Trans Spinal Delivery of Targeted Exosomal Formulation of Curcuminoids to Treat AD

TECHNICAL ABSTRACT Neurodegenerative disorders affect over 40 million people worldwide and most are mediated by inflammation. Even though several drugs are approved by the FDA for treating neurological disorders such as Alzheimer’s disease (AD), their efficacy as AD therapeutics has not been realized as extremely low levels of the drug reach the brain. The goal of this Phase I project is to develop a targeted delivery system for the bioactive curcuminoids, curcumin (CUR) and bisdemethoxycurcumin (BDMC) to treat and mitigate the progression of neuroinflammatory diseases, specifically AD. We will apply our extensive experience in exosomes, drug delivery, plant therapeutics and inflammatory responses for efficient, targeted delivery of bioactive curcuminoids to the microenvironment of the brain where progressive increase in inflammation, amyloid plaque formation and neurofibrillary tangles ultimately leads to manifestation of AD. We hypothesize that the combined CUR and BDMC will be highly effective at ameliorating neuroinflammation and aberrant AD-related gene expression returning these biomarkers to pre- disease levels due to synergistic action via different mechanisms. We also hypothesize that rabies virus glycoprotein (RVG)- and folic acid (FA)-functionalized exosomal formulations administered using a novel topical trans-spinal (t.s.) route will provide enhanced targeting to AD-related regions of the brain, including the cortex and hippocampus. Exosomes cross the BBB efficiently and areas of the brain associated with AD have high levels of folate receptors (FRs). Thus, t.s.-administered RVG/FA-ExoCUR/BDMC will deliver higher payload to the brain vs. conventional routes. Our hypotheses are supported by 1) effective drug loading of curcuminoids onto bovine colostrum exosomes, 2) Higher levels (>14-fold) of curcuminoids in the mouse brain after FA-ExoCUR/BDMC t.s. than p.o., 3) FA-exosomes can increase drug delivery to the brain which contains >20-fold higher expression of FR than other tissues, 4) reduced NFκB accumulation and decreased abundance of phosphorylated Tau (pTau) and amyloid precursor protein (APP) expression in brain lysates of mice treated orally with ExoCUR/BDMC in concurrence with increased expression of brain-derived neurotrophic factors (BDNF) comparable to levels in age- matched untreated WT mice while free CUR/BDMC was ineffective, and 5) higher brain accumulation of labeled exosomes in mice treated via t.s. vs. i.v. route. Investigators experienced in exosomes, drug delivery, plant therapeutics and animal models, leveraging experience of the neurologist, Dr. Robert Friedland in AD research, will pursue the following specific aims: Aim 1. Optimize ExoCUR/BDMC formulations in vitro and determine biodistribution in WT mice. Aim 2. Determine efficacy, toxicity and tissue levels of curcuminoids for ExoCUR/BDMC formulations in AD mice. This project will provide proof-of-principle for the effectiveness of t.s.- delivered RVG/FA-ExoCUR/BDMC on the modulation of key molecular targets and behavioral tests with AD progression. In Phase II, we will conduct dose-finding and longer-term intervention using multiple rodent AD models, chronic toxicity, etc. The t.s.-brain delivery could ultimately lead to the development of t.s. patches for AD.