Development of reconstituted high-density lipoprotein nanoparticles for targeted delivery of neuroprotective agents to retinal ganglion cells

Ended Project Grant Awarded Last action

Award ID
F31EY035916
Recipient
Awarding agency
Obligated
$213,920

Award facts

Assistance listing
93.867 Vision Research
Completion date
Place of performance
Fort Worth, TX 76107, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Glaucoma is a vision-threatening condition that affects millions of people worldwide, and current treatment options are limited in their efficacy. While reducing intraocular pressure is the most commonly used approach, IT does not address neurodegeneration and loss of retinal ganglion cells (RGCS) that ultimately lead to blindness. To address these challenges, we propose a novel approach that utilizes reconstituted high-density lipoprotein (RHDL) nanoparticles, which have been shown to target specific cell types mediated by their binding to the scavenger receptor class B1 (SR-B1) to deliver lipophilic drugs to RGCS. Our laboratory has extensive experience with developing strategies for neuroprotection in glaucoma, particularly, targeting the endothelin system in the retina. Our published work demonstrates that the FDA-approved drug macitentan, a pan-endothelin receptor antagonist elicits neuroprotective effects on RGCS by inhibiting pro-apoptotic JNK signaling when dosed orally in RAT morrison's model of ocular hypertension. Our approach involves the encapsulation of macitentan in RHDL nanoparticles for delivery to RGCS via their interaction with the SR-B1 receptors. To further increase specificity of delivery to RGCS, our RHDL nanoparticles will be linked to a cholera toxin B subunit (CTB) through conjugation with a fatty acid residue, generating a custom- made molecule that will bind to enriched gangliosides present on RGCS. Our three specific aims are to: (1) create and optimize the RHDL-apoai-CTB (RHAC) nanoparticles loaded with macitentan, (2) optimize the delivery and release of macitentan from the nanoparticles, and (3) investigate the neuroprotective mechanisms of macitentan when delivered intracellularly into RGCS. By targeting both the SR-B1 receptor and gangliosides, we can ensure that the neuroprotective drug will deliver specifically to RGCS. RHDL-CTB nanoparticles have the ability to cross biological barriers and selectively target RGCS. In addition, we believe that use of macitentan as a neuroprotective agent has the potential to slow the neurodegenerative processes in glaucoma. Our approach has the potential to significantly improve the specificity and efficacy of glaucoma treatments and could ultimately reduce vision loss resulting from this condition. Ultimately, our strategy has the potential to significantly improve patient outcomes and reduce healthcare costs associated with glaucoma treatments.

Transactions

Action Obligated Date
Amendment $0
Amendment $36,456
Amendment $36,456
Amendment $1,280
Amendment $1,280
Amendment $34,612
Amendment $34,612
Amendment $0
Amendment $0
Amendment $34,612
Amendment $34,612
Original award $0
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Quick answers

Who received award F31EY035916?

F31EY035916 was awarded to The University Of North Texas Health Science Center At Fort Worth by National Eye Institute (National Institutes of Health) on June 20, 2024.

How much is award F31EY035916 worth?

$213,920 has been obligated on F31EY035916.

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