Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Targeting the gatekeepers: Bolstering blood-brain barrier function using targeted nanomedicine in acute ischemic stroke

Award Number: R01NS131279
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2024
PERIOD OF PERFORMANCE END DATE: 05/31/2029

Group Awards By:

View Award Description

Targeting the gatekeepers: Bolstering blood-brain barrier function using targeted nanomedicine in acute ischemic stroke - Project Summary/Abstract: Pharmacologic treatment of acute ischemic stroke (AIS) is very challenging, largely due to the difficulty of rapidly and specifically delivering drugs to the ischemic region of the brain. Targeted drug delivery using affinity moieties (e.g., antibodies) can increase the local concentration of drugs, thereby improving the therapeutic index. But targeting to blood brain barrier (BBB) epitopes such as transferrin and insulin receptors achieves poor delivery with intravenous administration (e.g., with intravascular targeted-nanocarriers, T-NCs) and is not selective to the injured region of the brain. New targeting/delivery approaches are needed for AIS. We and others have demonstrated that Vascular Cellular Adhesion Molecule (VCAM) is highly overexpressed in the endothelial cells of the penumbra (brain regions at risk of death). Here, we will exploit this for targeted drug delivery with T-NC. We have demonstrated how VCAM T-NC provides unprecedented enhancement of drug delivery to the brain after IV administration (>20 times higher vs. precedent approaches), specifically to the injured brain. In our pilot studies in an animal model of AIS, we observed rapid and specific uptake of CAM-targeted mAbs and T-NCs encapsulating mRNA encoding for interleukin 10/IL-10 (anti- inflammatory cytokine), providing targeted treatment that reduced stroke volume by >60% and improved survival from 60% to 100%. Central hypothesis: VCAM-directed T-NCs can restore BBB function by delivering therapeutic RNAs to endothelial cells in the ischemic penumbra and core, limiting sustained inflammation and brain damage after AIS. We will deliver IL-10 mRNA and siRNA against ICAM with T-NCs, to promote a local anti- inflammatory environment that will restore BBB homeostasis. Our T-NCs: i) Will target RNAs to the BBB to decrease BBB permeability to plasma proteins and reduce leukocyte infiltration; ii) Will deliver RNAs with complementary temporal effects to act at different phases of the disease – IL-10 will reduce inflammation in the acute phase of AIS, and ICAM siRNA will protect during the subacute one. In the current proposal, we suggest: Aim 1: Vascular immunophenotype and nanocarrier delivery in AIS. Aim 2: CAM T-NC to enhance the BBB after AIS. Our deliverables are: i) generate a spatiotemporal map for the expression of CAMs in the AIS of mice and its vascular accessibility to deliver T-NC, ii) Independently of the therapeutic efficacy of our approach will validate our central hypothesis as we are going to quantify: i) expression of the therapeutic mRNA, ii) silencing of ICAM in the BBB, and iii) cellular infiltration. We will also identify in an unbiased way different pathways affected by ischemic stroke and how these pathways are altered after the treatment with anti-inflammatory molecules. This will help to identify new targets for treatment. In addition, we will identify the possible toxicities associated with this therapeutic approach. These results will be key for further investigations in large animal models.


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: 2026 ( Subtotal = $408,207 )
2026	2026	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	5/25/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$408,207
2026	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/15/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $408,207

Issue Date FY: 2025 ( Subtotal = $406,250 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/30/2025	NON-COMPETING CONTINUATION	$406,250
														Subtotal = $406,250

Issue Date FY: 2024 ( Subtotal = $406,250 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/4/2024	NEW	$406,250
														Subtotal = $406,250

Grand Total All Awards = $1,220,707

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Targeting the gatekeepers: Bolstering blood-brain barrier function using targeted nanomedicine in acute ischemic stroke

Award Number: R01NS131279

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2024

PERIOD OF PERFORMANCE END DATE: 05/31/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer