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Understanding the Relationship LNP Structure, Cholesterol Trafficking, and InVivo Delivery

Award Number: R01GM132985
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: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Understanding the Relationship LNP Structure, Cholesterol Trafficking, and InVivo Delivery - Project Summary Scientists can create thousands of chemically distinct nanoparticles using a growing number of high throughput chemistries, but it is still difficult to test more than a few nanoparticles in vivo. The goal of this work is to substantially improve how lipid nanoparticles (LNPs) deliver nucleic acid therapies by performing a systematic high throughput in vivo LNP study. This goal will be achieved using cutting edge DNA barcoded nanoparticles; deliverer mediated by 300 different nanoparticles can be measured in a single mouse. 4,320 chemically distinct nanoparticles will be tested in vitro and in vivo, focusing on 2 fundamental questions. First, how does nanoparticle structure affect cell targeting in vivo? Nanoparticle chemical and physical traits affect delivery in vitro. However, the extent to which the same LNP traits influence delivery in animals (in vivo) is unclear. A recently developed bioinformatics pipeline will be used to (i) systematically analyze how LNP structure affects in in vivo delivery in macrophages, endothelial cells, and hepatocytes, both in vitro and in vivo. The same data will be used to (ii) quantify the precision with which in vitro drug delivery predicts in vivo drug delivery. Second, how do clinically relevant physiological changes affect delivery in vivo? LNPs are similar to lipoproteins, which are natural lipid-containing nanostructures. Lipoproteins are actively trafficked to endothelial cells, macrophages, and hepatocytes in vivo. Given that lipoprotein trafficking changes in patients with high cholesterol, taking statins, and patients with many other conditions, LNP transport may also change. The top 600 in vivo LNPs from the 4,320 LNP in vivo screen will be administered to genetic mouse models of aberrant lipid transport in order to (iii) investigate how genetic alterations in cholesterol trafficking affect in vivo delivery. This work will make 5 significant contributions to nanotechnology. First, the extent to which LNP chemical traits influence delivery directly in vivo will be tested; relationships between nanoparticle structure and delivery are studied in vitro. Second, the precision with which in vitro nanoparticle delivery predicts in vivo delivery will be quantified. This could increase the efficiency with which clinical nanoparticles are discovered. Third, the effect of clinically relevant physiological changes on LNP delivery will be examined. Nanoparticles can interact with cholesterol trafficking pathways; these interactions are likely to change with disease and can affect nanoparticle targeting / safety. Fourth, the feasibility of studying thousands of LNPs in vivo will be demonstrated. Fifth, open source protocols for nanoparticle barcoding will be established and disseminated. These results will provide crucial insight into the ways LNP chemical traits and specific genes alter LNP delivery, informing the design of LNPs that deliver nucleic acid cargos (e.g., siRNA, mRNA, CRISPR-Cas9) for numerous therapeutic applications.


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 = -$7,299 )
2025	2023	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Biomedical Research and Research Training	000	6	11/26/2024	NON-COMPETING CONTINUATION	-$7,299
														Subtotal = -$7,299

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Biomedical Research and Research Training	001	5	8/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$7,214
2024	2022	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Biomedical Research and Research Training	000	4	8/20/2024	NON-COMPETING CONTINUATION	-$7,214
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $480,574 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Biomedical Research and Research Training	002	6	7/17/2023	NON-COMPETING CONTINUATION	$398,402
2023	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Biomedical Research and Research Training	001	5	2/10/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$377,924
2023	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Biomedical Research and Research Training	000	4	2/9/2023	NON-COMPETING CONTINUATION	-$295,752
														Subtotal = $480,574

Issue Date FY: 2022 ( Subtotal = $396,493 )
2022	2022	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Biomedical Research and Research Training	000	4	5/18/2022	NON-COMPETING CONTINUATION	$396,493
														Subtotal = $396,493

Issue Date FY: 2021 ( Subtotal = $371,835 )
2021	2021	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Biomedical Research and Research Training	000	3	8/20/2021	NON-COMPETING CONTINUATION	$371,835
														Subtotal = $371,835

Issue Date FY: 2020 ( Subtotal = $370,620 )
2020	2020	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Biomedical Research and Research Training	001	2	5/27/2020	NON-COMPETING CONTINUATION	$370,620
2020	2019	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Biomedical Research and Research Training	000	1	11/11/2019	NEW	$0
														Subtotal = $370,620

Issue Date FY: 2019 ( Subtotal = $365,759 )
2019	2019	GEORGIA TECH RESEARCH CORPORATION	505 10TH ST NW	ATLANTA	GA	30318	FULTON	USA	Biomedical Research and Research Training	000	1	8/27/2019	NEW	$365,759
														Subtotal = $365,759

Grand Total All Awards = $1,977,982

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Understanding the Relationship LNP Structure, Cholesterol Trafficking, and InVivo Delivery

Award Number: R01GM132985

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: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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