeutics through Vehicle Free Delivery

Award Number: R01CA205420

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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