Targeting of a Novel Kynurenic Acid Micelle Nanocomplex across the Blood Brain Barrier for the Amelioration of Huntington’S Disease

Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder in the huntingtin (Htt) gene on chromosome 4. Expansion of a repeating CAG trinucleotide generates an abnormally expanded polyglutamine (polyQ) sequence, characterized mainly by atrophy of the caudate nucleus and putamen. Intraneuronal protein aggregation is one of the pathological hallmarks of the polyQ expansion diseases. The pathogenesis of HD includes increased abnormal load, increased reactive oxidative stress, mitochondrial dysfunction, aberrant protein-protein interaction, impaired autophagolysosome function, increased inflammation, and excitotoxicity. At present, there is no effective treatment that can retard the progression of HD. Our earlier studies revealed that GDNF gene delivery therapy could significantly reduce about 80% of Htt aggregates in brain cortex/striatum areas in early HD stage, but the treatment effect is short-term. Our GDNF gene therapy strategy highlights importance in the drug reimbursement system and developing long-term treatment still requires further investigation. Neuroprotective strategies targeting different processes (such as oxidative stress, metabolites balance, excitotoxicity, apoptosis, etc.) to identify potential long-term solutions may serve as a new avenue for treating HD. Mutant Htt can induce excitotoxicity by promoting dysregulation of N-methyl-D-aspartate receptor (NMDAR) localization and activity. Kynurenic acid (KA) is neuroprotective due to its anti-oxidative and anti-inflammatory character. KA possesses neuroprotective properties by antagonizing the effect of NMDAR-mediated excitotoxicity. Since quinolinic acid (QA) is a neural excitotoxin which is elevated and released from activated microglia and causes neuronal dysfunction and degeneration. Studies suggested that imbalance of QA/KA in the kynurenine (KYN) pathway contributes to pathogenesis of HD. A deficiency of KA could contribute to the pathogenesis of neuronal degeneration in HD. Enhancing alternative route toward KA production has been suggested to be a potential therapeutic strategy for HD. However, systemic administration of KA is not reasonable, because its penetration through the blood-brain barrier (BBB) is very poor. Delivery of compound using a micelle nanocomplex will enable improving KA bioavailability and enhance exposure of the brain to KA to protect against excitotoxicity. Herein, the main purpose of this study is to facilitate the delivery of KA across the BBB into brain by applying micelle nanocomplex as nanoscale containers, to result in increase of KA levels and to counteract the cytotoxicity. In addition, whether KA micelle nanocomplex can inhibit mutant protein aggregation, enhance mitochondrial function and protect against oxidative stress will be examined.The aims for this study plan are:Aim 1 (Years 1~2): Investigating the synthesis, preparation and characterization of a novel KA micelle nanocomplex and the establishment of in vitro HD model system.Aim 2 (Years 2): Investigating the BBB permeability of KA molecules and KA micelle nanocomplex.Aim 3 (Years 2~3): Investigating the effects of KA micelle nanocomplex on NMDAR activation, free radical scavenging, polyQ aggregation, mitochondrial membrane potential measurement, and cell viability in vitro HD model system.Aim 4 (Years 2~3): Investigating the effects of KA micelle nanocomplex treatment on pathway downstream (CREB, p-JNK/JNK, p-P38/P38, P-Jun/c-Jun) to NMDAR activation, polyQ aggregation, oxidative stress, inflammation, and apoptosis in HD animal model system.

Project ID:PB10907-4039
External Project ID:MOST109-2221-E182-008-MY3