Thursday, November 21, 2024 11/21/2024

Mirror Image Aptamers: Next Generation RNA-Binding Reagents for Basic Research and Therapeutic Applications

Award Number: R35GM124974
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract The increasing appreciation of RNA’s structure-function relationships has led to a demand for new technologies that enable targeting of specific RNA structures. However, discovery of molecules that are capable of binding RNA structures with high affinity and selectivity has proven challenging using current approaches, resulting in a technological gap that precludes the development of new research tools to study RNA function and therapeutics to treat RNA-mediated diseases. Thus, development of new technologies that enable structure- specific targeting of RNA remains an important challenge in many fields. The central vision of my research program is to address the deficit of structure-specific RNA-binding reagents using a radically different type of nucleic acid affinity reagent: L-aptamers. L-Aptamers are unique because they are comprised of L-(deoxy)ribose-based nucleic acids (L-DNA and L-RNA), which are mirror images (enantiomers) of natural D-nucleotides. Because oligonucleotides of opposite stereochemistry (D versus L) are incapable of forming contiguous Watson-Crick base pairs with each other, we are able to evolve L-aptamers that adaptively bind structured D-RNA targets through tertiary interactions (shape) rather than primary sequence. This unique “cross-chiral” mode of recognition occurs with high affinity and selectivity, and these interactions can modulate the function of RNA targets through several modes of action. These properties, coupled with the intrinsic nuclease resistance of L-oligonucleotides, provide L-aptamer technology a broad range of opportunities in biomedical research and disease intervention. During the next five years, my research group aims to further develop L-aptamer technology to realize its promise as a practical research and therapeutic tool. We aim to improve the RNA-binding properties of L- aptamers using new in vitro selection strategies and to improve our understanding of cross-chiral recognition by providing the first three-dimensional structure of an L-aptamer-RNA heterochiral complex. Building on our prior work, we will continue to develop L-aptamers as inhibitors of oncogenic microRNAs, representing a promising therapeutic strategy for related cancers. However, we will also pursue several novel applications of L-aptamer technology, including RNA-targeted small molecule drug discovery and intracellular RNA imaging, thereby substantially broadening the impact of this work. Finally, we aim to comprehensively characterize the behavior of L-oligonucleotides in living cells — how they interact with these environments and the potential consequences — the results of which will have a broad impact on the development of all future L-oligonucleotide-based biotechnologies, including L-aptamers.


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 = $0 )
2025	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	6	11/5/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $289,893 )
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	6	8/13/2024	COMPETING CONTINUATION	$289,893
2024	2024	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	002	6	8/27/2024	COMPETING CONTINUATION	$60
2024	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	6/13/2024	NON-COMPETING CONTINUATION	-$60
														Subtotal = $289,893

Issue Date FY: 2021 ( Subtotal = $355,163 )
2021	2021	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	5	8/13/2021	NON-COMPETING CONTINUATION	$355,163
														Subtotal = $355,163

Issue Date FY: 2020 ( Subtotal = $355,929 )
2020	2020	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	4	8/17/2020	NON-COMPETING CONTINUATION	$355,929
														Subtotal = $355,929

Issue Date FY: 2019 ( Subtotal = $356,659 )
2019	2019	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	3	8/23/2019	NON-COMPETING CONTINUATION	$356,659
														Subtotal = $356,659

Issue Date FY: 2018 ( Subtotal = $457,354 )
2018	2018	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	001	2	9/12/2018	SUPPLEMENT FOR EXPANSION	$100,000
2018	2018	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	2	8/30/2018	NON-COMPETING CONTINUATION	$357,354
														Subtotal = $457,354

Issue Date FY: 2017 ( Subtotal = $362,427 )
2017	2017	TEXAS A & M UNIVERSITY	400 HARVEY MITCHELL PKY S STE 300	COLLEGE STATION	TX	77845	BRAZOS	USA	Biomedical Research and Research Training	000	1	9/12/2017	NEW	$362,427
														Subtotal = $362,427

Grand Total All Awards = $2,177,425

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Mirror Image Aptamers: Next Generation RNA-Binding Reagents for Basic Research and Therapeutic Applications

Award Number: R35GM124974

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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