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Defining the molecular interactions within nanoparticles that enable delivery of long nucleic acids

Award Number: R01EB025192
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Defining the molecular interactions within nanoparticles that enable delivery of long nucleic acids - Project Summary CRISPR/Cas-based gene editing has ushered in a hopeful era that dreams of new therapies for currently untreatable genetic diseases. Because mutated proteins are produced in specific cells, there is a critical need to develop organ- and cell-specific delivery strategies to realize the full potential of genomic medicines. We recently overcame this challenge through development of the first class of non-viral nanoparticles for tissue-specific genome editing. Selective ORgan Targeting (SORT) lipid nanoparticles (LNPs) enable targeted intravenous delivery of nucleic acids and proteins to the lungs, liver, and spleen, plus local delivery to the muscle, brain, and skin. Tropism is driven by inclusion of SORT molecules, which create tissue-selective 5-component SORT LNPs that are compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA / sgRNA, and Cas9 ribonucleoprotein (RNP) complexes. In this grant proposal, we Aim to (1) determine the mechanism of SORT, (2) improve the efficacy and tolerability of liver-, lung-, and spleen-targeting SORT LNPs, and (3) determine the cell-specific gene editing capabilities of SORT LNPs with the potential for expanded tropism. Results will determine the fundamental mechanisms and structure-activity relationships (SAR) for non-viral nanoparticle liver, lung, and spleen tropism. This will ultimately allow targeted and safer CRISPR/Cas gene editing in vivo. We will determine these factors by adapting a unique class of LNPs, called SORT LNPs, that we developed. We will employ human cells and genetically engineered mouse models that allow quantification of precise, cell specific gene editing events. Completion of the proposed studies will (1) Elucidate the fundamental mechanisms how and why SORT LNPs target extrahepatic tissues, (2) Determine how SORT molecules control efficacy and tolerability for improved gene editing outcomes, and (3) Determine and control cell-type gene editing specificity to expand targeted gene editing. Cumulatively, this will open new avenues for CRISPR/Cas-based correction of genetic diseases by developing efficacious, safe, and clinically translatable nanoparticle carriers.


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 = $405,826 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	8	5/7/2025	NON-COMPETING CONTINUATION	$405,826
														Subtotal = $405,826

Issue Date FY: 2024 ( Subtotal = $409,859 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	7	5/31/2024	NON-COMPETING CONTINUATION	$409,859
														Subtotal = $409,859

Issue Date FY: 2023 ( Subtotal = $419,679 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	6	4/18/2023	NON-COMPETING CONTINUATION	$419,679
2023	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	11/28/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $419,679

Issue Date FY: 2022 ( Subtotal = $419,679 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	5	7/6/2022	COMPETING CONTINUATION	$419,679
														Subtotal = $419,679

Issue Date FY: 2021 ( Subtotal = $357,210 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	7/9/2021	NON-COMPETING CONTINUATION	$357,210
														Subtotal = $357,210

Issue Date FY: 2020 ( Subtotal = $364,500 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	6/18/2020	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2019 ( Subtotal = $364,500 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	5/31/2019	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $364,500

Issue Date FY: 2018 ( Subtotal = $364,500 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	8/1/2018	NEW	$364,500
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	1	9/7/2018	NEW	$0
														Subtotal = $364,500

Grand Total All Awards = $3,105,753

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Defining the molecular interactions within nanoparticles that enable delivery of long nucleic acids

Award Number: R01EB025192

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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