Development of a Farnesol-Based Liposome Delivery System for Neuroprotection

Multiple Sclerosis (MS) is a debilitating autoimmune disease of the Central Nervous System (CNS) affecting nearly one million people in the U.S. It is characterized by neuroinflammatory demyelination and immune cell infiltration following blood-brain barrier (BBB) disruption. Our prior work showed that farnesol (FOL), a promising anti-inflammatory and neuroprotective compound, delayed the onset and reduced the severity of Experimental Autoimmune Encephalomyelitis (EAE), the animal model of MS. However, FOL’s clinical application is severely hampered by its poor water solubility (hydrophobicity) and low bioavailability, necessitating delivery with corn oil and providing only partial protection. This project directly addresses this pharmacological limitation and the critical challenge of drug delivery across the BBB and to targeted immune cells. We propose a novel, targeted liposomal formulation to enhance FOL’s therapeutic efficacy against MS. Our central hypothesis is that encapsulating FOL in mannose-transferrin-modified liposomes (FOL/LPs) will significantly enhance BBB transcytosis and promote specific uptake by peripheral and CNS antigenpresenting cells (APCs), thereby affording superior protection against the earliest, subclinical stages of EAEinduced neuroinflammation. We propose two specific aims: In Aim 1, we will characterize FOL/LPs and assess cytotoxicity and APC uptake. We will synthesize and characterize the FOL/LPs for favorable physicochemical properties (size, PDI, encapsulation efficiency, stability). Furthermore, we will establish their safety by assessing cytotoxicity in immune and epithelial cells. Using flow cytometry and confocal microscopy, we will quantify the hypothesized superior, targeted cellular uptake by APCs compared to nontargeted controls. Successful completion will yield a safe, optimized therapeutic vehicle. In Aim 2, we will determine if FOL/LPs protect against early stages of neuroinflammation in the EAE model. This translational aim tests the therapeutic efficacy in vivo. Efficacy will be measured using highly sensitive, clinically relevant assessments like optokinetic tracking for visual function and quantitative gait analysis for fine motor control. To confirm the mechanism, we will analyze CNS and optic nerve tissue for reduced visual evoked potentials (VEP), decreased immune cell infiltration, and reduced signs of inflammation and demyelination, while confirming liposome BBB transcytosis and presence in the CNS parenchyma. Our research will provide a viable, ready-to-translate therapeutic candidate, farnesol, that targets the initial inflammatory cascade of MS and establish a vital framework for assessing treatments using sensitive, subclinical biomarkers. Project Number: 5P20GM148321-04 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Javier Ochoa-Reparaz | Institution: BOISE STATE UNIVERSITY, BOISE, ID | Award Amount: $146,673 | Activity Code: P20 | Study Section: ZGM1-RCB-9(C1) View on NIH RePORTER: https://reporter.nih.gov/project-details/11527699