Project Summary/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.
