New BDNF Nanoparticles for Early Treatment of Alzheimer's Disease

Alzheimer's Disease (AD) represents a major chronic health problem in the US and abroad. MRI studies of AD demonstrated a decrease in the size of the hippocampus and other brain structures associated with learning and memory. Toxic proteins, like Aß and tau, accumulate in these brain regions, and MRS and PET imaging studies consistently showed metabolic deficits and oxidative stress in brains of patients with AD. BDNF can improve metabolism, promotes neuronal plasticity and restore brain functions. However, BDNF cannot easily cross an intact blood brain barrier (BBB) and is unstable in the blood or when delivered orally. In SBIR Phase 1 & 2, ExQor developed a nanotechnology platform that provides an innovative approach for treatment of AD. It consists of 2 components: a clathrin nanoparticle (CNP) and attached brain-derived neurotrophic factor (BDNF). CNPs successfully bypassed the blood-brain barrier (BBB) intranasally (i.n.) and CNS concentrations of BDNF were up to 400-fold higher than reported in previous BDNF i.n. studies. CNPs restored memory and regenerated hippocampal regions by increasing neurogenesis, synaptogenesis, and dendritic integrity in a mouse model of AD. CNP effects were detected in the mouse hippocampus with two different MR neuroimaging modalities. Voxel based morphometry showed CNP-enhanced hippocampal gray matter densities. Proton MR spectroscopy showed that CNP decreased lactate, alanine, aspartate, myoinositol and glutathione concentrations, indicating CNP reversed anaerobic metabolism, gliosis, and oxidative stress in the mouse hippocampus. CNP also increased choline-containing compounds associated with increased neurogenesis and neuronal plasticity. The goal of this effort is to scale-up production of BDNF-clathrin nanoparticles (CNPs), perform pharmacokinetic and safety studies required for IND, and confirm efficacy in the second animal model of AD. In Phase IIb SBIR, a series of in vivo studies will ascertain CNP distribution, safety and efficacy. TgF344-AD rats will be treated with CNPs or placebo early in the course of the disease for 6 months, and cognitive testing and MRI and 1H MRS will be performed after treatments. We plan to demonstrate the feasibility of this novel nanotechnology to enhance learning and memory, increase gray matter densities, and reverse metabolic abnormalities and oxidative stress associated with AD. This research project will provide new, noninvasive nanotechnology tools for early treatment of AD. The new nanotechnology will be able to enhance neuronal metabolism and plasticity, protect brain and restore brain functions more quickly and completely than existing treatment methods, while using much lower therapeutic drug doses and causing fewer side effects. The development of a stable, targeted molecular nanoparticle may also provide a major new tool for research of biomarkers in AD. This novel nanotechnology may serve as the basis for a next generation drug-delivery system that can specifically target relevant brain systems, and may have utility as an imaging agent to enhance diagnosis and monitor progression of AD.